Evidence-Based Reviews

Chronic depression has long been understood as a psychological constellation and a personality disorder. In the past, recommended treatment focused on long-term psychotherapy,¹ although it was acknowledged that the “depressive personality” rarely responded well.²

Psychiatrists today commonly offer antidepressant drug trials to patients with dysthymia. Yet while tricyclic antidepressants have been shown to have some value in the treatment of chronically depressed patients,³ investigations of selective serotonin reuptake inhibitors in this population have produced inconsistent results.⁴

This article presents two case studies that illustrate how I use the cognitive approach to dysthymia in my psychiatric practice. Both patients were treated successfully with a short-term approach to therapy. While the final verdict on brief psychotherapy as an approach to dysthymia is not in, I believe there are reasons for optimism.

What is dysthymia?

Chronic depression (dysthymia) is thought to be a heterogeneous condition in which comorbid psychiatric and medical conditions frequently occur.⁵ According to DSM-IV diagnostic criteria (Table 1), dysthymia differs from major depression in the number of changes necessary for diagnosis (only two of six) and in the longer duration of symptoms (at least 2 years).

Table 1

DSM-IV DIAGNOSTIC CRITERIA FOR DYSTHYMIA

Depressed mood (for most of the day, for more days than not) for at least 2 years Associated features (at least two): Patient has not been symptom-free for more than 2 months at a time for at least 2 years (1 year for children and adolescents) No major depressive episode during the first 2 years of the disturbance (1 year for children and adolescents) No manic, mixed or hypomanic episode, or cyclothymic disorder Disturbance does not occur exclusively with a chronic psychotic disorder (e.g., schizophrenia) Symptoms not directly caused by substance abuse or a medical condition Symptoms significantly impair social or occupational functioning

*Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000.

The lifetime prevalence of dysthymia is 6%. The chronically depressed face a 10% risk each year of developing major depression. Women are two to three times more likely to suffer dysthymia than men.⁶

Thase and Howland, in a classic 1995 article, described three clinical routes that lead to dysthymia:

• incompletely resolved major depression;
• chronic depressed mood with associated symptoms below the threshold for a diagnosis of major depression;
• dysthymia secondary to medical illness, medications, or substance abuse.⁷

The clinical term dysthymia has its roots in three older constructs: neurotic depression, depressive personality, and chronic depression.⁸ Use of the term “neurotic depression” is now discouraged as it has numerous meanings, some of which are contradictory. “Chronic depression” also obscures more than it illuminates. The term “depressive personality” has survived, with a new set of criteria for diagnosis outlined in DSM-IV. Its separation from “dysthymia” is not clear.

Although the subsyndromic nature of dysthymia might suggest a condition milder than major depression, its lifetime comorbidity with a range of serious emotional problems (Table 2) suggests otherwise.

Cognitive therapy for dysthymia

Cognitive therapy targets depressive thinking as the major culprit in depression.⁹ Researchers have found that a brief course of psychotherapy is sometimes as effective as pharmacotherapy in treating major depression.¹⁰ While it may seem counterintuitive that a short-term approach would solve a long-term problem such as dysthymia, I have found that cognitive therapy can offer a cost-effective, life-sustaining contribution of lasting value.

There is an urgent need to educate primary care clinicians about the value of a brief psychotherapy approach to chronic depression. They are the first clinicians to see 75% of patients with depression. In the medical setting, patients with dysthymia most often present with physical complaints, such as fatigue and insomnia.¹¹ When the internist or family physician does recognize dysthymia and treat it appropriately, pharmacologic approaches predominate.

Medical training guiding whom or which disorders to refer for psychotherapy is woefully lacking. Studies documenting the value of psychotherapy as a treatment for dysthymia are needed to broaden referring physicians’ options. While long-term, psychodynamic therapy for depression may sound obscure to the medical referrer, short-term cognitive therapy typically makes sense. Moreover, both consumers and managed care organizations are demanding quicker results from providers of mental health services.

Table 2

LIFETIME COMORBIDITY ASSOCIATED WITH DYSTHYMIA

Diagnosis	Incidence (%)
Any psychiatric disorder	77.1
Personality disorder	47.0
Anxiety disorder	46.2
Major depression	38.9
Substance abuse	29.8
Eating disorder	23.0
Panic disorder	10.5
Bipolar disorder	2.9
*Adapted from: Markowitz JC. Co-morbidity of dysthymia. Psychiatr Ann 1993;23(11):617-24.

Cognitive therapy is most clearly distinguished from traditional psychodynamic psychotherapy by its focus on the present. While a cognitive therapist may believe that current thinking in the patient with dysthymia has its roots in the past, reworking the past is not seen as necessary for change to occur.

 

The cognitive approach is more collaborative and problem-solving than traditional psychotherapy. The therapist questions, and the patient responds. Periods of monologue are uncommon, and dialogue prevails. How the patient thinks is assumed to have an impact on affect (e.g., sadness) and behavior (e.g., withdrawal). The primary focus is on meanings (expectations, beliefs, assumptions, attributions). The therapist often assigns homework to set the expectation that the patient will work between sessions and to structure the nature of that work.

Cognitive therapy is concerned with conscious thought, and the construct of an unconscious is not employed. While the relationship between therapist and patient may be a focus (at times) for the cognitive inquiry, transference is not encouraged, assumed, or interpreted as such.

Standard cognitive interventions encourage the patient:

• to take responsibility for an aspect of the problem;
• to take reasonable risks;
• to consider assertive behaviors;
• to express feelings appropriately.

Key elements The automatic thought is the central feature of cognitive therapy (Table 3). In psychoanalytic terminology, automatic thoughts would be considered “pre-conscious” (accessible but requiring attention to be identified). The early sessions of cognitive therapy are usually devoted to identifying the thoughts associated with the patient’s distress. In dysthymia, these thoughts may concern the patient’s self-view, his or her representation of a significant relationship, or a meaningful situation.

Errors in thinking are another important consideration for the cognitive therapist. In dysthymia, typical errors in a patient’s thinking include:

• polarization (black-and-white thinking);
• personalization (inordinate focus on the self);
• overgeneralization (drawing conclusions beyond the scope of the data).

Case 1: ‘There’s something wrong with me’

Rebecca, age 38, was referred to me by her former psychodynamic therapist for a course of cognitive therapy.

The older of two daughters in a middle-class family, Rebecca said she had been depressed “for as long as she could remember.” Recently, her sister died suddenly of a heart attack. Her mother had died at a young age from complications of hypertension, and her father died 2 years ago of lung cancer. This left Rebecca alone, but that was not the whole story.

Her memories of childhood were dominated by her father’s physical abuse of her mother and his negative and critical commentary about Rebecca. She described her sister, too, as “mean and inaccessible.” Not surprisingly, Rebecca poured herself into schoolwork, and she did extremely well. After college, she passed a challenging CPA exam and began a career in accounting. Although her work was fulfilling, she described “an inner voice” that was constantly belittling and blaming her. Relationships with men always ended badly, with Rebecca believing: “There’s something wrong with me; that’s why I always end up alone.”

Table 3

MAJOR FEATURES OF COGNITIVE THERAPY

Active, structured dialogue Focus on here-and-now Goal-directed, problem-solving collaboration Often time-limited Assumes that affect and behavior are affected by how one thinks Uses homework assignments Does not interpret unconscious factors Transference neurosis is neither encouraged, assumed, nor interpreted

After each relationship ended with disappointment, Rebecca would overgeneralize: “All men criticize me,” and then personalize: “So, I must be bad.” She had no physical symptoms of depression other than constant low energy and easy fatigue, along with low self-esteem.

Prior to consulting me, she had been treated unsuccessfully with an assortment of antidepressant medications. For 10 years, she had been treated with psychodynamic psychotherapy by a competent therapist with whom she had a “wonderful relationship.” Unfortunately, little had changed.

Comment My diagnosis was dysthymic disorder, 300.40. Rather than attempting another trial with antidepressants, I recommended—and she agreed to—weekly cognitive therapy sessions for an undetermined duration.

Disputation techniques

Once the dysthymic patient’s automatic thoughts have been identified, adopting alternate ways of thinking can bring about change. The therapist’s task is to teach disputation techniques and consideration of options. If a cognitive error is recurrent, calling attention to it may facilitate change.

Figure 1 TRIPLE COLUMN TECHNIQUE

Disputation is typically done in conversation, but some patients with dysthymia learn the process more easily when it is demonstrated visually. One effective approach is the triple column technique, in which situations, feelings, and thoughts are illustrated on a chalkboard (Figure 1).

Rebecca’s intake evaluation was completed in the initial session. I taught her the cognitive method for identifying automatic thoughts at the beginning of session two, using the blackboard to illustrate the relationship between situations and responses.

Primitive animals, I told her, do little more than respond to stimuli. Humans, however, assign a meaning to the situation that will affect their response, whether it is a feeling or a behavior. Cognitive therapy focuses on these meanings. I used her history to illustrate how the model worked.

 

Encouraged to talk about something distressing, Rebecca described in detail a love relationship that was ending. Cued by her distress at various points in the discussion, I asked about relevant meanings. She located a series of personalized and polarized assumptions with ease. We worked to separate her boyfriend’s contribution to the relationship’s outcome from her own. We labeled the errors in her thinking. She had a surprisingly easy time coming up with alternate ways to view the situations we discussed (Figure 2).

Searching for alternate meanings

Shift of set is another useful approach to disputation. Often a patient has searched diligently for answers to his or her problems and has come up “empty.” The patient many times describes this process as “feeling trapped.” With shift of set, the therapist uses metaphor, humor, or self-disclosure to analyze the problem from another perspective. Asking the patient to comment on the therapist’s “story” often elicits an alternative applicable to the patient’s own circumstance.

Metaphor It is beyond the scope of this article to consider the place of metaphor (or analogy) in psychotherapy. To explore the subject further, you might consult an excellent book by Barker.¹²

Humor is a useful accessory to disputation in cognitive therapy. Be forewarned, however, that the dysthymic patient may distort the point of the joke and personalize it as an insult. When a therapist is naturally witty or funny, I encourage him or her to use this resource. If not, it is better to avoid attempts at humor.

Self-disclosure Traditional psychotherapy preaches the avoidance of self-disclosure, which risks (even momentarily) shifting the focus from the patient to the therapist and breaking the rhythm of the therapy hour. Even so, I have found that properly thought-out self-disclosure can be useful in cognitive therapy.

Consistent with the power in a shift of set, self-disclosure offers the benefits of surprise, a sign of caring and involvement, and a chance for the patient to learn. A recent report by the Group for the Advancement of Psychiatry addresses self-disclosure in detail.¹³

Polls and balance sheets At times the therapist may suggest an experiment aimed at generating useful alternatives. Questioning peers or friends (poll-taking) may be one way for the patient to elicit viable options. Another tool for making particularly difficult decisions is a balance sheet (either written or conversational) in which the patient lists the pros and cons of various alternatives. When choices are identified, the patient and therapist typically discuss their consequences.

Resolution: ‘Feeling empowered’

By session four, Rebecca reported using the cognitive method regularly, and finding that she was “no longer accepting the conclusions she used to jump to.” She noticed that when she responded differently, others responded differently to her as well. She was “beginning to feel empowered,” she said.

Figure 2 CASE 1: REBECCA’S TRIPLE COLUMN

Over the next month, I met with her each week. Her mood brightened, and she reported that her energy level was up. She was “actively reviewing her life.” We focused therapy on her self-worth, especially the beliefs that had contributed significantly to it. Upon identifying and examining them, she found that these beliefs were often inconsistent with what she “knew of” herself. We discussed the inconsistencies and worked together to identify alternate views.

She described her views about men in detail. She found several beliefs to be “irrational” and others to represent “poor strategy” if a lasting relationship with a man was an important goal. In the 10th session, she announced that she was “no longer feeling or acting depressed.” She had had an epiphany: “It was all within me,” she said, “not outside of me …. I had kept myself in a perpetual state of feeling diminished and victimized.”

Two weeks later, we met for a final time to review what she had accomplished and to terminate therapy. She expressed amazement that she could accomplish “in 12 short weeks” what had not been achieved in 10 years of work. A follow-up call 6 months later found that her gains had been maintained.

Comment When an automatic thought (meaning) is identified, the next step is to test its usefulness for the patient. I encourage my patients to consider two key criteria: rationality and strategic worth. First, does the meaning make sense? Often, when examined in this way, it does not. Second, even a rational meaning may not serve the patient’s purpose. It may represent a poor strategy, unlikely to help the patient reach his or her goal. If the patient judges the meaning to be inadequate, we work together to find alternatives. We treat these options as choices and consider their consequences.

 

Case 2: A lifetime of anger

Richard, age 51, is an optometrist referred to me by his internist, who described a patient who was “too influenced by anger from the past, had consistently unsatisfactory relationships with women, and generally needed to take control of his life.”

Richard spent the first four sessions with me relating the story of his life. He described a dominating mother, a passive father, and a successful older brother (attorney). He said he constantly felt discriminated against because of his obesity and religion (Judaism).

While attending a school of optometry in the Midwest, he had suffered a severe attack of ulcerative colitis that sent him home for a year to live within his “dysfunctional family.” He married 2 years later, initiating a stormy 10-year relationship that produced his two daughters. Divorce, from a woman he described as “critical and controlling like my mother,” resulted in a serious financial setback.

Fifteen years ago, his father died and Richard underwent intestinal surgery. Soon thereafter, his ex-wife insisted that he raise the two girls, which he was pleased to do. He has not remarried, and subsequent relationships with women have been consistently unsatisfying. He is unhappy at work, where he teaches students and sees some clients, receiving “little recognition for successes.”

Comment I was impatient with the lengthy 4-hour intake, but it became clear that Richard wanted to tell his story his way. My diagnosis was dysthymic disorder in a personality with narcissistic features.

I taught him the cognitive model for identifying key meanings and disputing them. We worked over two sessions separating the controllable aspects of this life from the uncontrollable. We discussed the implications of stage-of-life changes (his younger daughter was in the process of leaving home for college), as well as his views of women in general.

He identified a strong need for approval, as well as a tendency to discount positive feedback, especially in the workplace. We employed the framework of identifying choices and tracing likely consequences. When he focused on being overweight, I suggested that he keep a baseline food record from which we could together formulate a weight-loss plan. The major cognitive error we discussed was polarization—he thought categorically, with no grays.

By session nine, Richard reported his first “decent week,” noting especially a marked reduction in anger. He had twice failed to produce a food record, however, saying: “I resist the things I know I need to do.” We talked about identity: his idea of who he was and what was important to him.

He began session 10 by forcefully telling me that something had “clicked for him last hour.” He realized for the first time that he “could define himself;” he did not have to be a “prisoner of the past.” He brought in several typed pages of thoughts he had had about himself. We reviewed them in detail. “I have the power to re-create myself,” he said. He felt renewed energy, more interest in his work, more accepted by his friends. “It had been there all along,” he said, “I was just unable to see it.”

He now kept his office door open at work, questioned his previous “all-or-nothing” attitude, and vowed to “get out more and meet people.” He was markedly less often angry and was actively using cognitive techniques when he felt dissatisfied. “These changes,” he told me “are the mental equivalent of bypass surgery!”

Comment We met three more times over the next 6 weeks (13 sessions in all), and his gains were maintained. He felt that he could tackle the remaining issues on his own. He has called twice in the past year. The first time, he reported that he lost a substantial amount of weight. The second call described a gratifying relationship with a woman.

Discussion

Each of these patients was strongly motivated to do the work of therapy, both in the office and between sessions. They alluded to a degree of “rethinking of the past” as a by-product of psychotherapy, not as its focus. I believe the relevant changes preceded the rethinking rather than following it.

Cognitive changes are a component of most successful psychotherapies, brief or otherwise. The therapist-patient relationship, thought to be essential to how change occurs in psychodynamic psychotherapy, is a necessary ingredient in cognitive therapy as well. The first stage of any successful psychotherapeutic venture is, quite properly, called engagement. No engagement likely means little gain for the patient. I felt strongly connected to each of these patients.

My second patient’s 4-hour soliloquy notwithstanding, my interaction with my patients typically takes the form of a conversational dialogue. I use analogy, humor, and sometimes self-disclosure to focus attention on an aspect of a problem or an alternative.

 

As I stated earlier, the final verdict on brief psychotherapy as an approach to dysthymia is not in. In its favor, patients often say they prefer psychotherapy to medication.¹⁴ On the other hand, they also prefer to discuss depression with their family physicians, rather than with mental health professionals.¹⁵ Markowitz reviewed empiric research on psychotherapy for dysthymia and found data supporting “some response” of chronic depression to brief cognitive therapy.¹⁶ Subsequently, two small studies by Dunner et al¹⁷ and Miranda and Munoz¹⁸ found small or no gains with psychotherapy.

Short-term cognitive therapy is being used with success in some patients as a psychotherapeutic approach to dysthymia. When it enables a chronically distressed individual to function normally, cognitive therapy may be a cost-effective, life-sustaining contribution of lasting value.

Related resources

• Schuyler D. A Practical Guide to Cognitive Therapy. New York: Norton, 1991.
• Moore JD, Bona JR. Depression and dysthymia. Med Clin North Am 2001;85(3):631-43.
• Markowitz JC. Psychotherapy of dysthymia. Am J Psychiatry 1994;151(8): 1114-21.
• Thase ME, Howland RH. Assessment and treatment of chronic depression. Clin Adv Treat Psychiatr Disord 1995;9(3):1-11.

Chronic depression has long been understood as a psychological constellation and a personality disorder. In the past, recommended treatment focused on long-term psychotherapy,¹ although it was acknowledged that the “depressive personality” rarely responded well.²

Psychiatrists today commonly offer antidepressant drug trials to patients with dysthymia. Yet while tricyclic antidepressants have been shown to have some value in the treatment of chronically depressed patients,³ investigations of selective serotonin reuptake inhibitors in this population have produced inconsistent results.⁴

This article presents two case studies that illustrate how I use the cognitive approach to dysthymia in my psychiatric practice. Both patients were treated successfully with a short-term approach to therapy. While the final verdict on brief psychotherapy as an approach to dysthymia is not in, I believe there are reasons for optimism.

What is dysthymia?

Chronic depression (dysthymia) is thought to be a heterogeneous condition in which comorbid psychiatric and medical conditions frequently occur.⁵ According to DSM-IV diagnostic criteria (Table 1), dysthymia differs from major depression in the number of changes necessary for diagnosis (only two of six) and in the longer duration of symptoms (at least 2 years).

Table 1

DSM-IV DIAGNOSTIC CRITERIA FOR DYSTHYMIA

Depressed mood (for most of the day, for more days than not) for at least 2 years Associated features (at least two): Patient has not been symptom-free for more than 2 months at a time for at least 2 years (1 year for children and adolescents) No major depressive episode during the first 2 years of the disturbance (1 year for children and adolescents) No manic, mixed or hypomanic episode, or cyclothymic disorder Disturbance does not occur exclusively with a chronic psychotic disorder (e.g., schizophrenia) Symptoms not directly caused by substance abuse or a medical condition Symptoms significantly impair social or occupational functioning

*Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000.

The lifetime prevalence of dysthymia is 6%. The chronically depressed face a 10% risk each year of developing major depression. Women are two to three times more likely to suffer dysthymia than men.⁶

Thase and Howland, in a classic 1995 article, described three clinical routes that lead to dysthymia:

• incompletely resolved major depression;
• chronic depressed mood with associated symptoms below the threshold for a diagnosis of major depression;
• dysthymia secondary to medical illness, medications, or substance abuse.⁷

The clinical term dysthymia has its roots in three older constructs: neurotic depression, depressive personality, and chronic depression.⁸ Use of the term “neurotic depression” is now discouraged as it has numerous meanings, some of which are contradictory. “Chronic depression” also obscures more than it illuminates. The term “depressive personality” has survived, with a new set of criteria for diagnosis outlined in DSM-IV. Its separation from “dysthymia” is not clear.

Although the subsyndromic nature of dysthymia might suggest a condition milder than major depression, its lifetime comorbidity with a range of serious emotional problems (Table 2) suggests otherwise.

Cognitive therapy for dysthymia

Cognitive therapy targets depressive thinking as the major culprit in depression.⁹ Researchers have found that a brief course of psychotherapy is sometimes as effective as pharmacotherapy in treating major depression.¹⁰ While it may seem counterintuitive that a short-term approach would solve a long-term problem such as dysthymia, I have found that cognitive therapy can offer a cost-effective, life-sustaining contribution of lasting value.

There is an urgent need to educate primary care clinicians about the value of a brief psychotherapy approach to chronic depression. They are the first clinicians to see 75% of patients with depression. In the medical setting, patients with dysthymia most often present with physical complaints, such as fatigue and insomnia.¹¹ When the internist or family physician does recognize dysthymia and treat it appropriately, pharmacologic approaches predominate.

Medical training guiding whom or which disorders to refer for psychotherapy is woefully lacking. Studies documenting the value of psychotherapy as a treatment for dysthymia are needed to broaden referring physicians’ options. While long-term, psychodynamic therapy for depression may sound obscure to the medical referrer, short-term cognitive therapy typically makes sense. Moreover, both consumers and managed care organizations are demanding quicker results from providers of mental health services.

Table 2

LIFETIME COMORBIDITY ASSOCIATED WITH DYSTHYMIA

Diagnosis	Incidence (%)
Any psychiatric disorder	77.1
Personality disorder	47.0
Anxiety disorder	46.2
Major depression	38.9
Substance abuse	29.8
Eating disorder	23.0
Panic disorder	10.5
Bipolar disorder	2.9
*Adapted from: Markowitz JC. Co-morbidity of dysthymia. Psychiatr Ann 1993;23(11):617-24.

Cognitive therapy is most clearly distinguished from traditional psychodynamic psychotherapy by its focus on the present. While a cognitive therapist may believe that current thinking in the patient with dysthymia has its roots in the past, reworking the past is not seen as necessary for change to occur.

 

The cognitive approach is more collaborative and problem-solving than traditional psychotherapy. The therapist questions, and the patient responds. Periods of monologue are uncommon, and dialogue prevails. How the patient thinks is assumed to have an impact on affect (e.g., sadness) and behavior (e.g., withdrawal). The primary focus is on meanings (expectations, beliefs, assumptions, attributions). The therapist often assigns homework to set the expectation that the patient will work between sessions and to structure the nature of that work.

Cognitive therapy is concerned with conscious thought, and the construct of an unconscious is not employed. While the relationship between therapist and patient may be a focus (at times) for the cognitive inquiry, transference is not encouraged, assumed, or interpreted as such.

Standard cognitive interventions encourage the patient:

• to take responsibility for an aspect of the problem;
• to take reasonable risks;
• to consider assertive behaviors;
• to express feelings appropriately.

Key elements The automatic thought is the central feature of cognitive therapy (Table 3). In psychoanalytic terminology, automatic thoughts would be considered “pre-conscious” (accessible but requiring attention to be identified). The early sessions of cognitive therapy are usually devoted to identifying the thoughts associated with the patient’s distress. In dysthymia, these thoughts may concern the patient’s self-view, his or her representation of a significant relationship, or a meaningful situation.

Errors in thinking are another important consideration for the cognitive therapist. In dysthymia, typical errors in a patient’s thinking include:

• polarization (black-and-white thinking);
• personalization (inordinate focus on the self);
• overgeneralization (drawing conclusions beyond the scope of the data).

Case 1: ‘There’s something wrong with me’

Rebecca, age 38, was referred to me by her former psychodynamic therapist for a course of cognitive therapy.

The older of two daughters in a middle-class family, Rebecca said she had been depressed “for as long as she could remember.” Recently, her sister died suddenly of a heart attack. Her mother had died at a young age from complications of hypertension, and her father died 2 years ago of lung cancer. This left Rebecca alone, but that was not the whole story.

Her memories of childhood were dominated by her father’s physical abuse of her mother and his negative and critical commentary about Rebecca. She described her sister, too, as “mean and inaccessible.” Not surprisingly, Rebecca poured herself into schoolwork, and she did extremely well. After college, she passed a challenging CPA exam and began a career in accounting. Although her work was fulfilling, she described “an inner voice” that was constantly belittling and blaming her. Relationships with men always ended badly, with Rebecca believing: “There’s something wrong with me; that’s why I always end up alone.”

Table 3

MAJOR FEATURES OF COGNITIVE THERAPY

Active, structured dialogue Focus on here-and-now Goal-directed, problem-solving collaboration Often time-limited Assumes that affect and behavior are affected by how one thinks Uses homework assignments Does not interpret unconscious factors Transference neurosis is neither encouraged, assumed, nor interpreted

After each relationship ended with disappointment, Rebecca would overgeneralize: “All men criticize me,” and then personalize: “So, I must be bad.” She had no physical symptoms of depression other than constant low energy and easy fatigue, along with low self-esteem.

Prior to consulting me, she had been treated unsuccessfully with an assortment of antidepressant medications. For 10 years, she had been treated with psychodynamic psychotherapy by a competent therapist with whom she had a “wonderful relationship.” Unfortunately, little had changed.

Comment My diagnosis was dysthymic disorder, 300.40. Rather than attempting another trial with antidepressants, I recommended—and she agreed to—weekly cognitive therapy sessions for an undetermined duration.

Disputation techniques

Once the dysthymic patient’s automatic thoughts have been identified, adopting alternate ways of thinking can bring about change. The therapist’s task is to teach disputation techniques and consideration of options. If a cognitive error is recurrent, calling attention to it may facilitate change.

Figure 1 TRIPLE COLUMN TECHNIQUE

Disputation is typically done in conversation, but some patients with dysthymia learn the process more easily when it is demonstrated visually. One effective approach is the triple column technique, in which situations, feelings, and thoughts are illustrated on a chalkboard (Figure 1).

Rebecca’s intake evaluation was completed in the initial session. I taught her the cognitive method for identifying automatic thoughts at the beginning of session two, using the blackboard to illustrate the relationship between situations and responses.

Primitive animals, I told her, do little more than respond to stimuli. Humans, however, assign a meaning to the situation that will affect their response, whether it is a feeling or a behavior. Cognitive therapy focuses on these meanings. I used her history to illustrate how the model worked.

 

Encouraged to talk about something distressing, Rebecca described in detail a love relationship that was ending. Cued by her distress at various points in the discussion, I asked about relevant meanings. She located a series of personalized and polarized assumptions with ease. We worked to separate her boyfriend’s contribution to the relationship’s outcome from her own. We labeled the errors in her thinking. She had a surprisingly easy time coming up with alternate ways to view the situations we discussed (Figure 2).

Searching for alternate meanings

Shift of set is another useful approach to disputation. Often a patient has searched diligently for answers to his or her problems and has come up “empty.” The patient many times describes this process as “feeling trapped.” With shift of set, the therapist uses metaphor, humor, or self-disclosure to analyze the problem from another perspective. Asking the patient to comment on the therapist’s “story” often elicits an alternative applicable to the patient’s own circumstance.

Metaphor It is beyond the scope of this article to consider the place of metaphor (or analogy) in psychotherapy. To explore the subject further, you might consult an excellent book by Barker.¹²

Humor is a useful accessory to disputation in cognitive therapy. Be forewarned, however, that the dysthymic patient may distort the point of the joke and personalize it as an insult. When a therapist is naturally witty or funny, I encourage him or her to use this resource. If not, it is better to avoid attempts at humor.

Self-disclosure Traditional psychotherapy preaches the avoidance of self-disclosure, which risks (even momentarily) shifting the focus from the patient to the therapist and breaking the rhythm of the therapy hour. Even so, I have found that properly thought-out self-disclosure can be useful in cognitive therapy.

Consistent with the power in a shift of set, self-disclosure offers the benefits of surprise, a sign of caring and involvement, and a chance for the patient to learn. A recent report by the Group for the Advancement of Psychiatry addresses self-disclosure in detail.¹³

Polls and balance sheets At times the therapist may suggest an experiment aimed at generating useful alternatives. Questioning peers or friends (poll-taking) may be one way for the patient to elicit viable options. Another tool for making particularly difficult decisions is a balance sheet (either written or conversational) in which the patient lists the pros and cons of various alternatives. When choices are identified, the patient and therapist typically discuss their consequences.

Resolution: ‘Feeling empowered’

By session four, Rebecca reported using the cognitive method regularly, and finding that she was “no longer accepting the conclusions she used to jump to.” She noticed that when she responded differently, others responded differently to her as well. She was “beginning to feel empowered,” she said.

Figure 2 CASE 1: REBECCA’S TRIPLE COLUMN

Over the next month, I met with her each week. Her mood brightened, and she reported that her energy level was up. She was “actively reviewing her life.” We focused therapy on her self-worth, especially the beliefs that had contributed significantly to it. Upon identifying and examining them, she found that these beliefs were often inconsistent with what she “knew of” herself. We discussed the inconsistencies and worked together to identify alternate views.

She described her views about men in detail. She found several beliefs to be “irrational” and others to represent “poor strategy” if a lasting relationship with a man was an important goal. In the 10th session, she announced that she was “no longer feeling or acting depressed.” She had had an epiphany: “It was all within me,” she said, “not outside of me …. I had kept myself in a perpetual state of feeling diminished and victimized.”

Two weeks later, we met for a final time to review what she had accomplished and to terminate therapy. She expressed amazement that she could accomplish “in 12 short weeks” what had not been achieved in 10 years of work. A follow-up call 6 months later found that her gains had been maintained.

Comment When an automatic thought (meaning) is identified, the next step is to test its usefulness for the patient. I encourage my patients to consider two key criteria: rationality and strategic worth. First, does the meaning make sense? Often, when examined in this way, it does not. Second, even a rational meaning may not serve the patient’s purpose. It may represent a poor strategy, unlikely to help the patient reach his or her goal. If the patient judges the meaning to be inadequate, we work together to find alternatives. We treat these options as choices and consider their consequences.

 

Case 2: A lifetime of anger

Richard, age 51, is an optometrist referred to me by his internist, who described a patient who was “too influenced by anger from the past, had consistently unsatisfactory relationships with women, and generally needed to take control of his life.”

Richard spent the first four sessions with me relating the story of his life. He described a dominating mother, a passive father, and a successful older brother (attorney). He said he constantly felt discriminated against because of his obesity and religion (Judaism).

While attending a school of optometry in the Midwest, he had suffered a severe attack of ulcerative colitis that sent him home for a year to live within his “dysfunctional family.” He married 2 years later, initiating a stormy 10-year relationship that produced his two daughters. Divorce, from a woman he described as “critical and controlling like my mother,” resulted in a serious financial setback.

Fifteen years ago, his father died and Richard underwent intestinal surgery. Soon thereafter, his ex-wife insisted that he raise the two girls, which he was pleased to do. He has not remarried, and subsequent relationships with women have been consistently unsatisfying. He is unhappy at work, where he teaches students and sees some clients, receiving “little recognition for successes.”

Comment I was impatient with the lengthy 4-hour intake, but it became clear that Richard wanted to tell his story his way. My diagnosis was dysthymic disorder in a personality with narcissistic features.

I taught him the cognitive model for identifying key meanings and disputing them. We worked over two sessions separating the controllable aspects of this life from the uncontrollable. We discussed the implications of stage-of-life changes (his younger daughter was in the process of leaving home for college), as well as his views of women in general.

He identified a strong need for approval, as well as a tendency to discount positive feedback, especially in the workplace. We employed the framework of identifying choices and tracing likely consequences. When he focused on being overweight, I suggested that he keep a baseline food record from which we could together formulate a weight-loss plan. The major cognitive error we discussed was polarization—he thought categorically, with no grays.

By session nine, Richard reported his first “decent week,” noting especially a marked reduction in anger. He had twice failed to produce a food record, however, saying: “I resist the things I know I need to do.” We talked about identity: his idea of who he was and what was important to him.

He began session 10 by forcefully telling me that something had “clicked for him last hour.” He realized for the first time that he “could define himself;” he did not have to be a “prisoner of the past.” He brought in several typed pages of thoughts he had had about himself. We reviewed them in detail. “I have the power to re-create myself,” he said. He felt renewed energy, more interest in his work, more accepted by his friends. “It had been there all along,” he said, “I was just unable to see it.”

He now kept his office door open at work, questioned his previous “all-or-nothing” attitude, and vowed to “get out more and meet people.” He was markedly less often angry and was actively using cognitive techniques when he felt dissatisfied. “These changes,” he told me “are the mental equivalent of bypass surgery!”

Comment We met three more times over the next 6 weeks (13 sessions in all), and his gains were maintained. He felt that he could tackle the remaining issues on his own. He has called twice in the past year. The first time, he reported that he lost a substantial amount of weight. The second call described a gratifying relationship with a woman.

Discussion

Each of these patients was strongly motivated to do the work of therapy, both in the office and between sessions. They alluded to a degree of “rethinking of the past” as a by-product of psychotherapy, not as its focus. I believe the relevant changes preceded the rethinking rather than following it.

Cognitive changes are a component of most successful psychotherapies, brief or otherwise. The therapist-patient relationship, thought to be essential to how change occurs in psychodynamic psychotherapy, is a necessary ingredient in cognitive therapy as well. The first stage of any successful psychotherapeutic venture is, quite properly, called engagement. No engagement likely means little gain for the patient. I felt strongly connected to each of these patients.

My second patient’s 4-hour soliloquy notwithstanding, my interaction with my patients typically takes the form of a conversational dialogue. I use analogy, humor, and sometimes self-disclosure to focus attention on an aspect of a problem or an alternative.

 

As I stated earlier, the final verdict on brief psychotherapy as an approach to dysthymia is not in. In its favor, patients often say they prefer psychotherapy to medication.¹⁴ On the other hand, they also prefer to discuss depression with their family physicians, rather than with mental health professionals.¹⁵ Markowitz reviewed empiric research on psychotherapy for dysthymia and found data supporting “some response” of chronic depression to brief cognitive therapy.¹⁶ Subsequently, two small studies by Dunner et al¹⁷ and Miranda and Munoz¹⁸ found small or no gains with psychotherapy.

Short-term cognitive therapy is being used with success in some patients as a psychotherapeutic approach to dysthymia. When it enables a chronically distressed individual to function normally, cognitive therapy may be a cost-effective, life-sustaining contribution of lasting value.

Related resources

• Schuyler D. A Practical Guide to Cognitive Therapy. New York: Norton, 1991.
• Moore JD, Bona JR. Depression and dysthymia. Med Clin North Am 2001;85(3):631-43.
• Markowitz JC. Psychotherapy of dysthymia. Am J Psychiatry 1994;151(8): 1114-21.
• Thase ME, Howland RH. Assessment and treatment of chronic depression. Clin Adv Treat Psychiatr Disord 1995;9(3):1-11.

Chronic depression has long been understood as a psychological constellation and a personality disorder. In the past, recommended treatment focused on long-term psychotherapy,¹ although it was acknowledged that the “depressive personality” rarely responded well.²

Psychiatrists today commonly offer antidepressant drug trials to patients with dysthymia. Yet while tricyclic antidepressants have been shown to have some value in the treatment of chronically depressed patients,³ investigations of selective serotonin reuptake inhibitors in this population have produced inconsistent results.⁴

This article presents two case studies that illustrate how I use the cognitive approach to dysthymia in my psychiatric practice. Both patients were treated successfully with a short-term approach to therapy. While the final verdict on brief psychotherapy as an approach to dysthymia is not in, I believe there are reasons for optimism.

What is dysthymia?

Chronic depression (dysthymia) is thought to be a heterogeneous condition in which comorbid psychiatric and medical conditions frequently occur.⁵ According to DSM-IV diagnostic criteria (Table 1), dysthymia differs from major depression in the number of changes necessary for diagnosis (only two of six) and in the longer duration of symptoms (at least 2 years).

Table 1

DSM-IV DIAGNOSTIC CRITERIA FOR DYSTHYMIA

Depressed mood (for most of the day, for more days than not) for at least 2 years Associated features (at least two): Patient has not been symptom-free for more than 2 months at a time for at least 2 years (1 year for children and adolescents) No major depressive episode during the first 2 years of the disturbance (1 year for children and adolescents) No manic, mixed or hypomanic episode, or cyclothymic disorder Disturbance does not occur exclusively with a chronic psychotic disorder (e.g., schizophrenia) Symptoms not directly caused by substance abuse or a medical condition Symptoms significantly impair social or occupational functioning

*Adapted from: Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association, 2000.

The lifetime prevalence of dysthymia is 6%. The chronically depressed face a 10% risk each year of developing major depression. Women are two to three times more likely to suffer dysthymia than men.⁶

Thase and Howland, in a classic 1995 article, described three clinical routes that lead to dysthymia:

• incompletely resolved major depression;
• chronic depressed mood with associated symptoms below the threshold for a diagnosis of major depression;
• dysthymia secondary to medical illness, medications, or substance abuse.⁷

The clinical term dysthymia has its roots in three older constructs: neurotic depression, depressive personality, and chronic depression.⁸ Use of the term “neurotic depression” is now discouraged as it has numerous meanings, some of which are contradictory. “Chronic depression” also obscures more than it illuminates. The term “depressive personality” has survived, with a new set of criteria for diagnosis outlined in DSM-IV. Its separation from “dysthymia” is not clear.

Although the subsyndromic nature of dysthymia might suggest a condition milder than major depression, its lifetime comorbidity with a range of serious emotional problems (Table 2) suggests otherwise.

Cognitive therapy for dysthymia

Cognitive therapy targets depressive thinking as the major culprit in depression.⁹ Researchers have found that a brief course of psychotherapy is sometimes as effective as pharmacotherapy in treating major depression.¹⁰ While it may seem counterintuitive that a short-term approach would solve a long-term problem such as dysthymia, I have found that cognitive therapy can offer a cost-effective, life-sustaining contribution of lasting value.

There is an urgent need to educate primary care clinicians about the value of a brief psychotherapy approach to chronic depression. They are the first clinicians to see 75% of patients with depression. In the medical setting, patients with dysthymia most often present with physical complaints, such as fatigue and insomnia.¹¹ When the internist or family physician does recognize dysthymia and treat it appropriately, pharmacologic approaches predominate.

Medical training guiding whom or which disorders to refer for psychotherapy is woefully lacking. Studies documenting the value of psychotherapy as a treatment for dysthymia are needed to broaden referring physicians’ options. While long-term, psychodynamic therapy for depression may sound obscure to the medical referrer, short-term cognitive therapy typically makes sense. Moreover, both consumers and managed care organizations are demanding quicker results from providers of mental health services.

Table 2

LIFETIME COMORBIDITY ASSOCIATED WITH DYSTHYMIA

Diagnosis	Incidence (%)
Any psychiatric disorder	77.1
Personality disorder	47.0
Anxiety disorder	46.2
Major depression	38.9
Substance abuse	29.8
Eating disorder	23.0
Panic disorder	10.5
Bipolar disorder	2.9
*Adapted from: Markowitz JC. Co-morbidity of dysthymia. Psychiatr Ann 1993;23(11):617-24.

Cognitive therapy is most clearly distinguished from traditional psychodynamic psychotherapy by its focus on the present. While a cognitive therapist may believe that current thinking in the patient with dysthymia has its roots in the past, reworking the past is not seen as necessary for change to occur.

 

The cognitive approach is more collaborative and problem-solving than traditional psychotherapy. The therapist questions, and the patient responds. Periods of monologue are uncommon, and dialogue prevails. How the patient thinks is assumed to have an impact on affect (e.g., sadness) and behavior (e.g., withdrawal). The primary focus is on meanings (expectations, beliefs, assumptions, attributions). The therapist often assigns homework to set the expectation that the patient will work between sessions and to structure the nature of that work.

Cognitive therapy is concerned with conscious thought, and the construct of an unconscious is not employed. While the relationship between therapist and patient may be a focus (at times) for the cognitive inquiry, transference is not encouraged, assumed, or interpreted as such.

Standard cognitive interventions encourage the patient:

• to take responsibility for an aspect of the problem;
• to take reasonable risks;
• to consider assertive behaviors;
• to express feelings appropriately.

Key elements The automatic thought is the central feature of cognitive therapy (Table 3). In psychoanalytic terminology, automatic thoughts would be considered “pre-conscious” (accessible but requiring attention to be identified). The early sessions of cognitive therapy are usually devoted to identifying the thoughts associated with the patient’s distress. In dysthymia, these thoughts may concern the patient’s self-view, his or her representation of a significant relationship, or a meaningful situation.

Errors in thinking are another important consideration for the cognitive therapist. In dysthymia, typical errors in a patient’s thinking include:

• polarization (black-and-white thinking);
• personalization (inordinate focus on the self);
• overgeneralization (drawing conclusions beyond the scope of the data).

Case 1: ‘There’s something wrong with me’

Rebecca, age 38, was referred to me by her former psychodynamic therapist for a course of cognitive therapy.

The older of two daughters in a middle-class family, Rebecca said she had been depressed “for as long as she could remember.” Recently, her sister died suddenly of a heart attack. Her mother had died at a young age from complications of hypertension, and her father died 2 years ago of lung cancer. This left Rebecca alone, but that was not the whole story.

Her memories of childhood were dominated by her father’s physical abuse of her mother and his negative and critical commentary about Rebecca. She described her sister, too, as “mean and inaccessible.” Not surprisingly, Rebecca poured herself into schoolwork, and she did extremely well. After college, she passed a challenging CPA exam and began a career in accounting. Although her work was fulfilling, she described “an inner voice” that was constantly belittling and blaming her. Relationships with men always ended badly, with Rebecca believing: “There’s something wrong with me; that’s why I always end up alone.”

Table 3

MAJOR FEATURES OF COGNITIVE THERAPY

Active, structured dialogue Focus on here-and-now Goal-directed, problem-solving collaboration Often time-limited Assumes that affect and behavior are affected by how one thinks Uses homework assignments Does not interpret unconscious factors Transference neurosis is neither encouraged, assumed, nor interpreted

After each relationship ended with disappointment, Rebecca would overgeneralize: “All men criticize me,” and then personalize: “So, I must be bad.” She had no physical symptoms of depression other than constant low energy and easy fatigue, along with low self-esteem.

Prior to consulting me, she had been treated unsuccessfully with an assortment of antidepressant medications. For 10 years, she had been treated with psychodynamic psychotherapy by a competent therapist with whom she had a “wonderful relationship.” Unfortunately, little had changed.

Comment My diagnosis was dysthymic disorder, 300.40. Rather than attempting another trial with antidepressants, I recommended—and she agreed to—weekly cognitive therapy sessions for an undetermined duration.

Disputation techniques

Once the dysthymic patient’s automatic thoughts have been identified, adopting alternate ways of thinking can bring about change. The therapist’s task is to teach disputation techniques and consideration of options. If a cognitive error is recurrent, calling attention to it may facilitate change.

Figure 1 TRIPLE COLUMN TECHNIQUE

Disputation is typically done in conversation, but some patients with dysthymia learn the process more easily when it is demonstrated visually. One effective approach is the triple column technique, in which situations, feelings, and thoughts are illustrated on a chalkboard (Figure 1).

Rebecca’s intake evaluation was completed in the initial session. I taught her the cognitive method for identifying automatic thoughts at the beginning of session two, using the blackboard to illustrate the relationship between situations and responses.

Primitive animals, I told her, do little more than respond to stimuli. Humans, however, assign a meaning to the situation that will affect their response, whether it is a feeling or a behavior. Cognitive therapy focuses on these meanings. I used her history to illustrate how the model worked.

 

Encouraged to talk about something distressing, Rebecca described in detail a love relationship that was ending. Cued by her distress at various points in the discussion, I asked about relevant meanings. She located a series of personalized and polarized assumptions with ease. We worked to separate her boyfriend’s contribution to the relationship’s outcome from her own. We labeled the errors in her thinking. She had a surprisingly easy time coming up with alternate ways to view the situations we discussed (Figure 2).

Searching for alternate meanings

Shift of set is another useful approach to disputation. Often a patient has searched diligently for answers to his or her problems and has come up “empty.” The patient many times describes this process as “feeling trapped.” With shift of set, the therapist uses metaphor, humor, or self-disclosure to analyze the problem from another perspective. Asking the patient to comment on the therapist’s “story” often elicits an alternative applicable to the patient’s own circumstance.

Metaphor It is beyond the scope of this article to consider the place of metaphor (or analogy) in psychotherapy. To explore the subject further, you might consult an excellent book by Barker.¹²

Humor is a useful accessory to disputation in cognitive therapy. Be forewarned, however, that the dysthymic patient may distort the point of the joke and personalize it as an insult. When a therapist is naturally witty or funny, I encourage him or her to use this resource. If not, it is better to avoid attempts at humor.

Self-disclosure Traditional psychotherapy preaches the avoidance of self-disclosure, which risks (even momentarily) shifting the focus from the patient to the therapist and breaking the rhythm of the therapy hour. Even so, I have found that properly thought-out self-disclosure can be useful in cognitive therapy.

Consistent with the power in a shift of set, self-disclosure offers the benefits of surprise, a sign of caring and involvement, and a chance for the patient to learn. A recent report by the Group for the Advancement of Psychiatry addresses self-disclosure in detail.¹³

Polls and balance sheets At times the therapist may suggest an experiment aimed at generating useful alternatives. Questioning peers or friends (poll-taking) may be one way for the patient to elicit viable options. Another tool for making particularly difficult decisions is a balance sheet (either written or conversational) in which the patient lists the pros and cons of various alternatives. When choices are identified, the patient and therapist typically discuss their consequences.

Resolution: ‘Feeling empowered’

By session four, Rebecca reported using the cognitive method regularly, and finding that she was “no longer accepting the conclusions she used to jump to.” She noticed that when she responded differently, others responded differently to her as well. She was “beginning to feel empowered,” she said.

Figure 2 CASE 1: REBECCA’S TRIPLE COLUMN

Over the next month, I met with her each week. Her mood brightened, and she reported that her energy level was up. She was “actively reviewing her life.” We focused therapy on her self-worth, especially the beliefs that had contributed significantly to it. Upon identifying and examining them, she found that these beliefs were often inconsistent with what she “knew of” herself. We discussed the inconsistencies and worked together to identify alternate views.

She described her views about men in detail. She found several beliefs to be “irrational” and others to represent “poor strategy” if a lasting relationship with a man was an important goal. In the 10th session, she announced that she was “no longer feeling or acting depressed.” She had had an epiphany: “It was all within me,” she said, “not outside of me …. I had kept myself in a perpetual state of feeling diminished and victimized.”

Two weeks later, we met for a final time to review what she had accomplished and to terminate therapy. She expressed amazement that she could accomplish “in 12 short weeks” what had not been achieved in 10 years of work. A follow-up call 6 months later found that her gains had been maintained.

Comment When an automatic thought (meaning) is identified, the next step is to test its usefulness for the patient. I encourage my patients to consider two key criteria: rationality and strategic worth. First, does the meaning make sense? Often, when examined in this way, it does not. Second, even a rational meaning may not serve the patient’s purpose. It may represent a poor strategy, unlikely to help the patient reach his or her goal. If the patient judges the meaning to be inadequate, we work together to find alternatives. We treat these options as choices and consider their consequences.

 

Case 2: A lifetime of anger

Richard, age 51, is an optometrist referred to me by his internist, who described a patient who was “too influenced by anger from the past, had consistently unsatisfactory relationships with women, and generally needed to take control of his life.”

Richard spent the first four sessions with me relating the story of his life. He described a dominating mother, a passive father, and a successful older brother (attorney). He said he constantly felt discriminated against because of his obesity and religion (Judaism).

While attending a school of optometry in the Midwest, he had suffered a severe attack of ulcerative colitis that sent him home for a year to live within his “dysfunctional family.” He married 2 years later, initiating a stormy 10-year relationship that produced his two daughters. Divorce, from a woman he described as “critical and controlling like my mother,” resulted in a serious financial setback.

Fifteen years ago, his father died and Richard underwent intestinal surgery. Soon thereafter, his ex-wife insisted that he raise the two girls, which he was pleased to do. He has not remarried, and subsequent relationships with women have been consistently unsatisfying. He is unhappy at work, where he teaches students and sees some clients, receiving “little recognition for successes.”

Comment I was impatient with the lengthy 4-hour intake, but it became clear that Richard wanted to tell his story his way. My diagnosis was dysthymic disorder in a personality with narcissistic features.

I taught him the cognitive model for identifying key meanings and disputing them. We worked over two sessions separating the controllable aspects of this life from the uncontrollable. We discussed the implications of stage-of-life changes (his younger daughter was in the process of leaving home for college), as well as his views of women in general.

He identified a strong need for approval, as well as a tendency to discount positive feedback, especially in the workplace. We employed the framework of identifying choices and tracing likely consequences. When he focused on being overweight, I suggested that he keep a baseline food record from which we could together formulate a weight-loss plan. The major cognitive error we discussed was polarization—he thought categorically, with no grays.

By session nine, Richard reported his first “decent week,” noting especially a marked reduction in anger. He had twice failed to produce a food record, however, saying: “I resist the things I know I need to do.” We talked about identity: his idea of who he was and what was important to him.

He began session 10 by forcefully telling me that something had “clicked for him last hour.” He realized for the first time that he “could define himself;” he did not have to be a “prisoner of the past.” He brought in several typed pages of thoughts he had had about himself. We reviewed them in detail. “I have the power to re-create myself,” he said. He felt renewed energy, more interest in his work, more accepted by his friends. “It had been there all along,” he said, “I was just unable to see it.”

He now kept his office door open at work, questioned his previous “all-or-nothing” attitude, and vowed to “get out more and meet people.” He was markedly less often angry and was actively using cognitive techniques when he felt dissatisfied. “These changes,” he told me “are the mental equivalent of bypass surgery!”

Comment We met three more times over the next 6 weeks (13 sessions in all), and his gains were maintained. He felt that he could tackle the remaining issues on his own. He has called twice in the past year. The first time, he reported that he lost a substantial amount of weight. The second call described a gratifying relationship with a woman.

Discussion

Each of these patients was strongly motivated to do the work of therapy, both in the office and between sessions. They alluded to a degree of “rethinking of the past” as a by-product of psychotherapy, not as its focus. I believe the relevant changes preceded the rethinking rather than following it.

Cognitive changes are a component of most successful psychotherapies, brief or otherwise. The therapist-patient relationship, thought to be essential to how change occurs in psychodynamic psychotherapy, is a necessary ingredient in cognitive therapy as well. The first stage of any successful psychotherapeutic venture is, quite properly, called engagement. No engagement likely means little gain for the patient. I felt strongly connected to each of these patients.

My second patient’s 4-hour soliloquy notwithstanding, my interaction with my patients typically takes the form of a conversational dialogue. I use analogy, humor, and sometimes self-disclosure to focus attention on an aspect of a problem or an alternative.

 

As I stated earlier, the final verdict on brief psychotherapy as an approach to dysthymia is not in. In its favor, patients often say they prefer psychotherapy to medication.¹⁴ On the other hand, they also prefer to discuss depression with their family physicians, rather than with mental health professionals.¹⁵ Markowitz reviewed empiric research on psychotherapy for dysthymia and found data supporting “some response” of chronic depression to brief cognitive therapy.¹⁶ Subsequently, two small studies by Dunner et al¹⁷ and Miranda and Munoz¹⁸ found small or no gains with psychotherapy.

Short-term cognitive therapy is being used with success in some patients as a psychotherapeutic approach to dysthymia. When it enables a chronically distressed individual to function normally, cognitive therapy may be a cost-effective, life-sustaining contribution of lasting value.

Related resources

• Schuyler D. A Practical Guide to Cognitive Therapy. New York: Norton, 1991.
• Moore JD, Bona JR. Depression and dysthymia. Med Clin North Am 2001;85(3):631-43.
• Markowitz JC. Psychotherapy of dysthymia. Am J Psychiatry 1994;151(8): 1114-21.
• Thase ME, Howland RH. Assessment and treatment of chronic depression. Clin Adv Treat Psychiatr Disord 1995;9(3):1-11.

You would be fully justified to state that traumatic brain injury (TBI) can cause and worsen a wide range of psychiatric symptoms including psychosis, mood symptoms, anxiety, cognitive deficits, and impulsivity. Could you also present sufficient evidence of TBI as a cause of violence?

That could be more difficult. TBI-induced criminality remains a central and controversial area within forensic psychiatry. Behavior resulting from injury has been implicated in violence and crime, especially when coexisting with substance abuse, a violent environment during childhood including abuse, and pre-existing personality disorder. The literature is vast and covers a spectrum of opinions, allowing the forensic psychiatrist to find evidence that would support the prosecution or the defense. Judge for yourself.

For the prosecution: TBI is no defense

In his study, “Brain injury and criminality,” Virkkunen concluded that “sociopathy, alcoholism, and drug abuse are the types of psychiatric disorders associated with criminal behavior, not organic brain syndrome.”¹

This statement was based upon a retrospective analysis of World War II veterans. A search was conducted through Finland’s Criminal Register to compare the frequencies of convictions for crimes punishable by imprisonment between a non-TBI control group and a TBI group. The overall crime rates between the two groups were not significantly different: 5.5% versus 4.2% for the control and TBI groups, respectively. Seventeen of 1,870 (0.9%) of the TBI patients committed violent crimes versus 3 of 500 (0.6%) of the control group. A closer examination revealed that most convictions were associated with alcohol in both groups.

Unlike Virkkunen, Kreutzer et al were unable to prove or disprove a cause and effect between TBI and violence. In their 1991 investigation based on 74 TBI patients, they found that 20% had been arrested pre-injury, and 10% had been arrested after the injury.² Most arrests occurred after use of alcohol or other drugs. The study concluded that criminal behavior might be a result of post-injury changes including poor judgment, apathy, and other new behaviors.

Box 1

Substance abuse, traumatic brain injury, and crime were indeed interconnected, the researchers said, but they did not go so far as to conclude that TBI causes criminality and violence. Rather, they believed that substance abuse, which was most common among those younger than 35, led to legal difficulties and TBI.

In 1995, based on a larger sample of 327 patients, Kreutzer and associates found that the TBI criminal population has a relatively high incidence of alcohol abuse before and after head injury.³ Most crimes were associated with substance abuse, such as drug possession or driving under the influence of alcohol.

The study found that TBI patients with a history of arrest were more likely to have substance abuse problems after the injury. TBI patients with both a criminal and substance abuse history also were more likely to commit crimes after the head injury. Kreutzer concluded that TBI is not a risk factor for crime without such a history.

For the defense: TBI does lead to criminality

In one study by Brooks et al of 42 individuals with severe TBI, threats of violence increased from 15% 1 year after sustaining head injury to 54% 5 years after.⁴ What’s more, at the 5-year follow-up, 31% of these patients had legal problems and 20% of their relatives had been assaulted by them at least once.

 

A study by Sarpata et al also supports the argument that TBI leads to criminality.⁵ They argue that TBI patients should be expected to commit crimes because they have poor cognitive skills, impulsivity, and increased aggression, as well as low tolerance for frustration and poor judgment. In their study of 18 subjects in a community corrections day program in Vigo County, Indiana, they found that a large percentage of offenders (50%) reported head injury.⁵ In contrast, the prevalence of head injury in the general population is 2%to 5%.

By self-report, the TBI offenders at the day program had worse cognition, greater lability, and more aggressiveness than non-offenders and non-TBI offenders. They concluded, “it would appear that had most of these people not experienced a head injury, they may not have become offenders.”⁵ The Sarpata et al study did not involve an imprisoned population; therefore, these offenders did not become brain-injured while incarcerated. They argued that TBI patients may have more difficulty understanding the legal process, are less able to assist with their defense, and thus are more likely to be found guilty than are suspects without brain injury. The authors recommended cognitive rehabilitation as a way to reduce the propensity for crime.

In a report of the Vietnam Head Injury Study, Grafman et al concluded that ventromedial frontal lobe lesions could result in violent behavior because frontal lobe damage makes it more difficult for the brain to access social skills leading to disinhibition and aggression.⁶ In this study, 279 Vietnam veterans with a history of TBI were matched with 57 healthy people, based on age, education, and length of Vietnam experience. Each received comprehensive testing, including neuropsychological and personality testing. Family members completed questionnaires, which were rated on the Katz Adjustment Scale (KAS), including the Any Violence Scale and the Extreme Violence Scale, to assess aggressiveness.

Based on the observations of family members through the KAS, 14% of the group with frontal lobe injury exhibited physical violence compared with roughly 5% of the controls. These findings were independent of education, IQ scores, or Beck Depression Inventory scores. Patients with lesions in the mediofrontal and orbitofrontal regions had higher Any Violence Scale and Extreme Violence Scale scores than the control group, as reported by family members.

“Knowledge stored in the human prefrontal cortex plays a managerial role in the control of behavior and takes the form of mental models, thematic understanding, plans, and social rules,” the authors said.⁶ They theorized that a prefrontal cortex lesion would hinder the ability to manage one’s instincts, leading to impulsivity, aggression, and violence. However, all patients with ventromedial prefrontal cortex lesions did not display aggression or violent behavior. Further, patients with lesions elsewhere and some normal subjects displayed aggressive and violent behaviors.

Martell estimated the prevalence of organic brain dysfunction in maximum-security forensic psychiatric patients at the Kirby Forensic Psychiatric Center on Ward’s Island in New York City.⁷ Of the 50 randomly selected patients, 22% had a history of a head injury in which they lost consciousness. Whereas 84% had a history of some sort of brain impairment, only 16% were given an organic diagnosis.

“All of the subjects with a DSM-III-R diagnosis of organic brain disorder had been arrested and charged for violent crimes. Of these patients, 75% were charged with murder, manslaughter, or attempted murder. The remaining 25% were charged with violent sex offenses,” said Martell, arguing for a more careful evaluation of organic brain impairment in forensic evaluations.⁷

Lewis et al evaluated the neuropsychiatric status of 15 death-row inmates.⁸ All had reached the final stage in the legal process prior to execution, and 4 had been executed by the time the study was published in 1986. All 15 had a history of TBI as evidenced by objective findings of scars, skull indents, neurologic findings, records, collateral from families, and neuroimaging. During childhood, for instance, one inmate had been beaten in the head by 2-by-4s and fell into a pit, with loss of consciousness for several hours. As an adult, he was in a motor vehicle accident, resulting in an injury to the right eye, and later fell from a roof after a blackout. Other inmates had seizures, abnormal CT scans, positive Babinski signs, ankle clonus, skull defects, and various other neurologic signs.

“When the Supreme Court reinstated the death penalty, it provided that there be a separate sentencing in which mitigating circumstances could be explored. Any evidence of mental disease or defect, including any evidence of central nervous system dysfunction, would be relevant to such hearings, since such disorders affect judgment, reality testing, and self-control,” the authors said.⁸

 

These 15 death-row inmates had numerous neuropsychiatric symptoms that were not addressed. It was thought that the attorneys and judges did not address the organic conditions because of their subtle nature. Objective evidence through collateral and testing ruled out malingering, as did the fact that these inmates were not searching for evaluations or exaggerating their symptoms. The authors concluded that neuropsychiatric status could be a potentially strong mitigating factor, but such evidence is often neglected.

TBI and the insanity defense

Criminal responsibility is dependent on actus reus, the harmful act, and mens rea, guilty or wrongful intent. The accountability and blameworthiness of the crime fall under mens rea. Do TBI patients have the mens rea for the crime? Can TBI be a basis for a plea of not guilty by reason of insanity (NGRI) or a diminished capacity defense? Can the worsening of TBI-related behaviors by substance abuse be the basis for an insanity defense or diminished capacity?

For an NGRI plea, a mental illness or defect must exist. TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors. The NGRI plea historically had two prongs: cognitive and volitional impairment.⁹ The M’Naghten test, the cognitive prong, is based on whether the defendant knew the nature and quality of the criminal act or knew the act was wrong. Under the American Law Institute (ALI)test and American Bar Association standards, the defendant can meet the criteria for insanity by demonstrating a substantial lack of capacity to appreciate, rather than knowing, the criminality or wrongfulness of the act.

There is a substantial amount of evidence for cognitive impairment in TBI patients. The TBI patient may have several co-existing “neurolinguistic deficits associated with the pragmatics of language.”¹⁰ For example, a TBI patient with damage in the nondominant hemisphere may misinterpret the prosody of language, leading to an inappropriate response. Other neurolinguistic deficits in TBI patients include decreased intelligibility, a constricted operational vocabulary, perseveration, and limited listening.

TBI can also lead to short-term memory impairment due to injury to the vulnerable hippocampus within the anterior temporal lobe. When the hippocampus is damaged, the transformation of memories from long-term to active is impaired. Consequently, retrieval of learned information is more difficult for the TBI patient.¹⁰

Also, higher-order cognitive processes can be damaged after TBI. Executive functioning, through the frontal lobe, involves data collection, prioritizing, formulating a plan, and carrying out the plan. This process is almost always impaired in TBI patients, according to a study by Szekeres et al in 1987.¹⁴ Poor abstraction associated with frontal lobe damage can lead to difficulties of TBI patients in understanding or appreciating certain concepts related to the wrongfulness, nature, and quality of their acts.

Finally, interpretation of sensory input is impaired as a result of widespread subcortical damage. Deficient central processing could lead to inability to realistically perceive the external world.¹⁰ In theory, the TBI patient could potentially have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act.

The insanity defense reforms after John Hinckley’s attempted assassination of former President Ronald Reagan have rendered the volitional prong largely irrelevant. One way to judge volitional control is the “policeman at the elbow,” defined as a lack of control such that the offender would have committed the act with a police officer present. Although studies have not focused on whether TBI can lead to “policeman at the elbow” impulsivity, they have proven that TBI-related deficits can lead to severe impulsivity through neuroanatomy and neurotransmitter systems. Silver et al developed the specific diagnosis of “organic aggression syndrome” to describe TBI patients whose aggression is characterized as being “reactive,” “nonreflective,” “nonpurposeful,” “explosive,” “periodic,” and “ego-dystonic.”¹⁰

Diminished capacity and mens rea testimony can be subdivided into four categories under the ALI model Penal Code formulation, including “purpose,” “knowledge,” “recklessness,” and “negligence.”⁹ If an offender has purpose or knowledge, he or she specifically intended to commit the crime. In contrast, with negligence, the offender should have been aware of the risk but may not have been. If the offender is reckless, he or she consciously disregarded a known risk. In general, TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.

As previously discussed, substance abuse is frequently comorbid in the TBI patient. Evidence for intoxication often exists at the time of the offense. Although the effects of drugs and alcohol might be more severe in such a patient, and the patient probably knew this, the intoxication remains voluntary. An NGRI plea might be unobtainable with voluntary intoxication, but diminished capacity remains a possibility (albeit a weak one).

 

A mitigating factor in sentencing

TBI is perhaps most pertinent to sentencing, especially in capital cases. Because the death penalty is on the line, psychiatrists will often be asked for their clinical opinions. Lockett v. Ohio¹¹ secured that any mitigating factors can be admitted during the sentencing phase of a capital case. In fact, it is widely recognized that substance abuse and TBI are potentially independent mitigating factors.⁹

Treatability and rehabilitative potential may also be mitigating. Communicating the potential for treatment to the court can be an undeniable mitigating factor for a TBI patient who has committed violent acts. Cognitive rehabilitation, psychopharmacology, and psychotherapy (individual and family) can be effective treatment options.

Related resources

• Centers for Disease Control and Prevention: Epidemiology of Traumatic Brain Injury in the United States.
• Reynolds CR, ed. Detection of Malingering during Head Injury Litigation. New York: Plenum Press, 1998.
• Murrey G, ed. The Forensic Evaluation of Traumatic Brain Injury: A Handbook for Clinicians and Attorneys. Atlanta, Ga: CDC Press, 2000.

You would be fully justified to state that traumatic brain injury (TBI) can cause and worsen a wide range of psychiatric symptoms including psychosis, mood symptoms, anxiety, cognitive deficits, and impulsivity. Could you also present sufficient evidence of TBI as a cause of violence?

That could be more difficult. TBI-induced criminality remains a central and controversial area within forensic psychiatry. Behavior resulting from injury has been implicated in violence and crime, especially when coexisting with substance abuse, a violent environment during childhood including abuse, and pre-existing personality disorder. The literature is vast and covers a spectrum of opinions, allowing the forensic psychiatrist to find evidence that would support the prosecution or the defense. Judge for yourself.

For the prosecution: TBI is no defense

In his study, “Brain injury and criminality,” Virkkunen concluded that “sociopathy, alcoholism, and drug abuse are the types of psychiatric disorders associated with criminal behavior, not organic brain syndrome.”¹

This statement was based upon a retrospective analysis of World War II veterans. A search was conducted through Finland’s Criminal Register to compare the frequencies of convictions for crimes punishable by imprisonment between a non-TBI control group and a TBI group. The overall crime rates between the two groups were not significantly different: 5.5% versus 4.2% for the control and TBI groups, respectively. Seventeen of 1,870 (0.9%) of the TBI patients committed violent crimes versus 3 of 500 (0.6%) of the control group. A closer examination revealed that most convictions were associated with alcohol in both groups.

Unlike Virkkunen, Kreutzer et al were unable to prove or disprove a cause and effect between TBI and violence. In their 1991 investigation based on 74 TBI patients, they found that 20% had been arrested pre-injury, and 10% had been arrested after the injury.² Most arrests occurred after use of alcohol or other drugs. The study concluded that criminal behavior might be a result of post-injury changes including poor judgment, apathy, and other new behaviors.

Box 1

Substance abuse, traumatic brain injury, and crime were indeed interconnected, the researchers said, but they did not go so far as to conclude that TBI causes criminality and violence. Rather, they believed that substance abuse, which was most common among those younger than 35, led to legal difficulties and TBI.

In 1995, based on a larger sample of 327 patients, Kreutzer and associates found that the TBI criminal population has a relatively high incidence of alcohol abuse before and after head injury.³ Most crimes were associated with substance abuse, such as drug possession or driving under the influence of alcohol.

The study found that TBI patients with a history of arrest were more likely to have substance abuse problems after the injury. TBI patients with both a criminal and substance abuse history also were more likely to commit crimes after the head injury. Kreutzer concluded that TBI is not a risk factor for crime without such a history.

For the defense: TBI does lead to criminality

In one study by Brooks et al of 42 individuals with severe TBI, threats of violence increased from 15% 1 year after sustaining head injury to 54% 5 years after.⁴ What’s more, at the 5-year follow-up, 31% of these patients had legal problems and 20% of their relatives had been assaulted by them at least once.

 

A study by Sarpata et al also supports the argument that TBI leads to criminality.⁵ They argue that TBI patients should be expected to commit crimes because they have poor cognitive skills, impulsivity, and increased aggression, as well as low tolerance for frustration and poor judgment. In their study of 18 subjects in a community corrections day program in Vigo County, Indiana, they found that a large percentage of offenders (50%) reported head injury.⁵ In contrast, the prevalence of head injury in the general population is 2%to 5%.

By self-report, the TBI offenders at the day program had worse cognition, greater lability, and more aggressiveness than non-offenders and non-TBI offenders. They concluded, “it would appear that had most of these people not experienced a head injury, they may not have become offenders.”⁵ The Sarpata et al study did not involve an imprisoned population; therefore, these offenders did not become brain-injured while incarcerated. They argued that TBI patients may have more difficulty understanding the legal process, are less able to assist with their defense, and thus are more likely to be found guilty than are suspects without brain injury. The authors recommended cognitive rehabilitation as a way to reduce the propensity for crime.

In a report of the Vietnam Head Injury Study, Grafman et al concluded that ventromedial frontal lobe lesions could result in violent behavior because frontal lobe damage makes it more difficult for the brain to access social skills leading to disinhibition and aggression.⁶ In this study, 279 Vietnam veterans with a history of TBI were matched with 57 healthy people, based on age, education, and length of Vietnam experience. Each received comprehensive testing, including neuropsychological and personality testing. Family members completed questionnaires, which were rated on the Katz Adjustment Scale (KAS), including the Any Violence Scale and the Extreme Violence Scale, to assess aggressiveness.

Based on the observations of family members through the KAS, 14% of the group with frontal lobe injury exhibited physical violence compared with roughly 5% of the controls. These findings were independent of education, IQ scores, or Beck Depression Inventory scores. Patients with lesions in the mediofrontal and orbitofrontal regions had higher Any Violence Scale and Extreme Violence Scale scores than the control group, as reported by family members.

“Knowledge stored in the human prefrontal cortex plays a managerial role in the control of behavior and takes the form of mental models, thematic understanding, plans, and social rules,” the authors said.⁶ They theorized that a prefrontal cortex lesion would hinder the ability to manage one’s instincts, leading to impulsivity, aggression, and violence. However, all patients with ventromedial prefrontal cortex lesions did not display aggression or violent behavior. Further, patients with lesions elsewhere and some normal subjects displayed aggressive and violent behaviors.

Martell estimated the prevalence of organic brain dysfunction in maximum-security forensic psychiatric patients at the Kirby Forensic Psychiatric Center on Ward’s Island in New York City.⁷ Of the 50 randomly selected patients, 22% had a history of a head injury in which they lost consciousness. Whereas 84% had a history of some sort of brain impairment, only 16% were given an organic diagnosis.

“All of the subjects with a DSM-III-R diagnosis of organic brain disorder had been arrested and charged for violent crimes. Of these patients, 75% were charged with murder, manslaughter, or attempted murder. The remaining 25% were charged with violent sex offenses,” said Martell, arguing for a more careful evaluation of organic brain impairment in forensic evaluations.⁷

Lewis et al evaluated the neuropsychiatric status of 15 death-row inmates.⁸ All had reached the final stage in the legal process prior to execution, and 4 had been executed by the time the study was published in 1986. All 15 had a history of TBI as evidenced by objective findings of scars, skull indents, neurologic findings, records, collateral from families, and neuroimaging. During childhood, for instance, one inmate had been beaten in the head by 2-by-4s and fell into a pit, with loss of consciousness for several hours. As an adult, he was in a motor vehicle accident, resulting in an injury to the right eye, and later fell from a roof after a blackout. Other inmates had seizures, abnormal CT scans, positive Babinski signs, ankle clonus, skull defects, and various other neurologic signs.

“When the Supreme Court reinstated the death penalty, it provided that there be a separate sentencing in which mitigating circumstances could be explored. Any evidence of mental disease or defect, including any evidence of central nervous system dysfunction, would be relevant to such hearings, since such disorders affect judgment, reality testing, and self-control,” the authors said.⁸

 

These 15 death-row inmates had numerous neuropsychiatric symptoms that were not addressed. It was thought that the attorneys and judges did not address the organic conditions because of their subtle nature. Objective evidence through collateral and testing ruled out malingering, as did the fact that these inmates were not searching for evaluations or exaggerating their symptoms. The authors concluded that neuropsychiatric status could be a potentially strong mitigating factor, but such evidence is often neglected.

TBI and the insanity defense

Criminal responsibility is dependent on actus reus, the harmful act, and mens rea, guilty or wrongful intent. The accountability and blameworthiness of the crime fall under mens rea. Do TBI patients have the mens rea for the crime? Can TBI be a basis for a plea of not guilty by reason of insanity (NGRI) or a diminished capacity defense? Can the worsening of TBI-related behaviors by substance abuse be the basis for an insanity defense or diminished capacity?

For an NGRI plea, a mental illness or defect must exist. TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors. The NGRI plea historically had two prongs: cognitive and volitional impairment.⁹ The M’Naghten test, the cognitive prong, is based on whether the defendant knew the nature and quality of the criminal act or knew the act was wrong. Under the American Law Institute (ALI)test and American Bar Association standards, the defendant can meet the criteria for insanity by demonstrating a substantial lack of capacity to appreciate, rather than knowing, the criminality or wrongfulness of the act.

There is a substantial amount of evidence for cognitive impairment in TBI patients. The TBI patient may have several co-existing “neurolinguistic deficits associated with the pragmatics of language.”¹⁰ For example, a TBI patient with damage in the nondominant hemisphere may misinterpret the prosody of language, leading to an inappropriate response. Other neurolinguistic deficits in TBI patients include decreased intelligibility, a constricted operational vocabulary, perseveration, and limited listening.

TBI can also lead to short-term memory impairment due to injury to the vulnerable hippocampus within the anterior temporal lobe. When the hippocampus is damaged, the transformation of memories from long-term to active is impaired. Consequently, retrieval of learned information is more difficult for the TBI patient.¹⁰

Also, higher-order cognitive processes can be damaged after TBI. Executive functioning, through the frontal lobe, involves data collection, prioritizing, formulating a plan, and carrying out the plan. This process is almost always impaired in TBI patients, according to a study by Szekeres et al in 1987.¹⁴ Poor abstraction associated with frontal lobe damage can lead to difficulties of TBI patients in understanding or appreciating certain concepts related to the wrongfulness, nature, and quality of their acts.

Finally, interpretation of sensory input is impaired as a result of widespread subcortical damage. Deficient central processing could lead to inability to realistically perceive the external world.¹⁰ In theory, the TBI patient could potentially have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act.

The insanity defense reforms after John Hinckley’s attempted assassination of former President Ronald Reagan have rendered the volitional prong largely irrelevant. One way to judge volitional control is the “policeman at the elbow,” defined as a lack of control such that the offender would have committed the act with a police officer present. Although studies have not focused on whether TBI can lead to “policeman at the elbow” impulsivity, they have proven that TBI-related deficits can lead to severe impulsivity through neuroanatomy and neurotransmitter systems. Silver et al developed the specific diagnosis of “organic aggression syndrome” to describe TBI patients whose aggression is characterized as being “reactive,” “nonreflective,” “nonpurposeful,” “explosive,” “periodic,” and “ego-dystonic.”¹⁰

Diminished capacity and mens rea testimony can be subdivided into four categories under the ALI model Penal Code formulation, including “purpose,” “knowledge,” “recklessness,” and “negligence.”⁹ If an offender has purpose or knowledge, he or she specifically intended to commit the crime. In contrast, with negligence, the offender should have been aware of the risk but may not have been. If the offender is reckless, he or she consciously disregarded a known risk. In general, TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.

As previously discussed, substance abuse is frequently comorbid in the TBI patient. Evidence for intoxication often exists at the time of the offense. Although the effects of drugs and alcohol might be more severe in such a patient, and the patient probably knew this, the intoxication remains voluntary. An NGRI plea might be unobtainable with voluntary intoxication, but diminished capacity remains a possibility (albeit a weak one).

 

A mitigating factor in sentencing

TBI is perhaps most pertinent to sentencing, especially in capital cases. Because the death penalty is on the line, psychiatrists will often be asked for their clinical opinions. Lockett v. Ohio¹¹ secured that any mitigating factors can be admitted during the sentencing phase of a capital case. In fact, it is widely recognized that substance abuse and TBI are potentially independent mitigating factors.⁹

Treatability and rehabilitative potential may also be mitigating. Communicating the potential for treatment to the court can be an undeniable mitigating factor for a TBI patient who has committed violent acts. Cognitive rehabilitation, psychopharmacology, and psychotherapy (individual and family) can be effective treatment options.

Related resources

• Centers for Disease Control and Prevention: Epidemiology of Traumatic Brain Injury in the United States.
• Reynolds CR, ed. Detection of Malingering during Head Injury Litigation. New York: Plenum Press, 1998.
• Murrey G, ed. The Forensic Evaluation of Traumatic Brain Injury: A Handbook for Clinicians and Attorneys. Atlanta, Ga: CDC Press, 2000.

You would be fully justified to state that traumatic brain injury (TBI) can cause and worsen a wide range of psychiatric symptoms including psychosis, mood symptoms, anxiety, cognitive deficits, and impulsivity. Could you also present sufficient evidence of TBI as a cause of violence?

That could be more difficult. TBI-induced criminality remains a central and controversial area within forensic psychiatry. Behavior resulting from injury has been implicated in violence and crime, especially when coexisting with substance abuse, a violent environment during childhood including abuse, and pre-existing personality disorder. The literature is vast and covers a spectrum of opinions, allowing the forensic psychiatrist to find evidence that would support the prosecution or the defense. Judge for yourself.

For the prosecution: TBI is no defense

In his study, “Brain injury and criminality,” Virkkunen concluded that “sociopathy, alcoholism, and drug abuse are the types of psychiatric disorders associated with criminal behavior, not organic brain syndrome.”¹

This statement was based upon a retrospective analysis of World War II veterans. A search was conducted through Finland’s Criminal Register to compare the frequencies of convictions for crimes punishable by imprisonment between a non-TBI control group and a TBI group. The overall crime rates between the two groups were not significantly different: 5.5% versus 4.2% for the control and TBI groups, respectively. Seventeen of 1,870 (0.9%) of the TBI patients committed violent crimes versus 3 of 500 (0.6%) of the control group. A closer examination revealed that most convictions were associated with alcohol in both groups.

Unlike Virkkunen, Kreutzer et al were unable to prove or disprove a cause and effect between TBI and violence. In their 1991 investigation based on 74 TBI patients, they found that 20% had been arrested pre-injury, and 10% had been arrested after the injury.² Most arrests occurred after use of alcohol or other drugs. The study concluded that criminal behavior might be a result of post-injury changes including poor judgment, apathy, and other new behaviors.

Box 1

Substance abuse, traumatic brain injury, and crime were indeed interconnected, the researchers said, but they did not go so far as to conclude that TBI causes criminality and violence. Rather, they believed that substance abuse, which was most common among those younger than 35, led to legal difficulties and TBI.

In 1995, based on a larger sample of 327 patients, Kreutzer and associates found that the TBI criminal population has a relatively high incidence of alcohol abuse before and after head injury.³ Most crimes were associated with substance abuse, such as drug possession or driving under the influence of alcohol.

The study found that TBI patients with a history of arrest were more likely to have substance abuse problems after the injury. TBI patients with both a criminal and substance abuse history also were more likely to commit crimes after the head injury. Kreutzer concluded that TBI is not a risk factor for crime without such a history.

For the defense: TBI does lead to criminality

In one study by Brooks et al of 42 individuals with severe TBI, threats of violence increased from 15% 1 year after sustaining head injury to 54% 5 years after.⁴ What’s more, at the 5-year follow-up, 31% of these patients had legal problems and 20% of their relatives had been assaulted by them at least once.

 

A study by Sarpata et al also supports the argument that TBI leads to criminality.⁵ They argue that TBI patients should be expected to commit crimes because they have poor cognitive skills, impulsivity, and increased aggression, as well as low tolerance for frustration and poor judgment. In their study of 18 subjects in a community corrections day program in Vigo County, Indiana, they found that a large percentage of offenders (50%) reported head injury.⁵ In contrast, the prevalence of head injury in the general population is 2%to 5%.

By self-report, the TBI offenders at the day program had worse cognition, greater lability, and more aggressiveness than non-offenders and non-TBI offenders. They concluded, “it would appear that had most of these people not experienced a head injury, they may not have become offenders.”⁵ The Sarpata et al study did not involve an imprisoned population; therefore, these offenders did not become brain-injured while incarcerated. They argued that TBI patients may have more difficulty understanding the legal process, are less able to assist with their defense, and thus are more likely to be found guilty than are suspects without brain injury. The authors recommended cognitive rehabilitation as a way to reduce the propensity for crime.

In a report of the Vietnam Head Injury Study, Grafman et al concluded that ventromedial frontal lobe lesions could result in violent behavior because frontal lobe damage makes it more difficult for the brain to access social skills leading to disinhibition and aggression.⁶ In this study, 279 Vietnam veterans with a history of TBI were matched with 57 healthy people, based on age, education, and length of Vietnam experience. Each received comprehensive testing, including neuropsychological and personality testing. Family members completed questionnaires, which were rated on the Katz Adjustment Scale (KAS), including the Any Violence Scale and the Extreme Violence Scale, to assess aggressiveness.

Based on the observations of family members through the KAS, 14% of the group with frontal lobe injury exhibited physical violence compared with roughly 5% of the controls. These findings were independent of education, IQ scores, or Beck Depression Inventory scores. Patients with lesions in the mediofrontal and orbitofrontal regions had higher Any Violence Scale and Extreme Violence Scale scores than the control group, as reported by family members.

“Knowledge stored in the human prefrontal cortex plays a managerial role in the control of behavior and takes the form of mental models, thematic understanding, plans, and social rules,” the authors said.⁶ They theorized that a prefrontal cortex lesion would hinder the ability to manage one’s instincts, leading to impulsivity, aggression, and violence. However, all patients with ventromedial prefrontal cortex lesions did not display aggression or violent behavior. Further, patients with lesions elsewhere and some normal subjects displayed aggressive and violent behaviors.

Martell estimated the prevalence of organic brain dysfunction in maximum-security forensic psychiatric patients at the Kirby Forensic Psychiatric Center on Ward’s Island in New York City.⁷ Of the 50 randomly selected patients, 22% had a history of a head injury in which they lost consciousness. Whereas 84% had a history of some sort of brain impairment, only 16% were given an organic diagnosis.

“All of the subjects with a DSM-III-R diagnosis of organic brain disorder had been arrested and charged for violent crimes. Of these patients, 75% were charged with murder, manslaughter, or attempted murder. The remaining 25% were charged with violent sex offenses,” said Martell, arguing for a more careful evaluation of organic brain impairment in forensic evaluations.⁷

Lewis et al evaluated the neuropsychiatric status of 15 death-row inmates.⁸ All had reached the final stage in the legal process prior to execution, and 4 had been executed by the time the study was published in 1986. All 15 had a history of TBI as evidenced by objective findings of scars, skull indents, neurologic findings, records, collateral from families, and neuroimaging. During childhood, for instance, one inmate had been beaten in the head by 2-by-4s and fell into a pit, with loss of consciousness for several hours. As an adult, he was in a motor vehicle accident, resulting in an injury to the right eye, and later fell from a roof after a blackout. Other inmates had seizures, abnormal CT scans, positive Babinski signs, ankle clonus, skull defects, and various other neurologic signs.

“When the Supreme Court reinstated the death penalty, it provided that there be a separate sentencing in which mitigating circumstances could be explored. Any evidence of mental disease or defect, including any evidence of central nervous system dysfunction, would be relevant to such hearings, since such disorders affect judgment, reality testing, and self-control,” the authors said.⁸

 

These 15 death-row inmates had numerous neuropsychiatric symptoms that were not addressed. It was thought that the attorneys and judges did not address the organic conditions because of their subtle nature. Objective evidence through collateral and testing ruled out malingering, as did the fact that these inmates were not searching for evaluations or exaggerating their symptoms. The authors concluded that neuropsychiatric status could be a potentially strong mitigating factor, but such evidence is often neglected.

TBI and the insanity defense

Criminal responsibility is dependent on actus reus, the harmful act, and mens rea, guilty or wrongful intent. The accountability and blameworthiness of the crime fall under mens rea. Do TBI patients have the mens rea for the crime? Can TBI be a basis for a plea of not guilty by reason of insanity (NGRI) or a diminished capacity defense? Can the worsening of TBI-related behaviors by substance abuse be the basis for an insanity defense or diminished capacity?

For an NGRI plea, a mental illness or defect must exist. TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors. The NGRI plea historically had two prongs: cognitive and volitional impairment.⁹ The M’Naghten test, the cognitive prong, is based on whether the defendant knew the nature and quality of the criminal act or knew the act was wrong. Under the American Law Institute (ALI)test and American Bar Association standards, the defendant can meet the criteria for insanity by demonstrating a substantial lack of capacity to appreciate, rather than knowing, the criminality or wrongfulness of the act.

There is a substantial amount of evidence for cognitive impairment in TBI patients. The TBI patient may have several co-existing “neurolinguistic deficits associated with the pragmatics of language.”¹⁰ For example, a TBI patient with damage in the nondominant hemisphere may misinterpret the prosody of language, leading to an inappropriate response. Other neurolinguistic deficits in TBI patients include decreased intelligibility, a constricted operational vocabulary, perseveration, and limited listening.

TBI can also lead to short-term memory impairment due to injury to the vulnerable hippocampus within the anterior temporal lobe. When the hippocampus is damaged, the transformation of memories from long-term to active is impaired. Consequently, retrieval of learned information is more difficult for the TBI patient.¹⁰

Also, higher-order cognitive processes can be damaged after TBI. Executive functioning, through the frontal lobe, involves data collection, prioritizing, formulating a plan, and carrying out the plan. This process is almost always impaired in TBI patients, according to a study by Szekeres et al in 1987.¹⁴ Poor abstraction associated with frontal lobe damage can lead to difficulties of TBI patients in understanding or appreciating certain concepts related to the wrongfulness, nature, and quality of their acts.

Finally, interpretation of sensory input is impaired as a result of widespread subcortical damage. Deficient central processing could lead to inability to realistically perceive the external world.¹⁰ In theory, the TBI patient could potentially have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act.

The insanity defense reforms after John Hinckley’s attempted assassination of former President Ronald Reagan have rendered the volitional prong largely irrelevant. One way to judge volitional control is the “policeman at the elbow,” defined as a lack of control such that the offender would have committed the act with a police officer present. Although studies have not focused on whether TBI can lead to “policeman at the elbow” impulsivity, they have proven that TBI-related deficits can lead to severe impulsivity through neuroanatomy and neurotransmitter systems. Silver et al developed the specific diagnosis of “organic aggression syndrome” to describe TBI patients whose aggression is characterized as being “reactive,” “nonreflective,” “nonpurposeful,” “explosive,” “periodic,” and “ego-dystonic.”¹⁰

Diminished capacity and mens rea testimony can be subdivided into four categories under the ALI model Penal Code formulation, including “purpose,” “knowledge,” “recklessness,” and “negligence.”⁹ If an offender has purpose or knowledge, he or she specifically intended to commit the crime. In contrast, with negligence, the offender should have been aware of the risk but may not have been. If the offender is reckless, he or she consciously disregarded a known risk. In general, TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.

As previously discussed, substance abuse is frequently comorbid in the TBI patient. Evidence for intoxication often exists at the time of the offense. Although the effects of drugs and alcohol might be more severe in such a patient, and the patient probably knew this, the intoxication remains voluntary. An NGRI plea might be unobtainable with voluntary intoxication, but diminished capacity remains a possibility (albeit a weak one).

 

A mitigating factor in sentencing

TBI is perhaps most pertinent to sentencing, especially in capital cases. Because the death penalty is on the line, psychiatrists will often be asked for their clinical opinions. Lockett v. Ohio¹¹ secured that any mitigating factors can be admitted during the sentencing phase of a capital case. In fact, it is widely recognized that substance abuse and TBI are potentially independent mitigating factors.⁹

Treatability and rehabilitative potential may also be mitigating. Communicating the potential for treatment to the court can be an undeniable mitigating factor for a TBI patient who has committed violent acts. Cognitive rehabilitation, psychopharmacology, and psychotherapy (individual and family) can be effective treatment options.

Related resources

• Centers for Disease Control and Prevention: Epidemiology of Traumatic Brain Injury in the United States.
• Reynolds CR, ed. Detection of Malingering during Head Injury Litigation. New York: Plenum Press, 1998.
• Murrey G, ed. The Forensic Evaluation of Traumatic Brain Injury: A Handbook for Clinicians and Attorneys. Atlanta, Ga: CDC Press, 2000.

Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.

That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.

Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.

How stuttering develops

Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).¹

Box 1

By definition, stuttering can interfere with social, academic, or occupational functioning. Persons who stutter often develop secondary behaviors such as avoidances of words, phrases, or even social situations, which in turn leads to a high level of social anxiety.²

Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.³ Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.⁴ In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.⁵

Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.⁶ Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).^7,8 Researchers are investigating potential molecular genetic markers for stuttering.

Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.

Functional positron emission tomography studies utilizing¹⁸ F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.

 

Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.⁹ The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.

Box 2

The dopamine hypothesis of stuttering

Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.¹⁰ As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.

To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.¹¹ These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.¹²

Evaluating the patient

One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.

Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.

Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.¹³ This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.

Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.

In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.

What we’ve learned about drug therapy

Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.

The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.

Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.^14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.

 

Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D₂) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.¹⁶ Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.

Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.¹⁷ Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.¹⁸

Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.¹⁹

A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.

In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.²⁰

It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.

Related resources

• National Stuttering Association http://www.nsastutter.org
  
• University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
  
• Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
  

Drug brand names

• Haloperidol • Haldol
  
• Nimodipine • Nimotop
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Risperidone • Risperdal
  

Disclosure

Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.

Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.

Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.

Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.

That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.

Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.

How stuttering develops

Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).¹

Box 1

By definition, stuttering can interfere with social, academic, or occupational functioning. Persons who stutter often develop secondary behaviors such as avoidances of words, phrases, or even social situations, which in turn leads to a high level of social anxiety.²

Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.³ Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.⁴ In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.⁵

Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.⁶ Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).^7,8 Researchers are investigating potential molecular genetic markers for stuttering.

Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.

Functional positron emission tomography studies utilizing¹⁸ F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.

 

Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.⁹ The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.

Box 2

The dopamine hypothesis of stuttering

Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.¹⁰ As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.

To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.¹¹ These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.¹²

Evaluating the patient

One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.

Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.

Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.¹³ This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.

Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.

In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.

What we’ve learned about drug therapy

Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.

The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.

Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.^14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.

 

Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D₂) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.¹⁶ Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.

Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.¹⁷ Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.¹⁸

Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.¹⁹

A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.

In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.²⁰

It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.

Related resources

• National Stuttering Association http://www.nsastutter.org
  
• University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
  
• Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
  

Drug brand names

• Haloperidol • Haldol
  
• Nimodipine • Nimotop
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Risperidone • Risperdal
  

Disclosure

Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.

Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.

Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.

Despite its prevalence, stuttering has not received as much attention as other psychiatric disorders from patients or psychiatrists—with good reason. Until recently, little was known about the neurophysiology of stuttering, and treatment was generally ineffective especially in adults (Box 1). Despite their own personal struggles with the disorder, patients have questioned the need for psychiatric treatment.

That has now changed. We know now that stuttering is likely a disorder of brain chemistry. Studies suggests that olanzapine, a novel dopamine antagonist, is a useful, well-tolerated medication for the treatment of stuttering. As a result, psychiatrists are now equipped to play an important role in its management.

Furthermore, we can give patients the therapeutic opportunity to discuss what often has been a lifetime of frustration with stuttering. We can enable them to understand the course and treatment of this disorder and encourage them to take advantage of the opportunities to lessen the symptoms of stuttering and, ultimately, improve their quality of life.

How stuttering develops

Stuttering is a speech disorder characterized by frequent prolongations, repetitions, or blocks of spoken sounds and/or syllables. A common disorder affecting 1% of adults and 4% of children, stuttering is classified in DSM-IV as an Axis I disorder (Box 2).¹

Box 1

By definition, stuttering can interfere with social, academic, or occupational functioning. Persons who stutter often develop secondary behaviors such as avoidances of words, phrases, or even social situations, which in turn leads to a high level of social anxiety.²

Stuttering usually begins in childhood and is likely a developmental disorder. Rare cases of acquired stuttering begin in adulthood but are related to secondary causes such as medications, brain trauma, or stroke.³ Some 80% to 90% of developmental stuttering begins by age 6; onset after age 9 is likely to have some psychogenic or neurogenic basis.⁴ In approximately 60% of the children who stutter, the symptoms will remit by age 16. Children who stutter require early intervention, given the importance of communication in a child’s development.⁵

Stuttering shares many similarities with Tourette syndrome. Both begin in childhood, follow a waxing or waning course, have a 4:1 male-to-female ratio, are made worse by anxiety, involve abnormalities in the basal ganglia, and respond to dopamine antagonist therapy.⁶ Persons who stutter often exhibit tic motions, similar to those seen in Tourette syndrome, which are associated with the struggles to produce speech. Genetic studies have shown possible high additive genetic effects; pair-wise concordance for stuttering was significantly higher in identical twins (63%) than it was in fraternal same-sex twins (19%).^7,8 Researchers are investigating potential molecular genetic markers for stuttering.

Functional brain imaging studies suggest that stuttering is associated with abnormal cerebral activation primarily involving abnormally low metabolism of the cortical speech areas and the striatum. The defects in stuttering occur primarily in the timing and initiation of spontaneous speech, with such tasks as singing and reading in chorus being spared. A clue to understanding stuttering lies with these “induced fluency” tasks.

Functional positron emission tomography studies utilizing¹⁸ F-deoxyglucose showed that stuttering is associated with abnormally low metabolism of speech cortical areas (Wernicke’s and Broca’s) and low metabolism of the basal ganglia, notably the striatum. During the induced fluency, Wernicke’s and Broca’s areas normalize but the striatum remains abnormally low.

 

Riley postulates two “loops” of speech, an inner or medial system and an outer or lateral system.⁹ The lateral system is preserved in stuttering and can be activated through singing, rhythmic speech, etc., but the inner loop, as mediated by the striatum and influenced by dopamine, remains impaired. Once a person who stutters initiates speech, he or she often avoids taking a breath as the whole system must again be jump-started. The low striatal metabolism may be the common-state phenomenon underlying this timing.

Box 2

The dopamine hypothesis of stuttering

Stuttering is likely related to abnormal elevations of cerebral dopamine activity. Stimulant medications, which increase dopamine activity, have been shown to increase stuttering symptoms.¹⁰ As will be reviewed later, dopamine antagonist medications have been shown to improve the symptoms of stuttering. Also, the striatal hypometabolism in stuttering seen in PET imaging may be a result of a hyperdopaminergic state.

To investigate this dopamine hypothesis of stuttering, Wu et al measured presynaptic dopamine levels in individuals who stutter.¹¹ These were found to have 50% to 200% higher levels of dopamine activity than did the controls. Dopamine is inhibitory to striatal metabolism, providing an explanation for the striatal hypometabolism seen in stuttering. Also, risperidone was found to increase striatal metabolism in those whose stuttering improved on this medication.¹²

Evaluating the patient

One should begin with a comprehensive psychiatric history. Because many patients began stuttering in childhood and have had difficulty dealing with their disorder, other psychiatric disorders such as social phobia may be present. Moreover, other medical etiologies (e.g., stroke) may cause a speech disorder that resembles stuttering.

Stuttering involves abnormalities in fluency as well as tic motions and cognitive avoidances. Inquiries should be made as to the patient’s fluency of speech during work, during introductions, speaking in front of an audience, with family, etc.; the level of stuttering can vary depending on the particular environment.

Stuttering fluency can be rated through an objective scale known as the Riley SSI-3.¹³ This scale measures the duration of each stuttering event, the percentage of syllables stuttered versus syllables spoken, the severity of associated tic motions, and a global score of the aforementioned components. Because most psychiatrists cannot routinely perform this scale to assess the patient’s progress, it is best to partner with a speech-language pathologist who can also assist the patient through speech therapy.

Nonetheless, you may assess the progress of treatment by relying on your own “ear,” the patient’s own assessment, and the input of a significant other or family member.

In addition to considering DSM-IV criteria, comprehensive treatment should address all aspects of this disorder, including not only the fluency enhancement but improvement in social avoidances and cognitive restructuring. Be aware that stuttering waxes and wanes over time. You should expect to see some “dips” in efficacy during the course of therapy. A longitudinal assessment over several months is needed to determine if the stuttering treatment is efficacious.

What we’ve learned about drug therapy

Many medications have been tried to treat stuttering but few have shown efficacy in well-controlled trials. Most pharmacologic studies did not include a placebo control or employ objective measures of stuttering severity, nor did they provide multiple baseline and treatment measures.

The critical new knowledge is this: Medications that lower dopamine activity have shown replicated efficacy in improving stuttering. The benzodiazepines have been shown to reduce anxiety short-term but have not been shown to improve fluency in stuttering. Limited studies of serotonergic antidepressants suggest a possible role in reducing the social anxiety of stuttering but have not been shown in well-controlled trials to improve stuttering fluency directly.

Multiple studies of haloperidol in the 1970s showed that this medication improved fluency in individuals who stutter. Long-term compliance with this medication, however, was poor given its dysphoric side effects, sexual dysfunction, extrapyramidal concerns, and risks of tardive dyskinesia. Limited research with calcium-channel-blocking medications (e.g., verapamil, nimodipine) showed limited efficacy in stuttering.^14,15 Calcium-channel blockers, however, may exert a mild antidopamine effect.

 

Further supporting dopamine hyperactivity in the pathology of stuttering, Stager et al compared pimozide (n = 6), a selective dopamine (D₂) antagonist, paroxetine (n = 5), a highly selective serotonin reuptake inhibitor, and placebo (n = 6). The researchers found a positive clinical response in those on pimozide compared with those taking placebo, whereas the paroxetine group exhibited no clinical response.¹⁶ Although small, such a study supports the hypothesis that dopamine may be a principal transmitter involved in stuttering pathology, and serotonin may play a minor role, if any.

Risperidone, a newer-generation dopamine antagonist with a side-effect profile more favorable than haloperidol, has been shown in a well-controlled, double-blind, placebo-controlled study to improve stuttering symptoms (0.5 mg to 2 mg/d). Although generally well tolerated, long-term compliance was hindered by prolactin-related side effects such as sexual dysfunction, galactorrhea, amenorrhea, and dysphoria.¹⁷ Dysphoria with risperidone has also recently been reported to occur with its use in Tourette disorder.¹⁸

Olanzapine is a novel psychotropic medication that possesses dopamine-blocking qualities but is not associated as much with prolactin-related side effects or dysphoria. A preliminary open-label study suggests that it too improves the symptoms of stuttering.¹⁹

A multicenter study of olanzapine in the treatment of adult developmental stuttering involved 23 adults in a 3-month, double-blind, placebo-controlled trial preceded by a 1-month baseline rating period. At the end of the double-blind phase, subjects were followed for 1 year. Olanzapine (2.5 mg titrated to 5 mg/d) was shown to exert a statistically significant improvement over placebo in multiple objective measures of stuttering severity. The medication was well tolerated without prolactin-associated side effects. Concerns of appetite increase and weight gain with olanzapine were minimized through simple education. The average weight gain was 4 lb in the treatment group, compared with 1 lb in the placebo group. Compliance was also high. All subjects elected to enter the open-label phase of the protocol.

In many patients in the study, stuttering symptoms have continued to improve over 6 months to 1 year or even longer, suggesting that an adequate treatment trial should be measured not in days or even weeks, but possibly months. Also, some individuals in the open-label phase have shown even further efficacy with dose escalation to 7.5 mg to 10 mg/d or higher of olanzapine.²⁰

It is likely, however, that pharmacologic treatment will not be the total answer. In the studies cited earlier, the novel dopamine antagonists led to significant—yet only partial—reductions in stuttering symptoms. The future of optimal stuttering treatment will likely involve the active collaboration between a speech language pathologist and a psychiatrist, using speech therapy to enhance the positive benefits of the medication.

Related resources

• National Stuttering Association http://www.nsastutter.org
  
• University of California-Irvine Medical Center: Facts About Stuttering. http://www.ucihealth.com/News/UCI%20Health/stutter2.htm
  
• Hulstijn W, Peters HFM, Van Lieshout PHHM, eds. Speech Production: Motor Control, Brain Research and Fluency Disorders. International Congress Series 1146. Amsterdam, Netherlands: Excerpta Medica, 1997.
  

Drug brand names

• Haloperidol • Haldol
  
• Nimodipine • Nimotop
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Pimozide • Orap
  
• Risperidone • Risperdal
  

Disclosure

Drs. Maguire and Franklin report that they receive grant/research support from, serve as consultants to, and are on the speaker’s bureau of Eli Lilly &Co.

Dr. Maguire also reports that he receives grant/research support from Johnson & Johnson, and serves on the speaker’s bureau of Pfizer Inc. and GlaxoSmithKline.

Dr. Yu reports that he serves on the speaker’s bureau of Cephalon Inc.

Drs. Riley and Ortiz report no financial relationship with any company whose products are mentioned in this article.

Are you at risk of being assaulted?

Most psychiatrists do not arm themselves with the bare essentials of self-protection. Consider these questions:

• Have you attended one of the available training institutes, such as the Crisis Prevention Institute (CPI)¹ or Management of Aggressive Behavior (MOAB)², or a state-sponsored program such as Prevention and Management of Aggressive Behavior (PMAB), offered by the Texas Department of Mental Health and Mental Retardation?³
  
• Have you developed a safety plan, especially in your practice? Examples of such plans include placement of furniture for easy exit if attacked, panic buttons that call or alert security services, and even video surveillance.
  
• Have you reported “minor” assaults by patients? Acts of violence in psychiatric settings are rarely discussed and dramatically underreported. Psychiatrists often go into denial when assaulted, rather than being motivated to get the appropriate training to manage future patient aggression episodes.
  
• Do you focus on pharmacotherapy as the first line of aggressive behavior management instead of methods of protection and de-escalation?
  

All too often, psychiatric residency training simply pays “lip service” to de-escalation of the violent patient, instead overemphasizing the pharmacology of behavioral emergencies. This has left many psychiatrists unprepared in an era where mental health advocacy groups, ethicists, and attorneys are applying pressure on us to find new ways to avoid seclusion, restraint, and intramuscular medication for psychiatric emergencies.

Let’s look at how to assess a patient’s potential for violence, as well as nonpharmacologic interventions you can use to keep you and your staff safe and prevent aggressive behaviors from escalating.

Three strategies for assessing violence

You can start to protect yourself against violent attacks by using a 3-part strategy that involves knowing the DSM-IV diagnoses associated with violence, using a checklist to gauge a patient’s potential for violence, and developing an observational awareness to quickly recognize the warning signs of an imminent violent act.

Table 1

DSM-IV DIAGNOSES ASSOCIATED WITH VIOLENCE OR AGGRESSION

Attention-deficit/hyperactivity disorder Bipolar I disorder, manic Conduct disorder Delirium Dementia Intermittent explosive disorder Mental retardation Mood disorder due to a general medical condition Personality change due to a general medical condition	Personality disorder Paranoid Antisocial Borderline Narcissistic Posttraumatic stress disorder Premenstrual dysphoric disorder Schizophrenia Sexual sadism Substance abuse and withdrawal Substance-induced mood disorder

How quickly can you recognize the DSM-IV diagnoses associated with aggression and violence (Table 1)? Here are some clues to fast action:

1. Rule out a medical or substance-induced etiology for the presenting symptoms. Intoxication with alcohol, amphetamines, cocaine, phencyclidine, and sedative-hypnotics is associated with violence. Withdrawal from benzodiazepines or alcohol may also lead to aggression.
   
2. Rule out delirium.
   
3. Among the many organic causes of violence and aggression, pay careful attention to the usual intracranial suspects including infection, stroke, trauma, autoimmune syndromes, neoplasm, and encephalopathy.
   
4. Rule out metabolic abnormalities, including thyrotoxicosis, hypoxemia, and endocrinopathy.
   
5. Violence in temporal lobe epilepsy may occur in the ictal, interictal, or postictal periods.
   

The second tool in violence assessment is a checklist (Table 3) that covers a range of risk factors including symptoms, demographics, and predisposing historical factors. I recommend that all clinicians preparing for work in emergency rooms or inpatient psychiatric units memorize such a checklist and remain prepared to use it. In assessing the potential for violence, there is no time to look up the risk factors in a textbook—or even in a personal digital assistant.

The third tool is to develop observational awareness, mostly using a watchful eye for behaviors that signal impending violence. Patients signal violence initially through psychomotor agitation (pacing, repeatedly asking to see the doctor, slamming doors), followed typically by verbal threats (cursing, insulting staff), and then outright acts of aggression. Many authors have detailed the phases of escalation and the pre-violence behaviors that psychiatric staff should observe and document.^4-6

Table 2

THE 10 COMMANDMENTS OF DE-ESCALATION

I	You shall respect personal space
II	You shall not be provocative
III	You shall establish verbal contact
IV	You shall be concise and repeat yourself
V	You shall identify wants and feelings
VI	You shall listen
VII	You shall agree or agree to disagree
VIII	You shall lay down the law
IX	You shall offer choices
X	You shall debrief the patient and staff

Do you obey the ‘10 commandments?’

The psychiatric literature describes many methods of preventing and managing aggressive behavior. I find that each time I am involved with a potentially aggressive patient, the script changes. Each encounter with violent patients is idiosyncratic. So instead of using a flowchart, I have developed what I call the “10 commandments” of preventing and managing aggressive behaviors (Table 2). These rules can be used whenever needed, and mixed and matched as necessary, to de-escalate agitated patients.

You shall respect personal space When approaching an aggressive patient, I usually use the 2-times-arm-length rule, that is, twice your arm length or the sum of your arm length and your estimate of the patient’s arm length. That’s the distance I keep between me and the patient, which is generally accepted as non-threatening. If the patient is paranoid, you may want to increase your distance.

 

Similarly, maintaining your usual social eye contact is more tolerable to the agitated patient than consistently staring or averting your eye. Adirect gaze may be interpreted as aggressive behavior, while averting your eyes signals fear; either state may prompt the patient to become aggressive.

Always maintain an “escape route” for you and the patient. Do not make the patient feel he or she is trapped with no egress. If the patient feels you are too close and tells you to “get out of the way,” do so immediately.

You shall not be provocative A calm demeanor and facial expression are important. Be soft-spoken and do not allow an angry tone to slip into your voice. Imagine yourself with a patient you enjoy working with, and use that level of empathy and concern with the agitated patient. Use a relaxed stance with your knees bent, arms uncrossed, and your palms upward. As you may be tense or anxious, try to prevent yourself from balling your hands into fists. A fist, made even as your hands hang down at your sides, will be noticed by the patient.

Never threaten the patient. The sure way to lose control of the situation—and destroy your therapeutic alliance—is to use any form of coercion. Your initial therapeutic alliance with the patient is a critical factor in an effective de-escalation. The agitated patient should be involved in a fair, collaborative, and meaningful process that allows the patient self-expression.

You shall establish verbal contact Members of your clinical staff should resist the temptation to intervene individually. The first person to make contact should be the designated clinician to de-escalate the patient. If for any reason you do not feel capable of performing this duty, quickly identify which staff member will verbally engage the patient.

Table 3

CHECKLIST FOR ASSESSING VIOLENT TENDENCIES

	Questions	Yes	No
1.	Is the patient abusing alcohol or other substances?	○	○
2.	Is the patient demonstrating alcohol or other substance intoxication?	○	○
3.	Is the patient making threats to harm others?	○	○
4.	Has the patient ever committed violent acts with subsequent arrests or in conjunction with criminal activity?	○	○
5.	Was the patient physically abused as a child?	○	○
6.	Has the patient demonstrated recent acts of violence (including damage to property)?	○	○
7.	Has the patient recently brandished weapons, including objects that may be used as weapons (e.g., forks, rocks)?	○	○
8.	Does the patient have thoughts or fears of harming others? …with intent? …with current plan? …with means?	○ ○ ○ ○	○ ○ ○ ○
9.	Does the patient have command auditory hallucinations? …with specific instructions? …with response…with familiar voice?	○ ○ ○ ○	○ ○ ○ ○
10.	Is the patient clinically depressed with severe psychomotor agitation, suicidal ideation, panic attacks, or suicidal plan with urge to take family with him/her?	○	○
11.	Is the patient experiencing a paranoid delusion? …with planned violence toward the person as persecuting the patient? …with a hallucination-related delusion? …with history of acting on such a delusion? …which is systematized? …with accompanying intense anger or fear?	○ ○ ○ ○ ○ ○	○ ○ ○ ○ ○ ○
12.	Is the patient experiencing threat control override symptoms? …thought insertion? …delusion of being followed? …made feelings? …sensation of mind control by external force?	○ ○ ○ ○ ○	○ ○ ○ ○ ○
13.	Does the patient have a personality disorder with rage, violence, or impulse dyscontrol?	○	○
14.	Does the patient have one of the following risk factors: male, age 15-24, low socioeconomic status, few social supports, brain disease, frontal lobe syndrome?	○	○
15.	Does the patient display catatonic or manic excitement?	○	○
16.	Does the patient have more than one major Axis I diagnosis?	○	○

Learn the patient’s name and address him or her using the last name. Using the patient’s first name may be perceived as too personal or not genuine. Tell the patient who you are, and establish that your job is to keep the patient safe and to allow no harm to befall him or her.

If the patient is yelling and screaming, or perhaps has already broken a chair or hit the wall, offer additional reassurance that you want to help him or her regain control.

You shall be concise When making verbal contact, remember the adage that less is more. Use short phrases or sentences and a simple vocabulary. Wordiness will cause confusion.

Here is a common scenario: You can see outside the nursing station that a patient’s temper is rising. The patient is pacing and slamming his or her fists on a tabletop. You ask the psychiatry resident to go help the patient. Barely 30 seconds later, the resident informs you that the patient just “ignored” him or her.

Agitated patients, especially those with psychosis, should not be expected to hear you the first time. After all, how often do your own spouse, children, or close friends hear you the first time? I often find that I may have to repeat a simple phrase to a patient as many as a dozen times until I am understood. Repetition is essential whenever you set limits, offer choices, or propose alternatives.

 

You shall identify wants and feelings You’ve gotten the patient’s attention. Now it’s time to empathize and solidify the therapeutic alliance. Recognizing the patient’s wants and feelings becomes crucial at this point (Table 4).

Thus, if I find a patient banging his or her fists on the table and the walls, I approach the patient saying, “You seem angry…is there something you want that you’re not getting …and do you still really want it? Perhaps I can get it for you.” If a patient is crouched in the corner, looking as if he is going to strike out and run, I say, “You seem afraid …do you feel something terrible is going to happen to you? Can I help keep you safe?”

Once again, repeat these simple statements until the patient appears to relax, an indication that he or she thinks you understand what is wrong.

You shall listen Try to understand what the patient is saying—not what you think he or she is saying. I find it helpful to make sure that I have correctly understood by commenting, “Let me see if I understand you correctly.” This tells the patient you are listening accurately, and conveys further empathy.

Whatever you do, don’t argue with the patient. And if the patient insults you, don’t up the ante with a verbal retaliation.

You shall agree or agree to disagree Some believe that the most important part of de-escalation is the act of agreeing with the patient.

Agreeing with the patient without furthering a delusion or lying, however, is very difficult. For example, if an agitated patient asks if you believe aliens are torturing him or her, many of us would simply say, “no.” I would agree by telling the patient, “While I have not seen the aliens or seen you tortured, I believe that you are being tortured.” By so doing, I can diffuse the patient’s anger.

Agree for as long as you can with the patient’s experience. If you cannot go any further, you can always say, “We can agree to disagree.”

Table 4

Identifying thoughts and feelings for making empathic statements

Thought	Feeling
I want something I didn’t get it I still want it	Angry
I want something I didn’t get it I’ll never get it	Sad
I want to avoid something bad happening	Fearful
Adapted from: Bedell JR, Lennox SS. Handbook for Communication and Problem-Solving Skills Training: A Cognitive-Behavioral Approach. 2nd ed. New York: John Wiley &Sons, 1996.

You shall lay down the law Clarity in describing to the patient what is acceptable behavior is critical.

Be honest. It is OK to tell the patient that he is scaring you, other patients, or the staff. Tell the patient that injury to himself or herself, or to others, is unacceptable. Be prepared to be challenged repeatedly as you set firm limits. You may find it necessary to tell the patient that arrest and prosecution are possible if he or she assaults anyone.

Early in the de-escalation process, emphasize that there are consequences to the patient’s behavior. State both the positive and negative consequence of a behavior, then ensure that this statement is not perceived as a threat by asking the patient to make a choice.

You shall offer choices Choice is a powerful tool. For the patient who believes there is nothing left but fight or flight, being offered a choice, such as taking a time-out or a medication to decrease the anger, can be a welcome relief.

When an assault is imminent, do not expect the patient to engage in problem solving. Do not ask if they can name a behavior other than assaulting the staff that promises a better outcome. Be assertive. Quickly propose the possible alternatives to violence.

You shall debrief the patient Despite your best efforts, some patients will still end up in seclusion or restraints after their emotions escalate. Some may require emergency intramuscular medications. I recommend that the psychiatrist who wrote the order for seclusion, restraint, or emergency medications take the time to debrief the patient after the episode is over and the patient is calm. The benefits of debriefing include restoring a therapeutic relationship, diminishing the traumatic nature of such events as emergency intramuscular injections, and decreasing the risk of additional violent events.

Find a quiet location and begin by explaining why the intervention was necessary. Let the patient explain the events from his or her perspective. Then it is time for some problem solving in which you and the patient explore alternatives should he or she get angry again. Teach the patient how to request quiet time and how to recognize the early warning signs of impending violence. Let the patient know it is safe to approach the staff early and express anger while making a request for what he or she wants. You can also explain the role of medications in preventing violent acts.

 

Don’t forget to debrief the staff as well. Takedowns, restraints, and seclusion can be traumatic for staff members, especially if there is an assault with injuries.

Just as internists learn advanced cardiac life support and run cardiac codes, psychiatrists can be responsible for directing behavioral codes when episodes of agitation and aggressive behavior occur, using verbal interventions to de-escalate patients. You will soon find yourself ordering fewer restraints, seclusions, and intramuscular medications.

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.

Are you at risk of being assaulted?

Most psychiatrists do not arm themselves with the bare essentials of self-protection. Consider these questions:

• Have you attended one of the available training institutes, such as the Crisis Prevention Institute (CPI)¹ or Management of Aggressive Behavior (MOAB)², or a state-sponsored program such as Prevention and Management of Aggressive Behavior (PMAB), offered by the Texas Department of Mental Health and Mental Retardation?³
  
• Have you developed a safety plan, especially in your practice? Examples of such plans include placement of furniture for easy exit if attacked, panic buttons that call or alert security services, and even video surveillance.
  
• Have you reported “minor” assaults by patients? Acts of violence in psychiatric settings are rarely discussed and dramatically underreported. Psychiatrists often go into denial when assaulted, rather than being motivated to get the appropriate training to manage future patient aggression episodes.
  
• Do you focus on pharmacotherapy as the first line of aggressive behavior management instead of methods of protection and de-escalation?
  

All too often, psychiatric residency training simply pays “lip service” to de-escalation of the violent patient, instead overemphasizing the pharmacology of behavioral emergencies. This has left many psychiatrists unprepared in an era where mental health advocacy groups, ethicists, and attorneys are applying pressure on us to find new ways to avoid seclusion, restraint, and intramuscular medication for psychiatric emergencies.

Let’s look at how to assess a patient’s potential for violence, as well as nonpharmacologic interventions you can use to keep you and your staff safe and prevent aggressive behaviors from escalating.

Three strategies for assessing violence

You can start to protect yourself against violent attacks by using a 3-part strategy that involves knowing the DSM-IV diagnoses associated with violence, using a checklist to gauge a patient’s potential for violence, and developing an observational awareness to quickly recognize the warning signs of an imminent violent act.

Table 1

DSM-IV DIAGNOSES ASSOCIATED WITH VIOLENCE OR AGGRESSION

Attention-deficit/hyperactivity disorder Bipolar I disorder, manic Conduct disorder Delirium Dementia Intermittent explosive disorder Mental retardation Mood disorder due to a general medical condition Personality change due to a general medical condition	Personality disorder Paranoid Antisocial Borderline Narcissistic Posttraumatic stress disorder Premenstrual dysphoric disorder Schizophrenia Sexual sadism Substance abuse and withdrawal Substance-induced mood disorder

How quickly can you recognize the DSM-IV diagnoses associated with aggression and violence (Table 1)? Here are some clues to fast action:

1. Rule out a medical or substance-induced etiology for the presenting symptoms. Intoxication with alcohol, amphetamines, cocaine, phencyclidine, and sedative-hypnotics is associated with violence. Withdrawal from benzodiazepines or alcohol may also lead to aggression.
   
2. Rule out delirium.
   
3. Among the many organic causes of violence and aggression, pay careful attention to the usual intracranial suspects including infection, stroke, trauma, autoimmune syndromes, neoplasm, and encephalopathy.
   
4. Rule out metabolic abnormalities, including thyrotoxicosis, hypoxemia, and endocrinopathy.
   
5. Violence in temporal lobe epilepsy may occur in the ictal, interictal, or postictal periods.
   

The second tool in violence assessment is a checklist (Table 3) that covers a range of risk factors including symptoms, demographics, and predisposing historical factors. I recommend that all clinicians preparing for work in emergency rooms or inpatient psychiatric units memorize such a checklist and remain prepared to use it. In assessing the potential for violence, there is no time to look up the risk factors in a textbook—or even in a personal digital assistant.

The third tool is to develop observational awareness, mostly using a watchful eye for behaviors that signal impending violence. Patients signal violence initially through psychomotor agitation (pacing, repeatedly asking to see the doctor, slamming doors), followed typically by verbal threats (cursing, insulting staff), and then outright acts of aggression. Many authors have detailed the phases of escalation and the pre-violence behaviors that psychiatric staff should observe and document.^4-6

Table 2

THE 10 COMMANDMENTS OF DE-ESCALATION

I	You shall respect personal space
II	You shall not be provocative
III	You shall establish verbal contact
IV	You shall be concise and repeat yourself
V	You shall identify wants and feelings
VI	You shall listen
VII	You shall agree or agree to disagree
VIII	You shall lay down the law
IX	You shall offer choices
X	You shall debrief the patient and staff

Do you obey the ‘10 commandments?’

The psychiatric literature describes many methods of preventing and managing aggressive behavior. I find that each time I am involved with a potentially aggressive patient, the script changes. Each encounter with violent patients is idiosyncratic. So instead of using a flowchart, I have developed what I call the “10 commandments” of preventing and managing aggressive behaviors (Table 2). These rules can be used whenever needed, and mixed and matched as necessary, to de-escalate agitated patients.

You shall respect personal space When approaching an aggressive patient, I usually use the 2-times-arm-length rule, that is, twice your arm length or the sum of your arm length and your estimate of the patient’s arm length. That’s the distance I keep between me and the patient, which is generally accepted as non-threatening. If the patient is paranoid, you may want to increase your distance.

 

Similarly, maintaining your usual social eye contact is more tolerable to the agitated patient than consistently staring or averting your eye. Adirect gaze may be interpreted as aggressive behavior, while averting your eyes signals fear; either state may prompt the patient to become aggressive.

Always maintain an “escape route” for you and the patient. Do not make the patient feel he or she is trapped with no egress. If the patient feels you are too close and tells you to “get out of the way,” do so immediately.

You shall not be provocative A calm demeanor and facial expression are important. Be soft-spoken and do not allow an angry tone to slip into your voice. Imagine yourself with a patient you enjoy working with, and use that level of empathy and concern with the agitated patient. Use a relaxed stance with your knees bent, arms uncrossed, and your palms upward. As you may be tense or anxious, try to prevent yourself from balling your hands into fists. A fist, made even as your hands hang down at your sides, will be noticed by the patient.

Never threaten the patient. The sure way to lose control of the situation—and destroy your therapeutic alliance—is to use any form of coercion. Your initial therapeutic alliance with the patient is a critical factor in an effective de-escalation. The agitated patient should be involved in a fair, collaborative, and meaningful process that allows the patient self-expression.

You shall establish verbal contact Members of your clinical staff should resist the temptation to intervene individually. The first person to make contact should be the designated clinician to de-escalate the patient. If for any reason you do not feel capable of performing this duty, quickly identify which staff member will verbally engage the patient.

Table 3

CHECKLIST FOR ASSESSING VIOLENT TENDENCIES

	Questions	Yes	No
1.	Is the patient abusing alcohol or other substances?	○	○
2.	Is the patient demonstrating alcohol or other substance intoxication?	○	○
3.	Is the patient making threats to harm others?	○	○
4.	Has the patient ever committed violent acts with subsequent arrests or in conjunction with criminal activity?	○	○
5.	Was the patient physically abused as a child?	○	○
6.	Has the patient demonstrated recent acts of violence (including damage to property)?	○	○
7.	Has the patient recently brandished weapons, including objects that may be used as weapons (e.g., forks, rocks)?	○	○
8.	Does the patient have thoughts or fears of harming others? …with intent? …with current plan? …with means?	○ ○ ○ ○	○ ○ ○ ○
9.	Does the patient have command auditory hallucinations? …with specific instructions? …with response…with familiar voice?	○ ○ ○ ○	○ ○ ○ ○
10.	Is the patient clinically depressed with severe psychomotor agitation, suicidal ideation, panic attacks, or suicidal plan with urge to take family with him/her?	○	○
11.	Is the patient experiencing a paranoid delusion? …with planned violence toward the person as persecuting the patient? …with a hallucination-related delusion? …with history of acting on such a delusion? …which is systematized? …with accompanying intense anger or fear?	○ ○ ○ ○ ○ ○	○ ○ ○ ○ ○ ○
12.	Is the patient experiencing threat control override symptoms? …thought insertion? …delusion of being followed? …made feelings? …sensation of mind control by external force?	○ ○ ○ ○ ○	○ ○ ○ ○ ○
13.	Does the patient have a personality disorder with rage, violence, or impulse dyscontrol?	○	○
14.	Does the patient have one of the following risk factors: male, age 15-24, low socioeconomic status, few social supports, brain disease, frontal lobe syndrome?	○	○
15.	Does the patient display catatonic or manic excitement?	○	○
16.	Does the patient have more than one major Axis I diagnosis?	○	○

Learn the patient’s name and address him or her using the last name. Using the patient’s first name may be perceived as too personal or not genuine. Tell the patient who you are, and establish that your job is to keep the patient safe and to allow no harm to befall him or her.

If the patient is yelling and screaming, or perhaps has already broken a chair or hit the wall, offer additional reassurance that you want to help him or her regain control.

You shall be concise When making verbal contact, remember the adage that less is more. Use short phrases or sentences and a simple vocabulary. Wordiness will cause confusion.

Here is a common scenario: You can see outside the nursing station that a patient’s temper is rising. The patient is pacing and slamming his or her fists on a tabletop. You ask the psychiatry resident to go help the patient. Barely 30 seconds later, the resident informs you that the patient just “ignored” him or her.

Agitated patients, especially those with psychosis, should not be expected to hear you the first time. After all, how often do your own spouse, children, or close friends hear you the first time? I often find that I may have to repeat a simple phrase to a patient as many as a dozen times until I am understood. Repetition is essential whenever you set limits, offer choices, or propose alternatives.

 

You shall identify wants and feelings You’ve gotten the patient’s attention. Now it’s time to empathize and solidify the therapeutic alliance. Recognizing the patient’s wants and feelings becomes crucial at this point (Table 4).

Thus, if I find a patient banging his or her fists on the table and the walls, I approach the patient saying, “You seem angry…is there something you want that you’re not getting …and do you still really want it? Perhaps I can get it for you.” If a patient is crouched in the corner, looking as if he is going to strike out and run, I say, “You seem afraid …do you feel something terrible is going to happen to you? Can I help keep you safe?”

Once again, repeat these simple statements until the patient appears to relax, an indication that he or she thinks you understand what is wrong.

You shall listen Try to understand what the patient is saying—not what you think he or she is saying. I find it helpful to make sure that I have correctly understood by commenting, “Let me see if I understand you correctly.” This tells the patient you are listening accurately, and conveys further empathy.

Whatever you do, don’t argue with the patient. And if the patient insults you, don’t up the ante with a verbal retaliation.

You shall agree or agree to disagree Some believe that the most important part of de-escalation is the act of agreeing with the patient.

Agreeing with the patient without furthering a delusion or lying, however, is very difficult. For example, if an agitated patient asks if you believe aliens are torturing him or her, many of us would simply say, “no.” I would agree by telling the patient, “While I have not seen the aliens or seen you tortured, I believe that you are being tortured.” By so doing, I can diffuse the patient’s anger.

Agree for as long as you can with the patient’s experience. If you cannot go any further, you can always say, “We can agree to disagree.”

Table 4

Identifying thoughts and feelings for making empathic statements

Thought	Feeling
I want something I didn’t get it I still want it	Angry
I want something I didn’t get it I’ll never get it	Sad
I want to avoid something bad happening	Fearful
Adapted from: Bedell JR, Lennox SS. Handbook for Communication and Problem-Solving Skills Training: A Cognitive-Behavioral Approach. 2nd ed. New York: John Wiley &Sons, 1996.

You shall lay down the law Clarity in describing to the patient what is acceptable behavior is critical.

Be honest. It is OK to tell the patient that he is scaring you, other patients, or the staff. Tell the patient that injury to himself or herself, or to others, is unacceptable. Be prepared to be challenged repeatedly as you set firm limits. You may find it necessary to tell the patient that arrest and prosecution are possible if he or she assaults anyone.

Early in the de-escalation process, emphasize that there are consequences to the patient’s behavior. State both the positive and negative consequence of a behavior, then ensure that this statement is not perceived as a threat by asking the patient to make a choice.

You shall offer choices Choice is a powerful tool. For the patient who believes there is nothing left but fight or flight, being offered a choice, such as taking a time-out or a medication to decrease the anger, can be a welcome relief.

When an assault is imminent, do not expect the patient to engage in problem solving. Do not ask if they can name a behavior other than assaulting the staff that promises a better outcome. Be assertive. Quickly propose the possible alternatives to violence.

You shall debrief the patient Despite your best efforts, some patients will still end up in seclusion or restraints after their emotions escalate. Some may require emergency intramuscular medications. I recommend that the psychiatrist who wrote the order for seclusion, restraint, or emergency medications take the time to debrief the patient after the episode is over and the patient is calm. The benefits of debriefing include restoring a therapeutic relationship, diminishing the traumatic nature of such events as emergency intramuscular injections, and decreasing the risk of additional violent events.

Find a quiet location and begin by explaining why the intervention was necessary. Let the patient explain the events from his or her perspective. Then it is time for some problem solving in which you and the patient explore alternatives should he or she get angry again. Teach the patient how to request quiet time and how to recognize the early warning signs of impending violence. Let the patient know it is safe to approach the staff early and express anger while making a request for what he or she wants. You can also explain the role of medications in preventing violent acts.

 

Don’t forget to debrief the staff as well. Takedowns, restraints, and seclusion can be traumatic for staff members, especially if there is an assault with injuries.

Just as internists learn advanced cardiac life support and run cardiac codes, psychiatrists can be responsible for directing behavioral codes when episodes of agitation and aggressive behavior occur, using verbal interventions to de-escalate patients. You will soon find yourself ordering fewer restraints, seclusions, and intramuscular medications.

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.

Are you at risk of being assaulted?

Most psychiatrists do not arm themselves with the bare essentials of self-protection. Consider these questions:

• Have you attended one of the available training institutes, such as the Crisis Prevention Institute (CPI)¹ or Management of Aggressive Behavior (MOAB)², or a state-sponsored program such as Prevention and Management of Aggressive Behavior (PMAB), offered by the Texas Department of Mental Health and Mental Retardation?³
  
• Have you developed a safety plan, especially in your practice? Examples of such plans include placement of furniture for easy exit if attacked, panic buttons that call or alert security services, and even video surveillance.
  
• Have you reported “minor” assaults by patients? Acts of violence in psychiatric settings are rarely discussed and dramatically underreported. Psychiatrists often go into denial when assaulted, rather than being motivated to get the appropriate training to manage future patient aggression episodes.
  
• Do you focus on pharmacotherapy as the first line of aggressive behavior management instead of methods of protection and de-escalation?
  

All too often, psychiatric residency training simply pays “lip service” to de-escalation of the violent patient, instead overemphasizing the pharmacology of behavioral emergencies. This has left many psychiatrists unprepared in an era where mental health advocacy groups, ethicists, and attorneys are applying pressure on us to find new ways to avoid seclusion, restraint, and intramuscular medication for psychiatric emergencies.

Let’s look at how to assess a patient’s potential for violence, as well as nonpharmacologic interventions you can use to keep you and your staff safe and prevent aggressive behaviors from escalating.

Three strategies for assessing violence

You can start to protect yourself against violent attacks by using a 3-part strategy that involves knowing the DSM-IV diagnoses associated with violence, using a checklist to gauge a patient’s potential for violence, and developing an observational awareness to quickly recognize the warning signs of an imminent violent act.

Table 1

DSM-IV DIAGNOSES ASSOCIATED WITH VIOLENCE OR AGGRESSION

Attention-deficit/hyperactivity disorder Bipolar I disorder, manic Conduct disorder Delirium Dementia Intermittent explosive disorder Mental retardation Mood disorder due to a general medical condition Personality change due to a general medical condition	Personality disorder Paranoid Antisocial Borderline Narcissistic Posttraumatic stress disorder Premenstrual dysphoric disorder Schizophrenia Sexual sadism Substance abuse and withdrawal Substance-induced mood disorder

How quickly can you recognize the DSM-IV diagnoses associated with aggression and violence (Table 1)? Here are some clues to fast action:

1. Rule out a medical or substance-induced etiology for the presenting symptoms. Intoxication with alcohol, amphetamines, cocaine, phencyclidine, and sedative-hypnotics is associated with violence. Withdrawal from benzodiazepines or alcohol may also lead to aggression.
   
2. Rule out delirium.
   
3. Among the many organic causes of violence and aggression, pay careful attention to the usual intracranial suspects including infection, stroke, trauma, autoimmune syndromes, neoplasm, and encephalopathy.
   
4. Rule out metabolic abnormalities, including thyrotoxicosis, hypoxemia, and endocrinopathy.
   
5. Violence in temporal lobe epilepsy may occur in the ictal, interictal, or postictal periods.
   

The second tool in violence assessment is a checklist (Table 3) that covers a range of risk factors including symptoms, demographics, and predisposing historical factors. I recommend that all clinicians preparing for work in emergency rooms or inpatient psychiatric units memorize such a checklist and remain prepared to use it. In assessing the potential for violence, there is no time to look up the risk factors in a textbook—or even in a personal digital assistant.

The third tool is to develop observational awareness, mostly using a watchful eye for behaviors that signal impending violence. Patients signal violence initially through psychomotor agitation (pacing, repeatedly asking to see the doctor, slamming doors), followed typically by verbal threats (cursing, insulting staff), and then outright acts of aggression. Many authors have detailed the phases of escalation and the pre-violence behaviors that psychiatric staff should observe and document.^4-6

Table 2

THE 10 COMMANDMENTS OF DE-ESCALATION

I	You shall respect personal space
II	You shall not be provocative
III	You shall establish verbal contact
IV	You shall be concise and repeat yourself
V	You shall identify wants and feelings
VI	You shall listen
VII	You shall agree or agree to disagree
VIII	You shall lay down the law
IX	You shall offer choices
X	You shall debrief the patient and staff

Do you obey the ‘10 commandments?’

The psychiatric literature describes many methods of preventing and managing aggressive behavior. I find that each time I am involved with a potentially aggressive patient, the script changes. Each encounter with violent patients is idiosyncratic. So instead of using a flowchart, I have developed what I call the “10 commandments” of preventing and managing aggressive behaviors (Table 2). These rules can be used whenever needed, and mixed and matched as necessary, to de-escalate agitated patients.

You shall respect personal space When approaching an aggressive patient, I usually use the 2-times-arm-length rule, that is, twice your arm length or the sum of your arm length and your estimate of the patient’s arm length. That’s the distance I keep between me and the patient, which is generally accepted as non-threatening. If the patient is paranoid, you may want to increase your distance.

 

Similarly, maintaining your usual social eye contact is more tolerable to the agitated patient than consistently staring or averting your eye. Adirect gaze may be interpreted as aggressive behavior, while averting your eyes signals fear; either state may prompt the patient to become aggressive.

Always maintain an “escape route” for you and the patient. Do not make the patient feel he or she is trapped with no egress. If the patient feels you are too close and tells you to “get out of the way,” do so immediately.

You shall not be provocative A calm demeanor and facial expression are important. Be soft-spoken and do not allow an angry tone to slip into your voice. Imagine yourself with a patient you enjoy working with, and use that level of empathy and concern with the agitated patient. Use a relaxed stance with your knees bent, arms uncrossed, and your palms upward. As you may be tense or anxious, try to prevent yourself from balling your hands into fists. A fist, made even as your hands hang down at your sides, will be noticed by the patient.

Never threaten the patient. The sure way to lose control of the situation—and destroy your therapeutic alliance—is to use any form of coercion. Your initial therapeutic alliance with the patient is a critical factor in an effective de-escalation. The agitated patient should be involved in a fair, collaborative, and meaningful process that allows the patient self-expression.

You shall establish verbal contact Members of your clinical staff should resist the temptation to intervene individually. The first person to make contact should be the designated clinician to de-escalate the patient. If for any reason you do not feel capable of performing this duty, quickly identify which staff member will verbally engage the patient.

Table 3

CHECKLIST FOR ASSESSING VIOLENT TENDENCIES

	Questions	Yes	No
1.	Is the patient abusing alcohol or other substances?	○	○
2.	Is the patient demonstrating alcohol or other substance intoxication?	○	○
3.	Is the patient making threats to harm others?	○	○
4.	Has the patient ever committed violent acts with subsequent arrests or in conjunction with criminal activity?	○	○
5.	Was the patient physically abused as a child?	○	○
6.	Has the patient demonstrated recent acts of violence (including damage to property)?	○	○
7.	Has the patient recently brandished weapons, including objects that may be used as weapons (e.g., forks, rocks)?	○	○
8.	Does the patient have thoughts or fears of harming others? …with intent? …with current plan? …with means?	○ ○ ○ ○	○ ○ ○ ○
9.	Does the patient have command auditory hallucinations? …with specific instructions? …with response…with familiar voice?	○ ○ ○ ○	○ ○ ○ ○
10.	Is the patient clinically depressed with severe psychomotor agitation, suicidal ideation, panic attacks, or suicidal plan with urge to take family with him/her?	○	○
11.	Is the patient experiencing a paranoid delusion? …with planned violence toward the person as persecuting the patient? …with a hallucination-related delusion? …with history of acting on such a delusion? …which is systematized? …with accompanying intense anger or fear?	○ ○ ○ ○ ○ ○	○ ○ ○ ○ ○ ○
12.	Is the patient experiencing threat control override symptoms? …thought insertion? …delusion of being followed? …made feelings? …sensation of mind control by external force?	○ ○ ○ ○ ○	○ ○ ○ ○ ○
13.	Does the patient have a personality disorder with rage, violence, or impulse dyscontrol?	○	○
14.	Does the patient have one of the following risk factors: male, age 15-24, low socioeconomic status, few social supports, brain disease, frontal lobe syndrome?	○	○
15.	Does the patient display catatonic or manic excitement?	○	○
16.	Does the patient have more than one major Axis I diagnosis?	○	○

Learn the patient’s name and address him or her using the last name. Using the patient’s first name may be perceived as too personal or not genuine. Tell the patient who you are, and establish that your job is to keep the patient safe and to allow no harm to befall him or her.

If the patient is yelling and screaming, or perhaps has already broken a chair or hit the wall, offer additional reassurance that you want to help him or her regain control.

You shall be concise When making verbal contact, remember the adage that less is more. Use short phrases or sentences and a simple vocabulary. Wordiness will cause confusion.

Here is a common scenario: You can see outside the nursing station that a patient’s temper is rising. The patient is pacing and slamming his or her fists on a tabletop. You ask the psychiatry resident to go help the patient. Barely 30 seconds later, the resident informs you that the patient just “ignored” him or her.

Agitated patients, especially those with psychosis, should not be expected to hear you the first time. After all, how often do your own spouse, children, or close friends hear you the first time? I often find that I may have to repeat a simple phrase to a patient as many as a dozen times until I am understood. Repetition is essential whenever you set limits, offer choices, or propose alternatives.

 

You shall identify wants and feelings You’ve gotten the patient’s attention. Now it’s time to empathize and solidify the therapeutic alliance. Recognizing the patient’s wants and feelings becomes crucial at this point (Table 4).

Thus, if I find a patient banging his or her fists on the table and the walls, I approach the patient saying, “You seem angry…is there something you want that you’re not getting …and do you still really want it? Perhaps I can get it for you.” If a patient is crouched in the corner, looking as if he is going to strike out and run, I say, “You seem afraid …do you feel something terrible is going to happen to you? Can I help keep you safe?”

Once again, repeat these simple statements until the patient appears to relax, an indication that he or she thinks you understand what is wrong.

You shall listen Try to understand what the patient is saying—not what you think he or she is saying. I find it helpful to make sure that I have correctly understood by commenting, “Let me see if I understand you correctly.” This tells the patient you are listening accurately, and conveys further empathy.

Whatever you do, don’t argue with the patient. And if the patient insults you, don’t up the ante with a verbal retaliation.

You shall agree or agree to disagree Some believe that the most important part of de-escalation is the act of agreeing with the patient.

Agreeing with the patient without furthering a delusion or lying, however, is very difficult. For example, if an agitated patient asks if you believe aliens are torturing him or her, many of us would simply say, “no.” I would agree by telling the patient, “While I have not seen the aliens or seen you tortured, I believe that you are being tortured.” By so doing, I can diffuse the patient’s anger.

Agree for as long as you can with the patient’s experience. If you cannot go any further, you can always say, “We can agree to disagree.”

Table 4

Identifying thoughts and feelings for making empathic statements

Thought	Feeling
I want something I didn’t get it I still want it	Angry
I want something I didn’t get it I’ll never get it	Sad
I want to avoid something bad happening	Fearful
Adapted from: Bedell JR, Lennox SS. Handbook for Communication and Problem-Solving Skills Training: A Cognitive-Behavioral Approach. 2nd ed. New York: John Wiley &Sons, 1996.

You shall lay down the law Clarity in describing to the patient what is acceptable behavior is critical.

Be honest. It is OK to tell the patient that he is scaring you, other patients, or the staff. Tell the patient that injury to himself or herself, or to others, is unacceptable. Be prepared to be challenged repeatedly as you set firm limits. You may find it necessary to tell the patient that arrest and prosecution are possible if he or she assaults anyone.

Early in the de-escalation process, emphasize that there are consequences to the patient’s behavior. State both the positive and negative consequence of a behavior, then ensure that this statement is not perceived as a threat by asking the patient to make a choice.

You shall offer choices Choice is a powerful tool. For the patient who believes there is nothing left but fight or flight, being offered a choice, such as taking a time-out or a medication to decrease the anger, can be a welcome relief.

When an assault is imminent, do not expect the patient to engage in problem solving. Do not ask if they can name a behavior other than assaulting the staff that promises a better outcome. Be assertive. Quickly propose the possible alternatives to violence.

You shall debrief the patient Despite your best efforts, some patients will still end up in seclusion or restraints after their emotions escalate. Some may require emergency intramuscular medications. I recommend that the psychiatrist who wrote the order for seclusion, restraint, or emergency medications take the time to debrief the patient after the episode is over and the patient is calm. The benefits of debriefing include restoring a therapeutic relationship, diminishing the traumatic nature of such events as emergency intramuscular injections, and decreasing the risk of additional violent events.

Find a quiet location and begin by explaining why the intervention was necessary. Let the patient explain the events from his or her perspective. Then it is time for some problem solving in which you and the patient explore alternatives should he or she get angry again. Teach the patient how to request quiet time and how to recognize the early warning signs of impending violence. Let the patient know it is safe to approach the staff early and express anger while making a request for what he or she wants. You can also explain the role of medications in preventing violent acts.

 

Don’t forget to debrief the staff as well. Takedowns, restraints, and seclusion can be traumatic for staff members, especially if there is an assault with injuries.

Just as internists learn advanced cardiac life support and run cardiac codes, psychiatrists can be responsible for directing behavioral codes when episodes of agitation and aggressive behavior occur, using verbal interventions to de-escalate patients. You will soon find yourself ordering fewer restraints, seclusions, and intramuscular medications.

Disclosure

The author reports no financial relationship with any company whose products are mentioned in this article.

What are we trying to accomplish in the maintenance treatment of patients with bipolar disorder? Given that the disorder recurs in more than 90% of patients who experience a manic episode,¹ there are 5 important goals:

1. Prevention of recurrent episodes;
2. Amelioration of subsyndromal symptoms;
3. Reduction of suicide risk;
4. Compliance enhancement;
5. Optimization of interpersonal, social, and vocational functioning.

There is a great premium on preventing mood episode recurrence in patients with bipolar disorder. Mood episodes themselves produce substantial morbidity, but morbidity is not confined to these episodes alone. Full recovery of functioning often lags many months behind remission of symptoms.² Recurrent mood episodes also may lead to progressive loss of function between episodes. Mood episodes also carry risks of mortality from suicide, violence, and impulsive risk taking.

Clearly, mood-stabilizing medications form the cornerstone of maintenance treatment,^3,4 along with a strong therapeutic alliance between patient and clinician and targeted psychosocial therapies. In the Expert Consensus Guidelines for medication treatment of bipolar I disorder, maintenance treatment was recommended for 1 year following an initial manic or mixed episode; longer (indefinite) treatment was recommended for patients with a family history of bipolar disorder or if 2 episodes occurred.³

Compared with clinical trials of agents for acute bipolar mania (and mixed episodes), there are relatively few randomized controlled trials of medications for the maintenance phase of bipolar disorder. Some naturalistic studies have provided data on relapse rates associated with treatment with a variety of different agents. Even fewer studies have examined psychosocial interventions designed specifically to reduce relapse rates.

But new data are beginning to emerge regarding the efficacy of divalproex, lamotrigine, and olanzapine as maintenance therapies. A number of clinical predictors of response to these agents have begun to be identified, as well as to lithium and carbamazepine. Eliciting these characteristics is important when making recommendations to patients about available drug therapies.

In addition, effective maintenance treatment often requires combinations of mood-stabilizing, antidepressant, and antipsychotic agents to control or eliminate subsyndromal and breakthrough symptoms.

In this review, we will cover the available new data on pharmacologic maintenance treatments of bipolar disorder and their clinical implications.

What the studies show

Lithium has been the mainstay of therapy for bipolar disorder for more than 35 years. Most randomized, controlled trials of lithium maintenance therapy were conducted in the 1960s and 1970s⁵ (Table 1). Unfortunately, these studies had several design limitations that inflated the expectations of lithium’s efficacy as a maintenance treatment.⁶ These included discontinuation designs in which patients stabilized on lithium were abruptly switched to placebo; exaggerated early placebo relapse rates; enrollment of both unipolar and bipolar patients; lack of specific diagnostic criteria; and reported results only for patients completing studies. Pooled data from these trials indicated that lithium reduced the risk of relapse fourfold compared with placebo at 6 months and 1 year.⁵

Two contemporary randomized, placebo-controlled maintenance studies utilizing more rigorous designs provided further evidence of lithium’s superiority over placebo in extending time to manic relapse.^7,8 Both studies enrolled patients who were currently or had recently been manic and had been stabilized in open-label treatment that included study medications.

In the first study, comparing 1-year relapse rates among patients randomized to lithium, divalproex, or placebo, lithium extended time to recurrence of mania by 55% compared with placebo.⁷ In the second, an 18-month trial comparing lithium, lamotrigine, and placebo, lithium significantly increased the time to intervention for recurrence of mania compared with placebo.⁸ The overall manic relapse rates were 17% for lithium-treated patients and 41% for those on placebo. However, lithium did not significantly extend time to depressive relapse or intervention for depressive relapse, respectively, in either study. Moreover, in the first study, patients who received lithium tended to have greater subthreshold depressive symptoms.⁸

Table 1

What works in maintenance treatment of bipolar disorder (ranked by number of randomized, controlled trials)

Medication RCTs (n)	Trial results	Strong evidence	Some evidence
Lithium (15)	Equal to divalproex and lamotrigine; equal to or better than carbamazepine; better than placebo	4-fold reduction of relapse risk vs. placebo at 6, 12 months; more efficacious in mania than in depression; higher lithium level correlated with lower relapse rates, but more side effects
Carbamazepine (7)	No significant benefit vs. lithium; better than placebo		May be more efficacious in mania than in depression; may be less tolerable than lithium; no data on serum levels
Divalproex (4)	Equal to lithium and olanzapine; better than placebo		May be more efficacious in mania than in depression; may be more tolerable than lithium; data on serum levels pending
Lamotrigine (2)	Better than placebo	More efficacious in depression than in mania	Dosage 200-400 mg/d
Olanzapine (1)	Equal to divalproex		Data on dosage and differential efficacy related to dosage pending
Clozapine (1)	Better than treatment as usual	Efficacy in treatment-resistant mania (bipolar schizoaffective disorder, bipolar type)

 

These findings were consistent with earlier placebo-controlled studies of lithium maintenance treatment and a recent crossover comparison trial with carbamazepine.⁹ Lithium was also recently compared with carbamazepine in a 2.5-year maintenance multisite study in Europe.¹⁰ There was no significant difference in efficacy between the two in time to hospitalization, the primary outcome measure. On other outcome measures, including time to relapse or need for additional medication, lithium was superior to carbamazepine.

Pooled results from a number of naturalistic studies, which mirror clinical practice, indicated that approximately one-third of patients maintained on lithium had good functional outcomes without relapses and only minimal symptoms.¹¹ In general, these studies found higher rates of relapse with longer durations of follow-up.

Valproate maintenance treatment has been studied in two randomized, controlled trials (one vs. placebo,⁷ and one vs. olanzapine¹²) and two open-label comparison studies against lithium.^13,14 In the placebo-controlled trial, which also included a lithium comparison group described earlier, there was no significant difference in the time to development of any mood episode among the three treatment groups.⁷ However, divalproex was superior to placebo on a number of other outcome measures, including rate of study termination for any mood episode, termination for depression, and termination for noncompliance.

Divalproex was superior to placebo in patients who received divalproex in the open-label treatment phase before randomization. This is clinically relevant, as this group reflects expected relapse rates in patients treated initially with divalproex for acute mania who then remain on the drug for maintenance therapy. Patients receiving divalproex had significantly lower rates of intolerance and noncompliance compared to those treated with lithium.

In the second comparison study, 167 patients initially randomized and responding to divalproex or olanzapine in a 3-week acute bipolar mania trial continued in a double-blind 44-week extension study.¹² There were no significant differences in relapse into mania between the two groups (olanzapine 41%, divalproex 50%, p = 0.4) or time to manic relapse (olanzapine 270 days, divalproex 74 days, p = 0.4). There was no significant difference in tolerability between the two.

Two open-label studies compared valproate with lithium. In an 18-month study conducted in France, patients randomized to the valpromide formulation of valproate displayed a 20% lower relapse rate than those receiving lithium.¹³ The second open-label comparison trial found comparable efficacy between lithium and divalproex in a 1-year naturalistic pharmacoeconomic study that allowed additional medications as needed for recurrent symptoms.¹⁴

Carbamazepine has been evaluated in a limited number of studies for maintenance treatment of bipolar disorder. The results of many early randomized, controlled maintenance trials were criticized on methodologic grounds.¹⁵ But two recent comparison trials with lithium, as noted earlier, provided clinically important data regarding carbamazepine’s prophylactic efficacy.^9,10 Several additional clinically relevant observations emerged from analyses of secondary outcome measures in these two trials.

In the first study, 52 patients with bipolar I or II disorder received lithium or carbamazepine for 1 year, crossed over to the alternate drug the second year, and received both drugs the third year.⁹ There was little difference in relapse rates during the first year between the lithium (31%) and carbamazepine (37%) groups. Similarly, in the overall trial, there was little difference in the percentage of patients who were rated as having a moderate or better response—33% on lithium, 31% on carbamazepine, and 55% on the combination. A higher proportion of patients receiving carbamazepine withdrew due to side effects. In the second trial, significantly more patients receiving carbamazepine required additional medications for breakthrough symptoms and experienced side effects requiring treatment discontinuation.¹⁰

Lamotrigine has been studied in two placebo-controlled, randomized maintenance studies in patients with bipolar disorder.^8,16 The first evaluated bipolar I patients who had experienced a manic or hypomanic episode within 60 days of entry into an open-label treatment phase with lamotrigine.⁸ Patients who, in turn, improved or remained stable during the open-label treatment phase were then randomized to treatment with lamotrigine 200-400 mg/d, lithium, or placebo for up to 18 months. Both lamotrigine and lithium were superior to placebo on the primary outcome measure, which was time to need for additional medication for a mood episode. The median time until 25% of patients relapsed was 72 weeks for lamotrigine, 58 weeks for lithium, and 35 weeks for placebo.

Table 2

PUTATIVE PREDICTORS OF RESPONSE TO MAINTENANCE MEDICATIONS

Medication	Predictor of response	Strength of evidence
Lithium	Nonrap id cycling Few episodes Few depressive symptoms Family history bipolar disorder Episode sequence M-D-I No substance/alcohol use disorder	◊◊◊ ◊ ◊ ◊ ◊ ◊
Divalproex	Equal efficacy in rapid & non-rapid cycling, manic & mixed, No personality disorder	◊ ◊
Carbamazepine	Equal efficacy in rapid & non-rapid cycling, manic & mixed Mood-incongruent symptoms	◊◊ ◊
Lamotrigine	Bipolar II > bipolar I Depression > mania	◊ ◊◊
Olanzapine	Equal efficacy in rapid & non-rapid cycling, manic & mixed, psychotic & nonpsychotic mania in acute studies; data pending in maintenance	◊
Clozapine	Efficacy in treatment-resistant mania rapid & nonrapid cycling, manic & mixed, psychotic & nonpsychotic in naturalistic studies	◊◊◊
Key ◊ = reported in 1 study; ◊◊ = reported in 2 studies; ◊◊◊ = reported in > 3 studies.

 

On secondary outcome measures, lamotrigine, but not lithium, was superior to placebo in delaying time to depressive relapse. In contrast, lithium, but not lamotrigine, was superior to placebo in delaying time to manic relapse. Finally, lamotrigine, but not lithium, was superior to placebo in time to discontinuation for any reason.

From this study, it appears that lamotrigine is most effective in preventing depressive relapse, whereas lithium is most effective in preventing manic relapse. Thus, lithium and lamotrigine may complement each other in maintenance treatment by preventing manic and depressive episodes in combination.

The findings of the first trial were consistent with those of the second placebo-controlled lamotrigine (100-500 mg/d) maintenance study conducted specifically in patients with rapid cycling bipolar I and II disorders.¹⁶ In this 6-month trial, there was no significant difference in time to need for additional medications, the primary outcome measure, between the lamotrigine and placebo groups.

Median survival time was significantly greater for the lamotrigine group (18 weeks) than for the placebo group (12 weeks). The lamotrigine group had significantly longer time to need for additional medications in bipolar II, but not bipolar I, patients. Patients with bipolar II disorder also displayed significantly greater improvement with lamotrigine on global scales compared with bipolar I patients. Because bipolar II disorder is characterized predominantly by depressive episodes, these findings suggest that lamotrigine was again more beneficial in preventing recurrent depression, in this case, specifically, in rapid cycling bipolar II patients.

Taken together, the results of these studies are also consistent with the results of two placebo-controlled trials of lamotrigine in the treatment of acute bipolar depression.^17,18 Its efficacy in acute bipolar I depression was first demonstrated in a 6-week, double-blind, randomized, parallel-group trial in which patients received lamotrigine 50 mg/d, 200 mg/d (after gradual titration over the first 4 weeks), and placebo.¹⁷

Both dosage groups of lamotrigine displayed significantly greater improvement in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (but not the Hamilton Depression Rating Scale) and by the Clinical Global Improvement Scale compared with the placebo group. There was a trend for the 200 mg/d group to have greater improvement than the 50 mg/d group, a trend that might have become significant had the study been longer, as the 200 mg/d group did not receive this dose for the full trial. There was no significant difference in the incidence of hypomanic or manic switches among the three study groups.

Frye and colleagues also found lamotrigine to be superior to placebo in global improvement in depressive (but not manic) symptoms in a crossover monotherapy trial in treatment-refractory bipolar I and II patients.¹⁸

Olanzapine, as described earlier, was comparable to divalproex in a head-to-head comparison 44-week extension trial in patients who responded to double-blind treatment in an acute mania study.¹² These results were consistent with the preliminary findings of an open-label extension study of olanzapine.¹⁹ There are no placebo-controlled trials of olanzapine or any other atypical antipsychotic in the maintenance phase of bipolar disorder published to date.

Clozapine was more effective than “treatment as usual” (combinations of mood-stabilizers and typical antipsychotics) in patients with treatment-refractory bipolar and schizoaffective (bipolar subtype) disorders.²⁰ Many patients with bipolar disorder now receive adjunctive maintenance treatment with typical antipsychotics, but the limited data from the few controlled trials of typical agents administered in combination with mood-stabilizers do not support the efficacy of this strategy.²¹ Moreover, some reports suggest that maintenance treatment incorporating typical antipsychotics may increase the frequency and severity of depressive episodes in patients with bipolar disorder.

Predicting response to pharmacologic treatment

Clinical experience and data from the randomized, controlled trials reviewed earlier have identified several tentative predictors of response—or nonresponse—to specific medications. Lithium, divalproex, and carbamazepine appear to have greater efficacy in the prevention of manic rather than depressive episodes.¹¹ In contrast, lamotrigine appears to have greater efficacy in preventing depressive rather than manic episodes.

It is unclear whether olanzapine and perhaps other atypical antipsychotics may have a more favorable effect in preventing one pole of the illness over another (Table 2). The currently available atypicals (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) in general appear to differ from typical antipsychotics in having bidirectional (antimanic and antidepressant) effects on mood symptoms.

Atypicals may exert antidepressant effects via a number of different mechanisms, including 5HT2 receptor antagonism (a property shared by all atypicals and the antidepressants trazodone, nefazodone, and mirtazapine); alpha2-adrenergic antagonism (clozapine and risperidone); and 5HT1D antagonism, 5HT1A agonism, and 5HT and NE reuptake inhibition (ziprasidone).²²

Patients with rapid-cycling bipolar disorder have a relatively poor response to lithium (response rates of approximately 20%).¹¹ Patients with rapid-cycling bipolar I disorder may have a greater likelihood of response to combined treatment with lithium and carbamazepine,⁹ or divalproex.¹¹ Alternately, patients with rapid-cycling bipolar II disorder have lower relapse rates on lamotrigine compared with placebo.¹⁶ Anecdotal reports and the results of acute treatment studies suggest that clozapine and olanzapine may be beneficial maintenance agents for rapid-cycling bipolar I patients.

 

Other predictors of favorable response to lithium prophylaxis include a family history of bipolar disorder, illness course characterized by maniadepression-euthymia episode sequence, and few prior mood episodes.²¹ Conversely, co-occurring alcohol or substance use disorder, multiple prior mood episodes, and familial negative affective style have been associated with poor response to lithium maintenance treatment.

Tentative predictors of response to divalproex maintenance treatment include mixed episodes, rapid cycling, and absence of co-occurring personality disorder. In one lithium comparison trial, patients with mixed episodes, bipolar II, and NOS disorders and mood-incongruent symptoms appeared to have a better response to carbamazepine.¹⁰

The dosage and relevant plasma concentrations of maintenance agents may also affect long-term efficacy. Gelenberg et al observed that the risk of relapse in bipolar patients maintained on low (0.4-0.6 mmol/L) serum concentrations was 2.6 times higher than for patients maintained on high (0.8-1.0 mmol/L) serum concentrations.²³ However, there was a tradeoff in tolerability. Patients treated at the higher concentrations experienced significantly more and often treatment-limiting side effects.

No data are available regarding a possible plasma concentration-response relationship between maintenance treatment with divalproex or carbamazepine, but based on data from acute treatment trials, concentrations well within the therapeutic range of each drug appear essential.

The problem of subsyndromal symptoms

Evidence from a number of long-term outcome studies in bipolar disorder indicates that many patients spend protracted periods of time neither well nor in syndromal manic or depressive episodes, but rather experiencing chronic subsyndromal symptoms.^24,25 In these studies, depressive symptoms were twice as prevalent as hypomanic symptoms between acute episodes of illness. Furthermore, persistent subsyndromal depressive symptoms were strongly associated with an increased risk for relapse and poor occupational functioning.

Keller et al²⁶ found that patients maintained on low lithium serum concentrations (0.4-0.6 mmol/L) were more likely to experience subsyndromal symptoms and that their symptoms were more likely to worsen at any time than were symptoms of patients maintained at higher serum concentrations (0.8-10 mmol/L). The first occurrence of subsyndromal symptoms increased the risk of fullepisode relapse fourfold. These findings indicate that the optimal pharmacological maintenance treatment of bipolar disorder requires titration of mood-stabilizer medications to eradicate subsyndromal symptoms. Eliminating these residual or recurrent symptoms, in turn, substantially decreases the risk of relapse and of enduring functional impairment.

Conventional wisdom, in part supported by limited data from a small number of studies, suggests that antidepressants be used sparingly and for limited periods of time in conjunction with mood-stabilizers for bipolar depression. However, new data indicate that this strategy may significantly increase the risk of recurrence of depressive symptoms and episodes.²⁷ Thus, combined treatment with mood-stabilizing agents and antidepressants for patients without rapid cycling and with recurrent depressive episodes may be indicated more often than previously thought.

In practice, perhaps the majority of patients with bipolar disorder require treatment with more than one mood-stabilizing medication to suppress subsyndromal symptoms as well as to prevent full episode recurrence. The use of combinations has been very poorly studied in randomized, controlled trials. In a pilot study of 12 patients with bipolar I disorder, Solomon et al compared the efficacy of lithium alone versus the combination of lithium and divalproex for 1 year.²⁸ Not surprisingly, the combination significantly reduced the risk of recurrence of mania and depression but was also associated with more bothersome side effects.

Clinical practice has greatly outstripped the limited data available from formal studies. Recently reported as useful maintenance treatment strategies are combinations of:

• lithium and divalproex
• lithium and carbamazepine
• divalproex and carbamazepine
• lithium, divalproex, and carbamazepine
• lithium and/or divalproex with atypical antipsychotics, antidepressants, and lamotrigine.

Related resources

• Nathan PE, Gorman JM, eds. A Guide to Treatments that Work. 2nd ed. New York: Oxford University Press, 2001.
• Buckley PF, Waddington JL, eds. Schizophrenia and Mood Disorders: the New Drug Therapies in Clinical Practice. Boston: Butterworth-Heiman, 2000.
• Goldberg JF, Harrow M. Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999.
• Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry 2000;48:573-81.
• Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of bipolar disorder (revision). Am J Psychiatry, in press.

Drug brand names

• Clozapine • Clozaril
• Divalproex • Depakote, Depakote Sprinkle
• Lamotrigine • Lamictal
• Mirtazapine • Remeron, Remeron Soltab
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel
• Valproate sodium • Depacon
• Ziprasidone • Geodon

Disclosure

Dr. Keck reports that he receives grant/research support from and serves as a consultant to Abbott Laboratories, AstraZeneca, Pfizer Inc., and Eli Lilly and Co. He also receives grant/research support from Merck and Co. and Otsuka America Pharmaceutical, and serves as a consultant to Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceutica.

 

Dr. McElroy reports that she receives grant/research support from and serves as a consultant to Abbott Laboratories, Elan Pharmaceuticals, Cephalon Inc. GlaxoSmithKline, and Eli Lilly and Co. She also receives grant/research support from Forest Pharmaceuticals and Solvay Pharmaceuticals, and serves as a consultant to Bristol-Myers Squibb Co., Ortho-McNeil Pharmaceutical, and Janssen Pharmaceutica.

Dr. Nelson reports no financial relationship with any company whose products are mentioned in this article.

What are we trying to accomplish in the maintenance treatment of patients with bipolar disorder? Given that the disorder recurs in more than 90% of patients who experience a manic episode,¹ there are 5 important goals:

1. Prevention of recurrent episodes;
2. Amelioration of subsyndromal symptoms;
3. Reduction of suicide risk;
4. Compliance enhancement;
5. Optimization of interpersonal, social, and vocational functioning.

There is a great premium on preventing mood episode recurrence in patients with bipolar disorder. Mood episodes themselves produce substantial morbidity, but morbidity is not confined to these episodes alone. Full recovery of functioning often lags many months behind remission of symptoms.² Recurrent mood episodes also may lead to progressive loss of function between episodes. Mood episodes also carry risks of mortality from suicide, violence, and impulsive risk taking.

Clearly, mood-stabilizing medications form the cornerstone of maintenance treatment,^3,4 along with a strong therapeutic alliance between patient and clinician and targeted psychosocial therapies. In the Expert Consensus Guidelines for medication treatment of bipolar I disorder, maintenance treatment was recommended for 1 year following an initial manic or mixed episode; longer (indefinite) treatment was recommended for patients with a family history of bipolar disorder or if 2 episodes occurred.³

Compared with clinical trials of agents for acute bipolar mania (and mixed episodes), there are relatively few randomized controlled trials of medications for the maintenance phase of bipolar disorder. Some naturalistic studies have provided data on relapse rates associated with treatment with a variety of different agents. Even fewer studies have examined psychosocial interventions designed specifically to reduce relapse rates.

But new data are beginning to emerge regarding the efficacy of divalproex, lamotrigine, and olanzapine as maintenance therapies. A number of clinical predictors of response to these agents have begun to be identified, as well as to lithium and carbamazepine. Eliciting these characteristics is important when making recommendations to patients about available drug therapies.

In addition, effective maintenance treatment often requires combinations of mood-stabilizing, antidepressant, and antipsychotic agents to control or eliminate subsyndromal and breakthrough symptoms.

In this review, we will cover the available new data on pharmacologic maintenance treatments of bipolar disorder and their clinical implications.

What the studies show

Lithium has been the mainstay of therapy for bipolar disorder for more than 35 years. Most randomized, controlled trials of lithium maintenance therapy were conducted in the 1960s and 1970s⁵ (Table 1). Unfortunately, these studies had several design limitations that inflated the expectations of lithium’s efficacy as a maintenance treatment.⁶ These included discontinuation designs in which patients stabilized on lithium were abruptly switched to placebo; exaggerated early placebo relapse rates; enrollment of both unipolar and bipolar patients; lack of specific diagnostic criteria; and reported results only for patients completing studies. Pooled data from these trials indicated that lithium reduced the risk of relapse fourfold compared with placebo at 6 months and 1 year.⁵

Two contemporary randomized, placebo-controlled maintenance studies utilizing more rigorous designs provided further evidence of lithium’s superiority over placebo in extending time to manic relapse.^7,8 Both studies enrolled patients who were currently or had recently been manic and had been stabilized in open-label treatment that included study medications.

In the first study, comparing 1-year relapse rates among patients randomized to lithium, divalproex, or placebo, lithium extended time to recurrence of mania by 55% compared with placebo.⁷ In the second, an 18-month trial comparing lithium, lamotrigine, and placebo, lithium significantly increased the time to intervention for recurrence of mania compared with placebo.⁸ The overall manic relapse rates were 17% for lithium-treated patients and 41% for those on placebo. However, lithium did not significantly extend time to depressive relapse or intervention for depressive relapse, respectively, in either study. Moreover, in the first study, patients who received lithium tended to have greater subthreshold depressive symptoms.⁸

Table 1

What works in maintenance treatment of bipolar disorder (ranked by number of randomized, controlled trials)

Medication RCTs (n)	Trial results	Strong evidence	Some evidence
Lithium (15)	Equal to divalproex and lamotrigine; equal to or better than carbamazepine; better than placebo	4-fold reduction of relapse risk vs. placebo at 6, 12 months; more efficacious in mania than in depression; higher lithium level correlated with lower relapse rates, but more side effects
Carbamazepine (7)	No significant benefit vs. lithium; better than placebo		May be more efficacious in mania than in depression; may be less tolerable than lithium; no data on serum levels
Divalproex (4)	Equal to lithium and olanzapine; better than placebo		May be more efficacious in mania than in depression; may be more tolerable than lithium; data on serum levels pending
Lamotrigine (2)	Better than placebo	More efficacious in depression than in mania	Dosage 200-400 mg/d
Olanzapine (1)	Equal to divalproex		Data on dosage and differential efficacy related to dosage pending
Clozapine (1)	Better than treatment as usual	Efficacy in treatment-resistant mania (bipolar schizoaffective disorder, bipolar type)

 

These findings were consistent with earlier placebo-controlled studies of lithium maintenance treatment and a recent crossover comparison trial with carbamazepine.⁹ Lithium was also recently compared with carbamazepine in a 2.5-year maintenance multisite study in Europe.¹⁰ There was no significant difference in efficacy between the two in time to hospitalization, the primary outcome measure. On other outcome measures, including time to relapse or need for additional medication, lithium was superior to carbamazepine.

Pooled results from a number of naturalistic studies, which mirror clinical practice, indicated that approximately one-third of patients maintained on lithium had good functional outcomes without relapses and only minimal symptoms.¹¹ In general, these studies found higher rates of relapse with longer durations of follow-up.

Valproate maintenance treatment has been studied in two randomized, controlled trials (one vs. placebo,⁷ and one vs. olanzapine¹²) and two open-label comparison studies against lithium.^13,14 In the placebo-controlled trial, which also included a lithium comparison group described earlier, there was no significant difference in the time to development of any mood episode among the three treatment groups.⁷ However, divalproex was superior to placebo on a number of other outcome measures, including rate of study termination for any mood episode, termination for depression, and termination for noncompliance.

Divalproex was superior to placebo in patients who received divalproex in the open-label treatment phase before randomization. This is clinically relevant, as this group reflects expected relapse rates in patients treated initially with divalproex for acute mania who then remain on the drug for maintenance therapy. Patients receiving divalproex had significantly lower rates of intolerance and noncompliance compared to those treated with lithium.

In the second comparison study, 167 patients initially randomized and responding to divalproex or olanzapine in a 3-week acute bipolar mania trial continued in a double-blind 44-week extension study.¹² There were no significant differences in relapse into mania between the two groups (olanzapine 41%, divalproex 50%, p = 0.4) or time to manic relapse (olanzapine 270 days, divalproex 74 days, p = 0.4). There was no significant difference in tolerability between the two.

Two open-label studies compared valproate with lithium. In an 18-month study conducted in France, patients randomized to the valpromide formulation of valproate displayed a 20% lower relapse rate than those receiving lithium.¹³ The second open-label comparison trial found comparable efficacy between lithium and divalproex in a 1-year naturalistic pharmacoeconomic study that allowed additional medications as needed for recurrent symptoms.¹⁴

Carbamazepine has been evaluated in a limited number of studies for maintenance treatment of bipolar disorder. The results of many early randomized, controlled maintenance trials were criticized on methodologic grounds.¹⁵ But two recent comparison trials with lithium, as noted earlier, provided clinically important data regarding carbamazepine’s prophylactic efficacy.^9,10 Several additional clinically relevant observations emerged from analyses of secondary outcome measures in these two trials.

In the first study, 52 patients with bipolar I or II disorder received lithium or carbamazepine for 1 year, crossed over to the alternate drug the second year, and received both drugs the third year.⁹ There was little difference in relapse rates during the first year between the lithium (31%) and carbamazepine (37%) groups. Similarly, in the overall trial, there was little difference in the percentage of patients who were rated as having a moderate or better response—33% on lithium, 31% on carbamazepine, and 55% on the combination. A higher proportion of patients receiving carbamazepine withdrew due to side effects. In the second trial, significantly more patients receiving carbamazepine required additional medications for breakthrough symptoms and experienced side effects requiring treatment discontinuation.¹⁰

Lamotrigine has been studied in two placebo-controlled, randomized maintenance studies in patients with bipolar disorder.^8,16 The first evaluated bipolar I patients who had experienced a manic or hypomanic episode within 60 days of entry into an open-label treatment phase with lamotrigine.⁸ Patients who, in turn, improved or remained stable during the open-label treatment phase were then randomized to treatment with lamotrigine 200-400 mg/d, lithium, or placebo for up to 18 months. Both lamotrigine and lithium were superior to placebo on the primary outcome measure, which was time to need for additional medication for a mood episode. The median time until 25% of patients relapsed was 72 weeks for lamotrigine, 58 weeks for lithium, and 35 weeks for placebo.

Table 2

PUTATIVE PREDICTORS OF RESPONSE TO MAINTENANCE MEDICATIONS

Medication	Predictor of response	Strength of evidence
Lithium	Nonrap id cycling Few episodes Few depressive symptoms Family history bipolar disorder Episode sequence M-D-I No substance/alcohol use disorder	◊◊◊ ◊ ◊ ◊ ◊ ◊
Divalproex	Equal efficacy in rapid & non-rapid cycling, manic & mixed, No personality disorder	◊ ◊
Carbamazepine	Equal efficacy in rapid & non-rapid cycling, manic & mixed Mood-incongruent symptoms	◊◊ ◊
Lamotrigine	Bipolar II > bipolar I Depression > mania	◊ ◊◊
Olanzapine	Equal efficacy in rapid & non-rapid cycling, manic & mixed, psychotic & nonpsychotic mania in acute studies; data pending in maintenance	◊
Clozapine	Efficacy in treatment-resistant mania rapid & nonrapid cycling, manic & mixed, psychotic & nonpsychotic in naturalistic studies	◊◊◊
Key ◊ = reported in 1 study; ◊◊ = reported in 2 studies; ◊◊◊ = reported in > 3 studies.

 

On secondary outcome measures, lamotrigine, but not lithium, was superior to placebo in delaying time to depressive relapse. In contrast, lithium, but not lamotrigine, was superior to placebo in delaying time to manic relapse. Finally, lamotrigine, but not lithium, was superior to placebo in time to discontinuation for any reason.

From this study, it appears that lamotrigine is most effective in preventing depressive relapse, whereas lithium is most effective in preventing manic relapse. Thus, lithium and lamotrigine may complement each other in maintenance treatment by preventing manic and depressive episodes in combination.

The findings of the first trial were consistent with those of the second placebo-controlled lamotrigine (100-500 mg/d) maintenance study conducted specifically in patients with rapid cycling bipolar I and II disorders.¹⁶ In this 6-month trial, there was no significant difference in time to need for additional medications, the primary outcome measure, between the lamotrigine and placebo groups.

Median survival time was significantly greater for the lamotrigine group (18 weeks) than for the placebo group (12 weeks). The lamotrigine group had significantly longer time to need for additional medications in bipolar II, but not bipolar I, patients. Patients with bipolar II disorder also displayed significantly greater improvement with lamotrigine on global scales compared with bipolar I patients. Because bipolar II disorder is characterized predominantly by depressive episodes, these findings suggest that lamotrigine was again more beneficial in preventing recurrent depression, in this case, specifically, in rapid cycling bipolar II patients.

Taken together, the results of these studies are also consistent with the results of two placebo-controlled trials of lamotrigine in the treatment of acute bipolar depression.^17,18 Its efficacy in acute bipolar I depression was first demonstrated in a 6-week, double-blind, randomized, parallel-group trial in which patients received lamotrigine 50 mg/d, 200 mg/d (after gradual titration over the first 4 weeks), and placebo.¹⁷

Both dosage groups of lamotrigine displayed significantly greater improvement in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (but not the Hamilton Depression Rating Scale) and by the Clinical Global Improvement Scale compared with the placebo group. There was a trend for the 200 mg/d group to have greater improvement than the 50 mg/d group, a trend that might have become significant had the study been longer, as the 200 mg/d group did not receive this dose for the full trial. There was no significant difference in the incidence of hypomanic or manic switches among the three study groups.

Frye and colleagues also found lamotrigine to be superior to placebo in global improvement in depressive (but not manic) symptoms in a crossover monotherapy trial in treatment-refractory bipolar I and II patients.¹⁸

Olanzapine, as described earlier, was comparable to divalproex in a head-to-head comparison 44-week extension trial in patients who responded to double-blind treatment in an acute mania study.¹² These results were consistent with the preliminary findings of an open-label extension study of olanzapine.¹⁹ There are no placebo-controlled trials of olanzapine or any other atypical antipsychotic in the maintenance phase of bipolar disorder published to date.

Clozapine was more effective than “treatment as usual” (combinations of mood-stabilizers and typical antipsychotics) in patients with treatment-refractory bipolar and schizoaffective (bipolar subtype) disorders.²⁰ Many patients with bipolar disorder now receive adjunctive maintenance treatment with typical antipsychotics, but the limited data from the few controlled trials of typical agents administered in combination with mood-stabilizers do not support the efficacy of this strategy.²¹ Moreover, some reports suggest that maintenance treatment incorporating typical antipsychotics may increase the frequency and severity of depressive episodes in patients with bipolar disorder.

Predicting response to pharmacologic treatment

Clinical experience and data from the randomized, controlled trials reviewed earlier have identified several tentative predictors of response—or nonresponse—to specific medications. Lithium, divalproex, and carbamazepine appear to have greater efficacy in the prevention of manic rather than depressive episodes.¹¹ In contrast, lamotrigine appears to have greater efficacy in preventing depressive rather than manic episodes.

It is unclear whether olanzapine and perhaps other atypical antipsychotics may have a more favorable effect in preventing one pole of the illness over another (Table 2). The currently available atypicals (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) in general appear to differ from typical antipsychotics in having bidirectional (antimanic and antidepressant) effects on mood symptoms.

Atypicals may exert antidepressant effects via a number of different mechanisms, including 5HT2 receptor antagonism (a property shared by all atypicals and the antidepressants trazodone, nefazodone, and mirtazapine); alpha2-adrenergic antagonism (clozapine and risperidone); and 5HT1D antagonism, 5HT1A agonism, and 5HT and NE reuptake inhibition (ziprasidone).²²

Patients with rapid-cycling bipolar disorder have a relatively poor response to lithium (response rates of approximately 20%).¹¹ Patients with rapid-cycling bipolar I disorder may have a greater likelihood of response to combined treatment with lithium and carbamazepine,⁹ or divalproex.¹¹ Alternately, patients with rapid-cycling bipolar II disorder have lower relapse rates on lamotrigine compared with placebo.¹⁶ Anecdotal reports and the results of acute treatment studies suggest that clozapine and olanzapine may be beneficial maintenance agents for rapid-cycling bipolar I patients.

 

Other predictors of favorable response to lithium prophylaxis include a family history of bipolar disorder, illness course characterized by maniadepression-euthymia episode sequence, and few prior mood episodes.²¹ Conversely, co-occurring alcohol or substance use disorder, multiple prior mood episodes, and familial negative affective style have been associated with poor response to lithium maintenance treatment.

Tentative predictors of response to divalproex maintenance treatment include mixed episodes, rapid cycling, and absence of co-occurring personality disorder. In one lithium comparison trial, patients with mixed episodes, bipolar II, and NOS disorders and mood-incongruent symptoms appeared to have a better response to carbamazepine.¹⁰

The dosage and relevant plasma concentrations of maintenance agents may also affect long-term efficacy. Gelenberg et al observed that the risk of relapse in bipolar patients maintained on low (0.4-0.6 mmol/L) serum concentrations was 2.6 times higher than for patients maintained on high (0.8-1.0 mmol/L) serum concentrations.²³ However, there was a tradeoff in tolerability. Patients treated at the higher concentrations experienced significantly more and often treatment-limiting side effects.

No data are available regarding a possible plasma concentration-response relationship between maintenance treatment with divalproex or carbamazepine, but based on data from acute treatment trials, concentrations well within the therapeutic range of each drug appear essential.

The problem of subsyndromal symptoms

Evidence from a number of long-term outcome studies in bipolar disorder indicates that many patients spend protracted periods of time neither well nor in syndromal manic or depressive episodes, but rather experiencing chronic subsyndromal symptoms.^24,25 In these studies, depressive symptoms were twice as prevalent as hypomanic symptoms between acute episodes of illness. Furthermore, persistent subsyndromal depressive symptoms were strongly associated with an increased risk for relapse and poor occupational functioning.

Keller et al²⁶ found that patients maintained on low lithium serum concentrations (0.4-0.6 mmol/L) were more likely to experience subsyndromal symptoms and that their symptoms were more likely to worsen at any time than were symptoms of patients maintained at higher serum concentrations (0.8-10 mmol/L). The first occurrence of subsyndromal symptoms increased the risk of fullepisode relapse fourfold. These findings indicate that the optimal pharmacological maintenance treatment of bipolar disorder requires titration of mood-stabilizer medications to eradicate subsyndromal symptoms. Eliminating these residual or recurrent symptoms, in turn, substantially decreases the risk of relapse and of enduring functional impairment.

Conventional wisdom, in part supported by limited data from a small number of studies, suggests that antidepressants be used sparingly and for limited periods of time in conjunction with mood-stabilizers for bipolar depression. However, new data indicate that this strategy may significantly increase the risk of recurrence of depressive symptoms and episodes.²⁷ Thus, combined treatment with mood-stabilizing agents and antidepressants for patients without rapid cycling and with recurrent depressive episodes may be indicated more often than previously thought.

In practice, perhaps the majority of patients with bipolar disorder require treatment with more than one mood-stabilizing medication to suppress subsyndromal symptoms as well as to prevent full episode recurrence. The use of combinations has been very poorly studied in randomized, controlled trials. In a pilot study of 12 patients with bipolar I disorder, Solomon et al compared the efficacy of lithium alone versus the combination of lithium and divalproex for 1 year.²⁸ Not surprisingly, the combination significantly reduced the risk of recurrence of mania and depression but was also associated with more bothersome side effects.

Clinical practice has greatly outstripped the limited data available from formal studies. Recently reported as useful maintenance treatment strategies are combinations of:

• lithium and divalproex
• lithium and carbamazepine
• divalproex and carbamazepine
• lithium, divalproex, and carbamazepine
• lithium and/or divalproex with atypical antipsychotics, antidepressants, and lamotrigine.

Related resources

• Nathan PE, Gorman JM, eds. A Guide to Treatments that Work. 2nd ed. New York: Oxford University Press, 2001.
• Buckley PF, Waddington JL, eds. Schizophrenia and Mood Disorders: the New Drug Therapies in Clinical Practice. Boston: Butterworth-Heiman, 2000.
• Goldberg JF, Harrow M. Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999.
• Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry 2000;48:573-81.
• Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of bipolar disorder (revision). Am J Psychiatry, in press.

Drug brand names

• Clozapine • Clozaril
• Divalproex • Depakote, Depakote Sprinkle
• Lamotrigine • Lamictal
• Mirtazapine • Remeron, Remeron Soltab
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel
• Valproate sodium • Depacon
• Ziprasidone • Geodon

Disclosure

Dr. Keck reports that he receives grant/research support from and serves as a consultant to Abbott Laboratories, AstraZeneca, Pfizer Inc., and Eli Lilly and Co. He also receives grant/research support from Merck and Co. and Otsuka America Pharmaceutical, and serves as a consultant to Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceutica.

 

Dr. McElroy reports that she receives grant/research support from and serves as a consultant to Abbott Laboratories, Elan Pharmaceuticals, Cephalon Inc. GlaxoSmithKline, and Eli Lilly and Co. She also receives grant/research support from Forest Pharmaceuticals and Solvay Pharmaceuticals, and serves as a consultant to Bristol-Myers Squibb Co., Ortho-McNeil Pharmaceutical, and Janssen Pharmaceutica.

Dr. Nelson reports no financial relationship with any company whose products are mentioned in this article.

What are we trying to accomplish in the maintenance treatment of patients with bipolar disorder? Given that the disorder recurs in more than 90% of patients who experience a manic episode,¹ there are 5 important goals:

1. Prevention of recurrent episodes;
2. Amelioration of subsyndromal symptoms;
3. Reduction of suicide risk;
4. Compliance enhancement;
5. Optimization of interpersonal, social, and vocational functioning.

There is a great premium on preventing mood episode recurrence in patients with bipolar disorder. Mood episodes themselves produce substantial morbidity, but morbidity is not confined to these episodes alone. Full recovery of functioning often lags many months behind remission of symptoms.² Recurrent mood episodes also may lead to progressive loss of function between episodes. Mood episodes also carry risks of mortality from suicide, violence, and impulsive risk taking.

Clearly, mood-stabilizing medications form the cornerstone of maintenance treatment,^3,4 along with a strong therapeutic alliance between patient and clinician and targeted psychosocial therapies. In the Expert Consensus Guidelines for medication treatment of bipolar I disorder, maintenance treatment was recommended for 1 year following an initial manic or mixed episode; longer (indefinite) treatment was recommended for patients with a family history of bipolar disorder or if 2 episodes occurred.³

Compared with clinical trials of agents for acute bipolar mania (and mixed episodes), there are relatively few randomized controlled trials of medications for the maintenance phase of bipolar disorder. Some naturalistic studies have provided data on relapse rates associated with treatment with a variety of different agents. Even fewer studies have examined psychosocial interventions designed specifically to reduce relapse rates.

But new data are beginning to emerge regarding the efficacy of divalproex, lamotrigine, and olanzapine as maintenance therapies. A number of clinical predictors of response to these agents have begun to be identified, as well as to lithium and carbamazepine. Eliciting these characteristics is important when making recommendations to patients about available drug therapies.

In addition, effective maintenance treatment often requires combinations of mood-stabilizing, antidepressant, and antipsychotic agents to control or eliminate subsyndromal and breakthrough symptoms.

In this review, we will cover the available new data on pharmacologic maintenance treatments of bipolar disorder and their clinical implications.

What the studies show

Lithium has been the mainstay of therapy for bipolar disorder for more than 35 years. Most randomized, controlled trials of lithium maintenance therapy were conducted in the 1960s and 1970s⁵ (Table 1). Unfortunately, these studies had several design limitations that inflated the expectations of lithium’s efficacy as a maintenance treatment.⁶ These included discontinuation designs in which patients stabilized on lithium were abruptly switched to placebo; exaggerated early placebo relapse rates; enrollment of both unipolar and bipolar patients; lack of specific diagnostic criteria; and reported results only for patients completing studies. Pooled data from these trials indicated that lithium reduced the risk of relapse fourfold compared with placebo at 6 months and 1 year.⁵

Two contemporary randomized, placebo-controlled maintenance studies utilizing more rigorous designs provided further evidence of lithium’s superiority over placebo in extending time to manic relapse.^7,8 Both studies enrolled patients who were currently or had recently been manic and had been stabilized in open-label treatment that included study medications.

In the first study, comparing 1-year relapse rates among patients randomized to lithium, divalproex, or placebo, lithium extended time to recurrence of mania by 55% compared with placebo.⁷ In the second, an 18-month trial comparing lithium, lamotrigine, and placebo, lithium significantly increased the time to intervention for recurrence of mania compared with placebo.⁸ The overall manic relapse rates were 17% for lithium-treated patients and 41% for those on placebo. However, lithium did not significantly extend time to depressive relapse or intervention for depressive relapse, respectively, in either study. Moreover, in the first study, patients who received lithium tended to have greater subthreshold depressive symptoms.⁸

Table 1

What works in maintenance treatment of bipolar disorder (ranked by number of randomized, controlled trials)

Medication RCTs (n)	Trial results	Strong evidence	Some evidence
Lithium (15)	Equal to divalproex and lamotrigine; equal to or better than carbamazepine; better than placebo	4-fold reduction of relapse risk vs. placebo at 6, 12 months; more efficacious in mania than in depression; higher lithium level correlated with lower relapse rates, but more side effects
Carbamazepine (7)	No significant benefit vs. lithium; better than placebo		May be more efficacious in mania than in depression; may be less tolerable than lithium; no data on serum levels
Divalproex (4)	Equal to lithium and olanzapine; better than placebo		May be more efficacious in mania than in depression; may be more tolerable than lithium; data on serum levels pending
Lamotrigine (2)	Better than placebo	More efficacious in depression than in mania	Dosage 200-400 mg/d
Olanzapine (1)	Equal to divalproex		Data on dosage and differential efficacy related to dosage pending
Clozapine (1)	Better than treatment as usual	Efficacy in treatment-resistant mania (bipolar schizoaffective disorder, bipolar type)

 

These findings were consistent with earlier placebo-controlled studies of lithium maintenance treatment and a recent crossover comparison trial with carbamazepine.⁹ Lithium was also recently compared with carbamazepine in a 2.5-year maintenance multisite study in Europe.¹⁰ There was no significant difference in efficacy between the two in time to hospitalization, the primary outcome measure. On other outcome measures, including time to relapse or need for additional medication, lithium was superior to carbamazepine.

Pooled results from a number of naturalistic studies, which mirror clinical practice, indicated that approximately one-third of patients maintained on lithium had good functional outcomes without relapses and only minimal symptoms.¹¹ In general, these studies found higher rates of relapse with longer durations of follow-up.

Valproate maintenance treatment has been studied in two randomized, controlled trials (one vs. placebo,⁷ and one vs. olanzapine¹²) and two open-label comparison studies against lithium.^13,14 In the placebo-controlled trial, which also included a lithium comparison group described earlier, there was no significant difference in the time to development of any mood episode among the three treatment groups.⁷ However, divalproex was superior to placebo on a number of other outcome measures, including rate of study termination for any mood episode, termination for depression, and termination for noncompliance.

Divalproex was superior to placebo in patients who received divalproex in the open-label treatment phase before randomization. This is clinically relevant, as this group reflects expected relapse rates in patients treated initially with divalproex for acute mania who then remain on the drug for maintenance therapy. Patients receiving divalproex had significantly lower rates of intolerance and noncompliance compared to those treated with lithium.

In the second comparison study, 167 patients initially randomized and responding to divalproex or olanzapine in a 3-week acute bipolar mania trial continued in a double-blind 44-week extension study.¹² There were no significant differences in relapse into mania between the two groups (olanzapine 41%, divalproex 50%, p = 0.4) or time to manic relapse (olanzapine 270 days, divalproex 74 days, p = 0.4). There was no significant difference in tolerability between the two.

Two open-label studies compared valproate with lithium. In an 18-month study conducted in France, patients randomized to the valpromide formulation of valproate displayed a 20% lower relapse rate than those receiving lithium.¹³ The second open-label comparison trial found comparable efficacy between lithium and divalproex in a 1-year naturalistic pharmacoeconomic study that allowed additional medications as needed for recurrent symptoms.¹⁴

Carbamazepine has been evaluated in a limited number of studies for maintenance treatment of bipolar disorder. The results of many early randomized, controlled maintenance trials were criticized on methodologic grounds.¹⁵ But two recent comparison trials with lithium, as noted earlier, provided clinically important data regarding carbamazepine’s prophylactic efficacy.^9,10 Several additional clinically relevant observations emerged from analyses of secondary outcome measures in these two trials.

In the first study, 52 patients with bipolar I or II disorder received lithium or carbamazepine for 1 year, crossed over to the alternate drug the second year, and received both drugs the third year.⁹ There was little difference in relapse rates during the first year between the lithium (31%) and carbamazepine (37%) groups. Similarly, in the overall trial, there was little difference in the percentage of patients who were rated as having a moderate or better response—33% on lithium, 31% on carbamazepine, and 55% on the combination. A higher proportion of patients receiving carbamazepine withdrew due to side effects. In the second trial, significantly more patients receiving carbamazepine required additional medications for breakthrough symptoms and experienced side effects requiring treatment discontinuation.¹⁰

Lamotrigine has been studied in two placebo-controlled, randomized maintenance studies in patients with bipolar disorder.^8,16 The first evaluated bipolar I patients who had experienced a manic or hypomanic episode within 60 days of entry into an open-label treatment phase with lamotrigine.⁸ Patients who, in turn, improved or remained stable during the open-label treatment phase were then randomized to treatment with lamotrigine 200-400 mg/d, lithium, or placebo for up to 18 months. Both lamotrigine and lithium were superior to placebo on the primary outcome measure, which was time to need for additional medication for a mood episode. The median time until 25% of patients relapsed was 72 weeks for lamotrigine, 58 weeks for lithium, and 35 weeks for placebo.

Table 2

PUTATIVE PREDICTORS OF RESPONSE TO MAINTENANCE MEDICATIONS

Medication	Predictor of response	Strength of evidence
Lithium	Nonrap id cycling Few episodes Few depressive symptoms Family history bipolar disorder Episode sequence M-D-I No substance/alcohol use disorder	◊◊◊ ◊ ◊ ◊ ◊ ◊
Divalproex	Equal efficacy in rapid & non-rapid cycling, manic & mixed, No personality disorder	◊ ◊
Carbamazepine	Equal efficacy in rapid & non-rapid cycling, manic & mixed Mood-incongruent symptoms	◊◊ ◊
Lamotrigine	Bipolar II > bipolar I Depression > mania	◊ ◊◊
Olanzapine	Equal efficacy in rapid & non-rapid cycling, manic & mixed, psychotic & nonpsychotic mania in acute studies; data pending in maintenance	◊
Clozapine	Efficacy in treatment-resistant mania rapid & nonrapid cycling, manic & mixed, psychotic & nonpsychotic in naturalistic studies	◊◊◊
Key ◊ = reported in 1 study; ◊◊ = reported in 2 studies; ◊◊◊ = reported in > 3 studies.

 

On secondary outcome measures, lamotrigine, but not lithium, was superior to placebo in delaying time to depressive relapse. In contrast, lithium, but not lamotrigine, was superior to placebo in delaying time to manic relapse. Finally, lamotrigine, but not lithium, was superior to placebo in time to discontinuation for any reason.

From this study, it appears that lamotrigine is most effective in preventing depressive relapse, whereas lithium is most effective in preventing manic relapse. Thus, lithium and lamotrigine may complement each other in maintenance treatment by preventing manic and depressive episodes in combination.

The findings of the first trial were consistent with those of the second placebo-controlled lamotrigine (100-500 mg/d) maintenance study conducted specifically in patients with rapid cycling bipolar I and II disorders.¹⁶ In this 6-month trial, there was no significant difference in time to need for additional medications, the primary outcome measure, between the lamotrigine and placebo groups.

Median survival time was significantly greater for the lamotrigine group (18 weeks) than for the placebo group (12 weeks). The lamotrigine group had significantly longer time to need for additional medications in bipolar II, but not bipolar I, patients. Patients with bipolar II disorder also displayed significantly greater improvement with lamotrigine on global scales compared with bipolar I patients. Because bipolar II disorder is characterized predominantly by depressive episodes, these findings suggest that lamotrigine was again more beneficial in preventing recurrent depression, in this case, specifically, in rapid cycling bipolar II patients.

Taken together, the results of these studies are also consistent with the results of two placebo-controlled trials of lamotrigine in the treatment of acute bipolar depression.^17,18 Its efficacy in acute bipolar I depression was first demonstrated in a 6-week, double-blind, randomized, parallel-group trial in which patients received lamotrigine 50 mg/d, 200 mg/d (after gradual titration over the first 4 weeks), and placebo.¹⁷

Both dosage groups of lamotrigine displayed significantly greater improvement in depressive symptoms as measured by the Montgomery-Asberg Depression Rating Scale (but not the Hamilton Depression Rating Scale) and by the Clinical Global Improvement Scale compared with the placebo group. There was a trend for the 200 mg/d group to have greater improvement than the 50 mg/d group, a trend that might have become significant had the study been longer, as the 200 mg/d group did not receive this dose for the full trial. There was no significant difference in the incidence of hypomanic or manic switches among the three study groups.

Frye and colleagues also found lamotrigine to be superior to placebo in global improvement in depressive (but not manic) symptoms in a crossover monotherapy trial in treatment-refractory bipolar I and II patients.¹⁸

Olanzapine, as described earlier, was comparable to divalproex in a head-to-head comparison 44-week extension trial in patients who responded to double-blind treatment in an acute mania study.¹² These results were consistent with the preliminary findings of an open-label extension study of olanzapine.¹⁹ There are no placebo-controlled trials of olanzapine or any other atypical antipsychotic in the maintenance phase of bipolar disorder published to date.

Clozapine was more effective than “treatment as usual” (combinations of mood-stabilizers and typical antipsychotics) in patients with treatment-refractory bipolar and schizoaffective (bipolar subtype) disorders.²⁰ Many patients with bipolar disorder now receive adjunctive maintenance treatment with typical antipsychotics, but the limited data from the few controlled trials of typical agents administered in combination with mood-stabilizers do not support the efficacy of this strategy.²¹ Moreover, some reports suggest that maintenance treatment incorporating typical antipsychotics may increase the frequency and severity of depressive episodes in patients with bipolar disorder.

Predicting response to pharmacologic treatment

Clinical experience and data from the randomized, controlled trials reviewed earlier have identified several tentative predictors of response—or nonresponse—to specific medications. Lithium, divalproex, and carbamazepine appear to have greater efficacy in the prevention of manic rather than depressive episodes.¹¹ In contrast, lamotrigine appears to have greater efficacy in preventing depressive rather than manic episodes.

It is unclear whether olanzapine and perhaps other atypical antipsychotics may have a more favorable effect in preventing one pole of the illness over another (Table 2). The currently available atypicals (clozapine, risperidone, olanzapine, quetiapine, and ziprasidone) in general appear to differ from typical antipsychotics in having bidirectional (antimanic and antidepressant) effects on mood symptoms.

Atypicals may exert antidepressant effects via a number of different mechanisms, including 5HT2 receptor antagonism (a property shared by all atypicals and the antidepressants trazodone, nefazodone, and mirtazapine); alpha2-adrenergic antagonism (clozapine and risperidone); and 5HT1D antagonism, 5HT1A agonism, and 5HT and NE reuptake inhibition (ziprasidone).²²

Patients with rapid-cycling bipolar disorder have a relatively poor response to lithium (response rates of approximately 20%).¹¹ Patients with rapid-cycling bipolar I disorder may have a greater likelihood of response to combined treatment with lithium and carbamazepine,⁹ or divalproex.¹¹ Alternately, patients with rapid-cycling bipolar II disorder have lower relapse rates on lamotrigine compared with placebo.¹⁶ Anecdotal reports and the results of acute treatment studies suggest that clozapine and olanzapine may be beneficial maintenance agents for rapid-cycling bipolar I patients.

 

Other predictors of favorable response to lithium prophylaxis include a family history of bipolar disorder, illness course characterized by maniadepression-euthymia episode sequence, and few prior mood episodes.²¹ Conversely, co-occurring alcohol or substance use disorder, multiple prior mood episodes, and familial negative affective style have been associated with poor response to lithium maintenance treatment.

Tentative predictors of response to divalproex maintenance treatment include mixed episodes, rapid cycling, and absence of co-occurring personality disorder. In one lithium comparison trial, patients with mixed episodes, bipolar II, and NOS disorders and mood-incongruent symptoms appeared to have a better response to carbamazepine.¹⁰

The dosage and relevant plasma concentrations of maintenance agents may also affect long-term efficacy. Gelenberg et al observed that the risk of relapse in bipolar patients maintained on low (0.4-0.6 mmol/L) serum concentrations was 2.6 times higher than for patients maintained on high (0.8-1.0 mmol/L) serum concentrations.²³ However, there was a tradeoff in tolerability. Patients treated at the higher concentrations experienced significantly more and often treatment-limiting side effects.

No data are available regarding a possible plasma concentration-response relationship between maintenance treatment with divalproex or carbamazepine, but based on data from acute treatment trials, concentrations well within the therapeutic range of each drug appear essential.

The problem of subsyndromal symptoms

Evidence from a number of long-term outcome studies in bipolar disorder indicates that many patients spend protracted periods of time neither well nor in syndromal manic or depressive episodes, but rather experiencing chronic subsyndromal symptoms.^24,25 In these studies, depressive symptoms were twice as prevalent as hypomanic symptoms between acute episodes of illness. Furthermore, persistent subsyndromal depressive symptoms were strongly associated with an increased risk for relapse and poor occupational functioning.

Keller et al²⁶ found that patients maintained on low lithium serum concentrations (0.4-0.6 mmol/L) were more likely to experience subsyndromal symptoms and that their symptoms were more likely to worsen at any time than were symptoms of patients maintained at higher serum concentrations (0.8-10 mmol/L). The first occurrence of subsyndromal symptoms increased the risk of fullepisode relapse fourfold. These findings indicate that the optimal pharmacological maintenance treatment of bipolar disorder requires titration of mood-stabilizer medications to eradicate subsyndromal symptoms. Eliminating these residual or recurrent symptoms, in turn, substantially decreases the risk of relapse and of enduring functional impairment.

Conventional wisdom, in part supported by limited data from a small number of studies, suggests that antidepressants be used sparingly and for limited periods of time in conjunction with mood-stabilizers for bipolar depression. However, new data indicate that this strategy may significantly increase the risk of recurrence of depressive symptoms and episodes.²⁷ Thus, combined treatment with mood-stabilizing agents and antidepressants for patients without rapid cycling and with recurrent depressive episodes may be indicated more often than previously thought.

In practice, perhaps the majority of patients with bipolar disorder require treatment with more than one mood-stabilizing medication to suppress subsyndromal symptoms as well as to prevent full episode recurrence. The use of combinations has been very poorly studied in randomized, controlled trials. In a pilot study of 12 patients with bipolar I disorder, Solomon et al compared the efficacy of lithium alone versus the combination of lithium and divalproex for 1 year.²⁸ Not surprisingly, the combination significantly reduced the risk of recurrence of mania and depression but was also associated with more bothersome side effects.

Clinical practice has greatly outstripped the limited data available from formal studies. Recently reported as useful maintenance treatment strategies are combinations of:

• lithium and divalproex
• lithium and carbamazepine
• divalproex and carbamazepine
• lithium, divalproex, and carbamazepine
• lithium and/or divalproex with atypical antipsychotics, antidepressants, and lamotrigine.

Related resources

• Nathan PE, Gorman JM, eds. A Guide to Treatments that Work. 2nd ed. New York: Oxford University Press, 2001.
• Buckley PF, Waddington JL, eds. Schizophrenia and Mood Disorders: the New Drug Therapies in Clinical Practice. Boston: Butterworth-Heiman, 2000.
• Goldberg JF, Harrow M. Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999.
• Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry 2000;48:573-81.
• Hirschfeld RMA, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of bipolar disorder (revision). Am J Psychiatry, in press.

Drug brand names

• Clozapine • Clozaril
• Divalproex • Depakote, Depakote Sprinkle
• Lamotrigine • Lamictal
• Mirtazapine • Remeron, Remeron Soltab
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trazodone • Desyrel
• Valproate sodium • Depacon
• Ziprasidone • Geodon

Disclosure

Dr. Keck reports that he receives grant/research support from and serves as a consultant to Abbott Laboratories, AstraZeneca, Pfizer Inc., and Eli Lilly and Co. He also receives grant/research support from Merck and Co. and Otsuka America Pharmaceutical, and serves as a consultant to Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceutica.

 

Dr. McElroy reports that she receives grant/research support from and serves as a consultant to Abbott Laboratories, Elan Pharmaceuticals, Cephalon Inc. GlaxoSmithKline, and Eli Lilly and Co. She also receives grant/research support from Forest Pharmaceuticals and Solvay Pharmaceuticals, and serves as a consultant to Bristol-Myers Squibb Co., Ortho-McNeil Pharmaceutical, and Janssen Pharmaceutica.

Dr. Nelson reports no financial relationship with any company whose products are mentioned in this article.

Are you prepared to deal with a violent patient? Psychiatrists face a 40%to 50% chance of being assaulted during their careers, especially during residency training.¹ Self-reported violence has been found to be 5 to 18 times more prevalent in patients with Axis I psychiatric disorders than in the general population.² That finding, however, does not account for the inestimable acts of patient aggression that go unreported in psychiatric settings.

Lax security at inpatient facilities leaves emergency service psychiatrists alarmingly vulnerable. Avrim Fishkind, MD, reports that a metal-detecting arch uncovered the following potential weapons brought to his Houston emergency room within 1 year:

• 2,066 cigarette lighters
  
• 1,155 knives
  
• 65 razors
  
• 26 canisters of mace/pepper gas
  
• 2 rounds of ammunition
  
• 1 stun gun
  
• 1 firearm
  
• Assortment of potential weapons such as can openers, tweezers, etc.
  

Then there’s the lingering impact on your staff. Patient violence has been linked to emotional trauma, absenteeism, diminished job satisfaction, and high turnover among psychiatric staff.³

The insights of Dr. Fishkind and J. Randolph Hillard, MD, in this issue could save your practice—even your life.

In “Choosing antipsychotics for rapid tranquilization in the ER,” Dr. Hillard reviews the history behind emergency psychiatric pharmacologic therapy, then spells out a rational approach to fast tranquilization when needed, favoring an antipsychotic or a benzodiazepine.

In “Calming agitation with words, not drugs” Dr. Fishkind offers a 3-part strategy designed to help psychiatrists avoid pharmacologic intervention and resolve disruptive episodes peacefully in most cases. His strategy includes a firm knowledge of DSM-IV diagnoses associated with violence, a violence assessment checklist, and the ability to quickly recognize impending violent acts.