Evidence-Based Reviews

Current antipsychotics are reasonably effective in treating positive symptoms, but they do less to improve the negative and cognitive symptoms¹ that contribute to patients’ long-term poor functional capacity and quality of life.² So what do psychiatrists do in clinical practice to mitigate antipsychotics’ limitations? We augment.

Schizophrenia patients routinely are treated with polypharmacy—often with antidepressants or anticonvulsants—in attempts to improve negative symptoms, aggression, and impulsivity.³ Most adjuncts, however—including divalproex, antidepressants, and lithium—have shown very small, inconsistent, or no effects.^4,5 The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine,⁶ an anticonvulsant approved for use in epilepsy.⁷

This article examines the evidence supporting off-label use of lamotrigine as an augmenting agent in schizophrenia and explains the rationale, based on lamotrigine’s probable mechanism of action as a stabilizer of glutamate neurotransmission.

Is lamotrigine worth trying?

Some 20% of schizophrenia patients are considered treatment-resistant, with persistent positive symptoms despite having undergone ≥2 adequate antipsychotic trials.⁸ Evidence suggests clozapine then should be tried,⁴ but approximately one-half of treatment-resistant patients do not respond to clozapine. Treatment guidelines are limited for these 10% of schizophrenia patients with an inadequate response to available therapies, including clozapine.⁴

In a meta-analysis of 5 controlled trials in patients with treatment-resistant schizophrenia, adjunctive lamotrigine was shown to significantly reduce Positive and Negative Syndrome Scale (PANSS) total scores, positive symptom subscores, and negative symptom subscores.⁶ In these trials, lamotrigine was added to various antipsychotics, including clozapine. Based on the results—as outlined below—we suggest:

• In treatment-resistant patients with residual symptoms while taking clozapine, lamotrigine given in dosages ≥200 mg/d could be a first-line adjunct (Figure 1).
• Lamotrigine augmentation also might help patients whose positive symptoms are adequately controlled but who have persistent negative and/or cognitive symptoms.
• Evidence does not support routine use of lamotrigine in patients taking antipsychotics other than clozapine.

Managing side effects. Lamotrigine is generally well tolerated; in the meta-analysis, nausea was the only side effect more common with lamotrigine (9%) than with placebo (3.9%).⁶ Close follow-up is required, however, as a few case reports have noted worsening positive symptoms when lamotrigine was added to antipsychotics.^9,10

Lamotrigine produces a skin rash in approximately 10% of patients; the rash usually is benign but may be severe, including the potentially fatal Stevens-Johnson syndrome.¹¹ In the meta-analysis, rash was no more likely in patients receiving placebo (3%) than those receiving lamotrigine (2.2%), and no serious rashes were reported.⁶ Even so, lamotrigine needs to be titrated upwards very slowly over weeks, and patients must be able to monitor for rash.

Figure 1 An evidence-based approach to treatment-resistant schizophrenia

Treatment-resistant schizophrenia is defined as residual positive symptoms after ≥2 adequate antipsychotic trials. Evidence supports trying clozapine as the next step.⁴ When patients show an inadequate response to clozapine, a meta-analysis of 5 controlled trials⁶ indicates that lamotrigine may be a useful first-line adjunct.

Why consider lamotrigine?

During clinical trials of lamotrigine for epilepsy, patients showed improved mood¹² as is seen with other anticonvulsants such as valproate and carbamazepine.¹³ A series of randomized trials then demonstrated lamotrigine’s effectiveness in treating patients with bipolar I disorder, especially during depressive episodes,^14,15 and the FDA approved lamotrigine for maintenance treatment of bipolar I disorder.¹⁶ In those early studies, lamotrigine also improved bipolar patients’ quality of life and cognitive function in addition to showing mood-stabilizing properties.¹²

The glutamate hypothesis. Lamotrigine is an inhibitor of voltage-gated sodium channels and has been shown to inhibit the excessive synaptic release of glutamate.¹⁷ Glutamate is the primary excitatory neurotransmitter for at least 60% of neurons in the brain, including all cortical pyramidal neurons. A large body of evidence implicates dysfunctional glutamate signaling in the pathophysiology of schizophrenia.¹⁸

For example, phencyclidine (PCP) and ketamine—antagonists of one subtype of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor—are well known to produce positive psychotic symptoms, negative symptoms, and cognitive dysfunction.¹⁹ This led to a long-held hypothesis that schizophrenia is caused by too little glutamate. However, ketamine and PCP also increase the release of glutamate at synapses that then can act on glutamate receptors other than the NMDA receptor, which suggests that too much glutamate also may be involved in schizophrenia.

Too little or too much glutamate? These competing hypotheses could both be at least partially true, suggesting an “inverted-U” pattern of glutamate signaling (Figure 2). Because glutamate is involved in most cortical functions, too little glutamate can cause cognitive and processing deficits such as those seen in schizophrenia. On the other hand, too much glutamate can be toxic to neurons and may be a factor in neurodegeneration, such as in Alzheimer’s disease.²⁰ Indeed, schizophrenia may be associated with gradual neurodegeneration.²¹

Figure 2 Inverted U-curve may explain dysfunctional glutamate signaling in schizophrenia

Both too little or too much glutamate may play a role in schizophrenia’s pathophysiology. Glutamate, the major excitatory neurotransmitter of the cerebral cortex, is involved in most cognitive functions. Too little (or glutamate inhibition) can impair cognition, whereas too much can lead to seizures, neurotoxicity, and cell death.

Glutamate stabilization?

Because lamotrigine prevents excessive glutamate release at synapses, it stabilizes neuronal membranes by preventing toxicity from too much glutamate without interfering with glutamate’s normal functions.²² Thus, lamotrigine may have potential to maintain optimal glutamate signaling in patients with schizophrenia.

In 16 healthy volunteers, a 300-mg dose of lamotrigine was significantly more effective than placebo in reducing ketamine-induced positive symptoms, as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P < .001). Lamotrigine pretreatment also reduced negative symptoms and improved learning and memory.²³

More recently, lamotrigine pretreatment was shown to prevent many ketamine-induced changes on functional MRI.²⁴ Few antipsychotics have clinically significant effects on ketamine-induced symptoms—especially in a single dose—although repeated dosing with clozapine attenuates some ketamine-induced effects.²⁵

Given the limitations of available antipsychotics, adding a drug such as lamotrigine—which may modulate and stabilize the glutamate system—could be effective in treatment-resistant schizophrenia.

What is the evidence?

Case reports and open-label case series first showed that lamotrigine augmentation could be effective in treatment-resistant schizophrenia patients receiving clozapine.^26–28 One naturalistic case series also included patients receiving olanzapine or risperidone and suggested greater improvement with lamotrigine augmentation in patients on clozapine.²⁶

Controlled trials. In a placebo-controlled trial, Tiihonen et al²⁹ reported significantly lower ratings of positive symptoms—but not negative symptoms—after 38 treatment-resistant schizophrenia patients on clozapine received adjunctive lamotrigine, 200 mg/d, for 14 weeks (Table 1).

A subsequent controlled trial in which Kremer et al³⁰ added lamotrigine, ≤400 mg/d, showed significant improvements in positive and negative symptoms among 31 treatment-resistant schizophrenia patients who completed the 10-week study. Patients were taking conventional and atypical antipsychotics, including clozapine. All groups improved, but the study was not powered to detect differences among the groups.

Table 1

Lamotrigine augmentation: 5 double-blind, placebo-controlled trials

A third trial by Akhondzadeh et al,³¹ augmenting risperidone with lamotrigine, 150 mg/d, resulted in modest improvements in negative and cognitive symptoms and slight improvement in positive symptoms.

Multicenter trials. Preliminary trials led to 2 randomized, double-blind, multicenter studies. In a total of 429 schizophrenia outpatients with residual psychotic symptoms on atypical antipsychotics, lamotrigine, 100 to 400 mg/d, or placebo was added for 12 weeks.³² The combined results failed to show significant improvement with adjunctive lamotrigine in any symptom domain compared with placebo. One study showed some improved negative symptoms, and the other showed improved cognitive symptoms.

Possible reasons for these negative results were unclear, although:

• a relatively large placebo response, compared with other studies, suggests a “failed” clinical trial
• the small number of patients receiving clozapine in this study suggests that they may have been less treatment-resistant than those enrolled in prior studies.

Meta-analysis. A meta-analysis of data from these 5 randomized, controlled trials found the “positive, negative, and general psychopathology subscale scores as measured with the PANSS … showed significant difference favoring adjuvant lamotrigine” (Table 2).⁶ As for study limitations, the authors noted that effectiveness data could be usefully analyzed in <70 of the 537 patients from the controlled trials, and “the small mean decrease in scores may not be really clinically relevant.”⁶ Thus, they said, caution is warranted in translating these results to clinical practice.

One more trial. Since the meta-analysis, an additional placebo-controlled trial has been reported.³³ In this 24-week trial, lamotrigine augmentation, ≤200 mg/d, was statistically more effective than placebo in reducing positive and negative symptoms in 51 stable treatment-resistant patients on clozapine. Cognitive function also improved.

Table 2

How symptom scores changed with add-on lamotrigine in the meta-analysis of controlled trials

Only treatment-resistant patients?

In controlled trials, lamotrigine augmentation has had the greatest effect on positive and negative symptoms in treatment-resistant schizophrenia patients, especially those on clozapine. Could lamotrigine augmentation be of benefit only in treatment-resistant schizophrenia?

Analysis of trial findings. As mentioned, outpatients who comprised the majority of subjects in the 2 large “negative” (or possibly failed) trials³² might have been less treatment-resistant than subjects in the other trials. Lower mean lamotrigine dosages (205 mg/d and 241 mg/d) also were used in the 2 negative trials and in the trial by Akhondzadeh et al (150 mg/d)³¹—compared with up to 400 mg/d in the trial by Kremer et al.³⁰ This suggests that insufficient dosing might have caused the nonsignificant findings.

Given schizophrenia’s heterogeneity, treatment-resistant patients may represent a subgroup that has greater glutamatergic dysfunction, whereas patients who respond more completely to antipsychotics may have greater dopaminergic dysfunction. Thus, lamotrigine augmentation might be more beneficial in the subset of treatment-resistant patients. Lamotrigine or other glutamate stabilizers have been proposed to act as neuroprotective agents, slowing functional decline in chronic schizophrenia³⁴ (although long-term studies needed to test this hypothesis are unlikely to occur because of cost and time constraints).

Another hypothetical, yet intriguing, explanation for the greater effects of lamotrigine augmentation in patients on clozapine is a pharmacodynamic interaction between these 2 drugs. Clozapine (and possibly olanzapine) have been shown to enhance cortical glutamatergic transmission.²⁵ We propose that clozapine-induced boosting of glutamate in concert with stabilization of the glutamate system by lamotrigine improves neuronal functioning. Clinical trial data regarding lamotrigine augmentation of antipsychotics other than clozapine are needed to determine if the relationship between clozapine and lamotrigine is unique.

Related resources

• Lamotrigine prescribing information and patient handout. www.lamictal.com/bipolar/hcp/prescibing_information. html.
• Augmentation strategies for schizophrenia. IPAP Schizophrenia algorithm flowchart (online interactive version), node 11. www.ipap.org/algorithms.php.

Drug brand names

• Carbamazepine • Carbatrol, Equetro, Tegretol
• Clozapine • Clozaril
• Divalproex • Depakote
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Valproate • Depacon, Depakene

Disclosures

Dr. Gray reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Risch receives research support from the National Institute of Mental Health and is a speaker for AstraZeneca and Pfizer Inc.

Current antipsychotics are reasonably effective in treating positive symptoms, but they do less to improve the negative and cognitive symptoms¹ that contribute to patients’ long-term poor functional capacity and quality of life.² So what do psychiatrists do in clinical practice to mitigate antipsychotics’ limitations? We augment.

Schizophrenia patients routinely are treated with polypharmacy—often with antidepressants or anticonvulsants—in attempts to improve negative symptoms, aggression, and impulsivity.³ Most adjuncts, however—including divalproex, antidepressants, and lithium—have shown very small, inconsistent, or no effects.^4,5 The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine,⁶ an anticonvulsant approved for use in epilepsy.⁷

This article examines the evidence supporting off-label use of lamotrigine as an augmenting agent in schizophrenia and explains the rationale, based on lamotrigine’s probable mechanism of action as a stabilizer of glutamate neurotransmission.

Is lamotrigine worth trying?

Some 20% of schizophrenia patients are considered treatment-resistant, with persistent positive symptoms despite having undergone ≥2 adequate antipsychotic trials.⁸ Evidence suggests clozapine then should be tried,⁴ but approximately one-half of treatment-resistant patients do not respond to clozapine. Treatment guidelines are limited for these 10% of schizophrenia patients with an inadequate response to available therapies, including clozapine.⁴

In a meta-analysis of 5 controlled trials in patients with treatment-resistant schizophrenia, adjunctive lamotrigine was shown to significantly reduce Positive and Negative Syndrome Scale (PANSS) total scores, positive symptom subscores, and negative symptom subscores.⁶ In these trials, lamotrigine was added to various antipsychotics, including clozapine. Based on the results—as outlined below—we suggest:

• In treatment-resistant patients with residual symptoms while taking clozapine, lamotrigine given in dosages ≥200 mg/d could be a first-line adjunct (Figure 1).
• Lamotrigine augmentation also might help patients whose positive symptoms are adequately controlled but who have persistent negative and/or cognitive symptoms.
• Evidence does not support routine use of lamotrigine in patients taking antipsychotics other than clozapine.

Managing side effects. Lamotrigine is generally well tolerated; in the meta-analysis, nausea was the only side effect more common with lamotrigine (9%) than with placebo (3.9%).⁶ Close follow-up is required, however, as a few case reports have noted worsening positive symptoms when lamotrigine was added to antipsychotics.^9,10

Lamotrigine produces a skin rash in approximately 10% of patients; the rash usually is benign but may be severe, including the potentially fatal Stevens-Johnson syndrome.¹¹ In the meta-analysis, rash was no more likely in patients receiving placebo (3%) than those receiving lamotrigine (2.2%), and no serious rashes were reported.⁶ Even so, lamotrigine needs to be titrated upwards very slowly over weeks, and patients must be able to monitor for rash.

Figure 1 An evidence-based approach to treatment-resistant schizophrenia

Treatment-resistant schizophrenia is defined as residual positive symptoms after ≥2 adequate antipsychotic trials. Evidence supports trying clozapine as the next step.⁴ When patients show an inadequate response to clozapine, a meta-analysis of 5 controlled trials⁶ indicates that lamotrigine may be a useful first-line adjunct.

Why consider lamotrigine?

During clinical trials of lamotrigine for epilepsy, patients showed improved mood¹² as is seen with other anticonvulsants such as valproate and carbamazepine.¹³ A series of randomized trials then demonstrated lamotrigine’s effectiveness in treating patients with bipolar I disorder, especially during depressive episodes,^14,15 and the FDA approved lamotrigine for maintenance treatment of bipolar I disorder.¹⁶ In those early studies, lamotrigine also improved bipolar patients’ quality of life and cognitive function in addition to showing mood-stabilizing properties.¹²

The glutamate hypothesis. Lamotrigine is an inhibitor of voltage-gated sodium channels and has been shown to inhibit the excessive synaptic release of glutamate.¹⁷ Glutamate is the primary excitatory neurotransmitter for at least 60% of neurons in the brain, including all cortical pyramidal neurons. A large body of evidence implicates dysfunctional glutamate signaling in the pathophysiology of schizophrenia.¹⁸

For example, phencyclidine (PCP) and ketamine—antagonists of one subtype of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor—are well known to produce positive psychotic symptoms, negative symptoms, and cognitive dysfunction.¹⁹ This led to a long-held hypothesis that schizophrenia is caused by too little glutamate. However, ketamine and PCP also increase the release of glutamate at synapses that then can act on glutamate receptors other than the NMDA receptor, which suggests that too much glutamate also may be involved in schizophrenia.

Too little or too much glutamate? These competing hypotheses could both be at least partially true, suggesting an “inverted-U” pattern of glutamate signaling (Figure 2). Because glutamate is involved in most cortical functions, too little glutamate can cause cognitive and processing deficits such as those seen in schizophrenia. On the other hand, too much glutamate can be toxic to neurons and may be a factor in neurodegeneration, such as in Alzheimer’s disease.²⁰ Indeed, schizophrenia may be associated with gradual neurodegeneration.²¹

Figure 2 Inverted U-curve may explain dysfunctional glutamate signaling in schizophrenia

Both too little or too much glutamate may play a role in schizophrenia’s pathophysiology. Glutamate, the major excitatory neurotransmitter of the cerebral cortex, is involved in most cognitive functions. Too little (or glutamate inhibition) can impair cognition, whereas too much can lead to seizures, neurotoxicity, and cell death.

Glutamate stabilization?

Because lamotrigine prevents excessive glutamate release at synapses, it stabilizes neuronal membranes by preventing toxicity from too much glutamate without interfering with glutamate’s normal functions.²² Thus, lamotrigine may have potential to maintain optimal glutamate signaling in patients with schizophrenia.

In 16 healthy volunteers, a 300-mg dose of lamotrigine was significantly more effective than placebo in reducing ketamine-induced positive symptoms, as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P < .001). Lamotrigine pretreatment also reduced negative symptoms and improved learning and memory.²³

More recently, lamotrigine pretreatment was shown to prevent many ketamine-induced changes on functional MRI.²⁴ Few antipsychotics have clinically significant effects on ketamine-induced symptoms—especially in a single dose—although repeated dosing with clozapine attenuates some ketamine-induced effects.²⁵

Given the limitations of available antipsychotics, adding a drug such as lamotrigine—which may modulate and stabilize the glutamate system—could be effective in treatment-resistant schizophrenia.

What is the evidence?

Case reports and open-label case series first showed that lamotrigine augmentation could be effective in treatment-resistant schizophrenia patients receiving clozapine.^26–28 One naturalistic case series also included patients receiving olanzapine or risperidone and suggested greater improvement with lamotrigine augmentation in patients on clozapine.²⁶

Controlled trials. In a placebo-controlled trial, Tiihonen et al²⁹ reported significantly lower ratings of positive symptoms—but not negative symptoms—after 38 treatment-resistant schizophrenia patients on clozapine received adjunctive lamotrigine, 200 mg/d, for 14 weeks (Table 1).

A subsequent controlled trial in which Kremer et al³⁰ added lamotrigine, ≤400 mg/d, showed significant improvements in positive and negative symptoms among 31 treatment-resistant schizophrenia patients who completed the 10-week study. Patients were taking conventional and atypical antipsychotics, including clozapine. All groups improved, but the study was not powered to detect differences among the groups.

Table 1

Lamotrigine augmentation: 5 double-blind, placebo-controlled trials

A third trial by Akhondzadeh et al,³¹ augmenting risperidone with lamotrigine, 150 mg/d, resulted in modest improvements in negative and cognitive symptoms and slight improvement in positive symptoms.

Multicenter trials. Preliminary trials led to 2 randomized, double-blind, multicenter studies. In a total of 429 schizophrenia outpatients with residual psychotic symptoms on atypical antipsychotics, lamotrigine, 100 to 400 mg/d, or placebo was added for 12 weeks.³² The combined results failed to show significant improvement with adjunctive lamotrigine in any symptom domain compared with placebo. One study showed some improved negative symptoms, and the other showed improved cognitive symptoms.

Possible reasons for these negative results were unclear, although:

• a relatively large placebo response, compared with other studies, suggests a “failed” clinical trial
• the small number of patients receiving clozapine in this study suggests that they may have been less treatment-resistant than those enrolled in prior studies.

Meta-analysis. A meta-analysis of data from these 5 randomized, controlled trials found the “positive, negative, and general psychopathology subscale scores as measured with the PANSS … showed significant difference favoring adjuvant lamotrigine” (Table 2).⁶ As for study limitations, the authors noted that effectiveness data could be usefully analyzed in <70 of the 537 patients from the controlled trials, and “the small mean decrease in scores may not be really clinically relevant.”⁶ Thus, they said, caution is warranted in translating these results to clinical practice.

One more trial. Since the meta-analysis, an additional placebo-controlled trial has been reported.³³ In this 24-week trial, lamotrigine augmentation, ≤200 mg/d, was statistically more effective than placebo in reducing positive and negative symptoms in 51 stable treatment-resistant patients on clozapine. Cognitive function also improved.

Table 2

How symptom scores changed with add-on lamotrigine in the meta-analysis of controlled trials

Only treatment-resistant patients?

In controlled trials, lamotrigine augmentation has had the greatest effect on positive and negative symptoms in treatment-resistant schizophrenia patients, especially those on clozapine. Could lamotrigine augmentation be of benefit only in treatment-resistant schizophrenia?

Analysis of trial findings. As mentioned, outpatients who comprised the majority of subjects in the 2 large “negative” (or possibly failed) trials³² might have been less treatment-resistant than subjects in the other trials. Lower mean lamotrigine dosages (205 mg/d and 241 mg/d) also were used in the 2 negative trials and in the trial by Akhondzadeh et al (150 mg/d)³¹—compared with up to 400 mg/d in the trial by Kremer et al.³⁰ This suggests that insufficient dosing might have caused the nonsignificant findings.

Given schizophrenia’s heterogeneity, treatment-resistant patients may represent a subgroup that has greater glutamatergic dysfunction, whereas patients who respond more completely to antipsychotics may have greater dopaminergic dysfunction. Thus, lamotrigine augmentation might be more beneficial in the subset of treatment-resistant patients. Lamotrigine or other glutamate stabilizers have been proposed to act as neuroprotective agents, slowing functional decline in chronic schizophrenia³⁴ (although long-term studies needed to test this hypothesis are unlikely to occur because of cost and time constraints).

Another hypothetical, yet intriguing, explanation for the greater effects of lamotrigine augmentation in patients on clozapine is a pharmacodynamic interaction between these 2 drugs. Clozapine (and possibly olanzapine) have been shown to enhance cortical glutamatergic transmission.²⁵ We propose that clozapine-induced boosting of glutamate in concert with stabilization of the glutamate system by lamotrigine improves neuronal functioning. Clinical trial data regarding lamotrigine augmentation of antipsychotics other than clozapine are needed to determine if the relationship between clozapine and lamotrigine is unique.

Related resources

• Lamotrigine prescribing information and patient handout. www.lamictal.com/bipolar/hcp/prescibing_information. html.
• Augmentation strategies for schizophrenia. IPAP Schizophrenia algorithm flowchart (online interactive version), node 11. www.ipap.org/algorithms.php.

Drug brand names

• Carbamazepine • Carbatrol, Equetro, Tegretol
• Clozapine • Clozaril
• Divalproex • Depakote
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Valproate • Depacon, Depakene

Disclosures

Dr. Gray reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Risch receives research support from the National Institute of Mental Health and is a speaker for AstraZeneca and Pfizer Inc.

Current antipsychotics are reasonably effective in treating positive symptoms, but they do less to improve the negative and cognitive symptoms¹ that contribute to patients’ long-term poor functional capacity and quality of life.² So what do psychiatrists do in clinical practice to mitigate antipsychotics’ limitations? We augment.

Schizophrenia patients routinely are treated with polypharmacy—often with antidepressants or anticonvulsants—in attempts to improve negative symptoms, aggression, and impulsivity.³ Most adjuncts, however—including divalproex, antidepressants, and lithium—have shown very small, inconsistent, or no effects.^4,5 The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine,⁶ an anticonvulsant approved for use in epilepsy.⁷

This article examines the evidence supporting off-label use of lamotrigine as an augmenting agent in schizophrenia and explains the rationale, based on lamotrigine’s probable mechanism of action as a stabilizer of glutamate neurotransmission.

Is lamotrigine worth trying?

Some 20% of schizophrenia patients are considered treatment-resistant, with persistent positive symptoms despite having undergone ≥2 adequate antipsychotic trials.⁸ Evidence suggests clozapine then should be tried,⁴ but approximately one-half of treatment-resistant patients do not respond to clozapine. Treatment guidelines are limited for these 10% of schizophrenia patients with an inadequate response to available therapies, including clozapine.⁴

In a meta-analysis of 5 controlled trials in patients with treatment-resistant schizophrenia, adjunctive lamotrigine was shown to significantly reduce Positive and Negative Syndrome Scale (PANSS) total scores, positive symptom subscores, and negative symptom subscores.⁶ In these trials, lamotrigine was added to various antipsychotics, including clozapine. Based on the results—as outlined below—we suggest:

• In treatment-resistant patients with residual symptoms while taking clozapine, lamotrigine given in dosages ≥200 mg/d could be a first-line adjunct (Figure 1).
• Lamotrigine augmentation also might help patients whose positive symptoms are adequately controlled but who have persistent negative and/or cognitive symptoms.
• Evidence does not support routine use of lamotrigine in patients taking antipsychotics other than clozapine.

Managing side effects. Lamotrigine is generally well tolerated; in the meta-analysis, nausea was the only side effect more common with lamotrigine (9%) than with placebo (3.9%).⁶ Close follow-up is required, however, as a few case reports have noted worsening positive symptoms when lamotrigine was added to antipsychotics.^9,10

Lamotrigine produces a skin rash in approximately 10% of patients; the rash usually is benign but may be severe, including the potentially fatal Stevens-Johnson syndrome.¹¹ In the meta-analysis, rash was no more likely in patients receiving placebo (3%) than those receiving lamotrigine (2.2%), and no serious rashes were reported.⁶ Even so, lamotrigine needs to be titrated upwards very slowly over weeks, and patients must be able to monitor for rash.

Figure 1 An evidence-based approach to treatment-resistant schizophrenia

Treatment-resistant schizophrenia is defined as residual positive symptoms after ≥2 adequate antipsychotic trials. Evidence supports trying clozapine as the next step.⁴ When patients show an inadequate response to clozapine, a meta-analysis of 5 controlled trials⁶ indicates that lamotrigine may be a useful first-line adjunct.

Why consider lamotrigine?

During clinical trials of lamotrigine for epilepsy, patients showed improved mood¹² as is seen with other anticonvulsants such as valproate and carbamazepine.¹³ A series of randomized trials then demonstrated lamotrigine’s effectiveness in treating patients with bipolar I disorder, especially during depressive episodes,^14,15 and the FDA approved lamotrigine for maintenance treatment of bipolar I disorder.¹⁶ In those early studies, lamotrigine also improved bipolar patients’ quality of life and cognitive function in addition to showing mood-stabilizing properties.¹²

The glutamate hypothesis. Lamotrigine is an inhibitor of voltage-gated sodium channels and has been shown to inhibit the excessive synaptic release of glutamate.¹⁷ Glutamate is the primary excitatory neurotransmitter for at least 60% of neurons in the brain, including all cortical pyramidal neurons. A large body of evidence implicates dysfunctional glutamate signaling in the pathophysiology of schizophrenia.¹⁸

For example, phencyclidine (PCP) and ketamine—antagonists of one subtype of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor—are well known to produce positive psychotic symptoms, negative symptoms, and cognitive dysfunction.¹⁹ This led to a long-held hypothesis that schizophrenia is caused by too little glutamate. However, ketamine and PCP also increase the release of glutamate at synapses that then can act on glutamate receptors other than the NMDA receptor, which suggests that too much glutamate also may be involved in schizophrenia.

Too little or too much glutamate? These competing hypotheses could both be at least partially true, suggesting an “inverted-U” pattern of glutamate signaling (Figure 2). Because glutamate is involved in most cortical functions, too little glutamate can cause cognitive and processing deficits such as those seen in schizophrenia. On the other hand, too much glutamate can be toxic to neurons and may be a factor in neurodegeneration, such as in Alzheimer’s disease.²⁰ Indeed, schizophrenia may be associated with gradual neurodegeneration.²¹

Figure 2 Inverted U-curve may explain dysfunctional glutamate signaling in schizophrenia

Both too little or too much glutamate may play a role in schizophrenia’s pathophysiology. Glutamate, the major excitatory neurotransmitter of the cerebral cortex, is involved in most cognitive functions. Too little (or glutamate inhibition) can impair cognition, whereas too much can lead to seizures, neurotoxicity, and cell death.

Glutamate stabilization?

Because lamotrigine prevents excessive glutamate release at synapses, it stabilizes neuronal membranes by preventing toxicity from too much glutamate without interfering with glutamate’s normal functions.²² Thus, lamotrigine may have potential to maintain optimal glutamate signaling in patients with schizophrenia.

In 16 healthy volunteers, a 300-mg dose of lamotrigine was significantly more effective than placebo in reducing ketamine-induced positive symptoms, as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P < .001). Lamotrigine pretreatment also reduced negative symptoms and improved learning and memory.²³

More recently, lamotrigine pretreatment was shown to prevent many ketamine-induced changes on functional MRI.²⁴ Few antipsychotics have clinically significant effects on ketamine-induced symptoms—especially in a single dose—although repeated dosing with clozapine attenuates some ketamine-induced effects.²⁵

Given the limitations of available antipsychotics, adding a drug such as lamotrigine—which may modulate and stabilize the glutamate system—could be effective in treatment-resistant schizophrenia.

What is the evidence?

Case reports and open-label case series first showed that lamotrigine augmentation could be effective in treatment-resistant schizophrenia patients receiving clozapine.^26–28 One naturalistic case series also included patients receiving olanzapine or risperidone and suggested greater improvement with lamotrigine augmentation in patients on clozapine.²⁶

Controlled trials. In a placebo-controlled trial, Tiihonen et al²⁹ reported significantly lower ratings of positive symptoms—but not negative symptoms—after 38 treatment-resistant schizophrenia patients on clozapine received adjunctive lamotrigine, 200 mg/d, for 14 weeks (Table 1).

A subsequent controlled trial in which Kremer et al³⁰ added lamotrigine, ≤400 mg/d, showed significant improvements in positive and negative symptoms among 31 treatment-resistant schizophrenia patients who completed the 10-week study. Patients were taking conventional and atypical antipsychotics, including clozapine. All groups improved, but the study was not powered to detect differences among the groups.

Table 1

Lamotrigine augmentation: 5 double-blind, placebo-controlled trials

A third trial by Akhondzadeh et al,³¹ augmenting risperidone with lamotrigine, 150 mg/d, resulted in modest improvements in negative and cognitive symptoms and slight improvement in positive symptoms.

Multicenter trials. Preliminary trials led to 2 randomized, double-blind, multicenter studies. In a total of 429 schizophrenia outpatients with residual psychotic symptoms on atypical antipsychotics, lamotrigine, 100 to 400 mg/d, or placebo was added for 12 weeks.³² The combined results failed to show significant improvement with adjunctive lamotrigine in any symptom domain compared with placebo. One study showed some improved negative symptoms, and the other showed improved cognitive symptoms.

Possible reasons for these negative results were unclear, although:

• a relatively large placebo response, compared with other studies, suggests a “failed” clinical trial
• the small number of patients receiving clozapine in this study suggests that they may have been less treatment-resistant than those enrolled in prior studies.

Meta-analysis. A meta-analysis of data from these 5 randomized, controlled trials found the “positive, negative, and general psychopathology subscale scores as measured with the PANSS … showed significant difference favoring adjuvant lamotrigine” (Table 2).⁶ As for study limitations, the authors noted that effectiveness data could be usefully analyzed in <70 of the 537 patients from the controlled trials, and “the small mean decrease in scores may not be really clinically relevant.”⁶ Thus, they said, caution is warranted in translating these results to clinical practice.

One more trial. Since the meta-analysis, an additional placebo-controlled trial has been reported.³³ In this 24-week trial, lamotrigine augmentation, ≤200 mg/d, was statistically more effective than placebo in reducing positive and negative symptoms in 51 stable treatment-resistant patients on clozapine. Cognitive function also improved.

Table 2

How symptom scores changed with add-on lamotrigine in the meta-analysis of controlled trials

Only treatment-resistant patients?

In controlled trials, lamotrigine augmentation has had the greatest effect on positive and negative symptoms in treatment-resistant schizophrenia patients, especially those on clozapine. Could lamotrigine augmentation be of benefit only in treatment-resistant schizophrenia?

Analysis of trial findings. As mentioned, outpatients who comprised the majority of subjects in the 2 large “negative” (or possibly failed) trials³² might have been less treatment-resistant than subjects in the other trials. Lower mean lamotrigine dosages (205 mg/d and 241 mg/d) also were used in the 2 negative trials and in the trial by Akhondzadeh et al (150 mg/d)³¹—compared with up to 400 mg/d in the trial by Kremer et al.³⁰ This suggests that insufficient dosing might have caused the nonsignificant findings.

Given schizophrenia’s heterogeneity, treatment-resistant patients may represent a subgroup that has greater glutamatergic dysfunction, whereas patients who respond more completely to antipsychotics may have greater dopaminergic dysfunction. Thus, lamotrigine augmentation might be more beneficial in the subset of treatment-resistant patients. Lamotrigine or other glutamate stabilizers have been proposed to act as neuroprotective agents, slowing functional decline in chronic schizophrenia³⁴ (although long-term studies needed to test this hypothesis are unlikely to occur because of cost and time constraints).

Another hypothetical, yet intriguing, explanation for the greater effects of lamotrigine augmentation in patients on clozapine is a pharmacodynamic interaction between these 2 drugs. Clozapine (and possibly olanzapine) have been shown to enhance cortical glutamatergic transmission.²⁵ We propose that clozapine-induced boosting of glutamate in concert with stabilization of the glutamate system by lamotrigine improves neuronal functioning. Clinical trial data regarding lamotrigine augmentation of antipsychotics other than clozapine are needed to determine if the relationship between clozapine and lamotrigine is unique.

Related resources

• Lamotrigine prescribing information and patient handout. www.lamictal.com/bipolar/hcp/prescibing_information. html.
• Augmentation strategies for schizophrenia. IPAP Schizophrenia algorithm flowchart (online interactive version), node 11. www.ipap.org/algorithms.php.

Drug brand names

• Carbamazepine • Carbatrol, Equetro, Tegretol
• Clozapine • Clozaril
• Divalproex • Depakote
• Ketamine • Ketalar
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Risperidone • Risperdal
• Valproate • Depacon, Depakene

Disclosures

Dr. Gray reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Risch receives research support from the National Institute of Mental Health and is a speaker for AstraZeneca and Pfizer Inc.

Traditionally, clinicians have identified children at high risk for substance abuse disorders (SUDs) by their family history—such as “children of alcoholics.” Advances in etiology research, however, have led to the identification of other risks for SUDs seen during childhood (Table). The clustering of these SUD risk factors—genetic influences, family characteristics, and predictive phenotypes—makes it feasible to identify children and adolescents who are very likely to develop problematic substance use.

Table

Risk factors for substance abuse in children and adolescents

Nature vs nurture

Genetic influences. Heritable risk accounts for a substantial proportion of the variation in SUDs, as multiple genes differentially influence substance initiation, metabolism, and reinforcing properties.¹ For example, well-characterized genetic variations determine individual differences in alcohol dehydrogenase and aldehyde dehydrogenase—the enzymes involved in alcohol metabolism—and influence liability to alcohol use disorders (AUDs).^2,3 Researchers are exploring ways in which genes might impact SUD risk (Box 1).^1,4,5

Genetic influences on substance use may be less important during adolescence than adulthood. In a study of 1,796 male twins’ alcohol, nicotine, and cannabis use from early adolescence to middle adulthood, genetic variations had little or no influence on substance use in early adolescence. The influence of genetic factors gradually increased with age.⁶

Familial environmental factors, by contrast, were important in early adolescence and gradually decreased in effect with increasing age. During adolescence, the family’s influence on substance use apparently operates more through environmental characteristics than through heritable factors.⁶

Familial influences. Parents with ongoing SUDs model problematic substance use and create environments of child maltreatment and inadequate supervision.

Child maltreatment. Children of parents with SUDs are more likely to suffer sexual abuse, physical abuse, or neglect.⁷ The effects of sexual abuse on the child may vary by abuse severity and the child’s gender, developmental stage, and relationship to the perpetrator. Maltreatment may cause the child difficulties in psychological regulation and social development, leading to related psychopathology; these characteristics may contribute to later SUDs.⁸

Inadequate supervision. Adolescents who report that their parents do not effectively monitor their activities have an increased likelihood of developing SUDs. However, children/adolescents who exhibit difficulties with psychological regulation—such as impulsive behavior and irritability—are difficult to parent, and adolescents with early substance involvement may subvert parental supervision efforts.^9,10

Box 1

Predictive phenotypes

Predictive phenotypes—measurable individual characteristics that predict SUDs—may be considered risk factors but should not be viewed as causal influences akin to genetic and familial/environmental factors. Rather, predictive phenotypes may reflect propensities that are manifested by specific behaviors and other features according to developmental stage and environmental facilitation.

• specific psychiatric disorders
  
• specific personality traits that collectively are called psychological dysregulation
  
• early substance use.¹¹
  

Recent studies have demonstrated that this clustering of problems—including impulsive behavior, inattention, and negative affect—represents a single continuous dimension termed psychological dysregulation.¹² The construct of psychological dysregulation has origins in neuropathology and provides a conceptual link between childhood psychopathological characteristics known to predict SUD and neurobiological deficits.⁵ Childhood indices of psychological dysregulation—such as the Behavior Rating Inventory of Executive Function (BRIEF)¹⁴—complement other risk factors, such as parental SUDs and early substance use, in predicting accelerated substance use and SUDs.¹⁵

Neurobiological characteristics. Recent investigations have focused on relationships between variations in normal brain development and differences in psychological regulation.⁵ Several brain structures thought relevant to the development of psychological regulation—including the prefrontal cortex, limbic structures, and reward circuits—develop during adolescence. Delays or deficits in the development of these structures are called neurodevelopmental dysmaturation.⁵

Variation in genes that influence these brain areas may interact with environmental influences—including child maltreatment and early substance use—to produce neurodevelopmental dysmaturation that manifests as psychological dysregulation. Thus, genetic and environmental causes are hypothesized to lead to an endophenotype (neurodevelopmental dysmaturation) and developmentally specific phenotypes, such as:

• ADHD in childhood
  
• CD and accelerated substance use initiation in early adolescence
  
• SUDs involving alcohol and cannabis in late adolescence.⁵
  

Consuming small quantities of alcohol under parental supervision is culturally normative and does not predict problematic drinking.¹⁷ On the other hand, regularly consuming “standard drink” quantities of alcohol in late childhood typically occurs in unsupervised settings and predicts adolescent-onset AUDs.¹⁸

Problem-focused interview methods—including CAGE, TWEAK, and CRAFFT—have been developed and tested to screen adolescents for AUDs. None has been as consistently successful as the World Health Organization’s Alcohol Use Disorders Identification Test (AUDIT) questionnaire¹⁸ (see Related Resources).

Childhood cigarette smoking also predicts accelerated substance use and SUDs.¹⁵ Marijuana use predicts both cannabis use disorders and other illicit drug use.¹ This observation supports the controversial “gateway hypothesis,” which proposes that marijuana use accelerates the onset of other illicit drug use.^15,19,20 An alternate hypothesis proposes that use of marijuana and other illicit drugs is a developmentally specific manifestation of a more general liability for SUDs.¹

Identifying those at high risk

Screening for SUD risk factors makes it possible to identify children and adolescents who are very likely to develop problematic substance use. For example, in a study of 560 children age 10 to 12 at recruitment, this author (DBC) identified subjects as high risk if they had 2 parents with SUDs, tobacco or alcohol use by age 12, and high psychological dysregulation as measured by combined assessments of cognitive, emotional, and behavioral regulation. By age 18:

• three-quarters of these adolescents used tobacco daily
  
• more than one-half had alcohol problems
  
• nearly one-half had cannabis abuse or dependence.¹⁵
  

Recommendations. Children and adolescents receiving health care services—including primary care, ongoing treatment for chronic conditions, and treatment for psychiatric disorders—should be evaluated for SUD risk. Screening ideally occurs at the initial evaluation or early in the course of treatment. Family history determines genetic risk.

Direct questioning is needed because unstructured evaluations often fail to reveal the presence of important SUD risks.²¹ Explore possible child maltreatment by questioning the parent and child about physical abuse, sexual abuse, and neglect. Key mental disorders include CD, ADHD, and PTSD. Ask about use of tobacco, alcohol, cannabis, and other drugs. Follow acknowledgement of use with inquiries on frequency, quantity, and problems.

Prevention and early intervention

By identifying characteristics that confer risk for SUDs, you can target these characteristics in prevention and early treatment efforts. These efforts may involve parents as well as children. Many promising approaches have been developed, including universal or selective interventions based on family, school, community, or multi-component approaches.²²

Because parental SUDs are a prominent risk factor for children, interventions to reduce or eliminate parental substance use may be helpful, particularly for diminishing childhood psychological dysregulation.²³ Early treatment of childhood predictive phenotypes, including CD and ADHD, is another promising approach.¹² Community efforts to limit adolescents’ access to addictive substances have met with some success.²²

Parents, teachers, and children and adolescents can obtain a wealth of information from the Web sites of the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse (Box 2). The Centers for Disease Control and Prevention offers infomation about preventing smoking (see Related Resources.)

Box 2

• Alcohol Use Disorders Identification Test (AUDIT). World Health Organization. http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf.
  
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
  
• National Institute on Drug Abuse. www.nida.nih.gov.
  
• Centers for Disease Control and Prevention. Youth Tobacco Prevention. www.cdc.gov/tobacco/youth.
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Traditionally, clinicians have identified children at high risk for substance abuse disorders (SUDs) by their family history—such as “children of alcoholics.” Advances in etiology research, however, have led to the identification of other risks for SUDs seen during childhood (Table). The clustering of these SUD risk factors—genetic influences, family characteristics, and predictive phenotypes—makes it feasible to identify children and adolescents who are very likely to develop problematic substance use.

Table

Risk factors for substance abuse in children and adolescents

Nature vs nurture

Genetic influences. Heritable risk accounts for a substantial proportion of the variation in SUDs, as multiple genes differentially influence substance initiation, metabolism, and reinforcing properties.¹ For example, well-characterized genetic variations determine individual differences in alcohol dehydrogenase and aldehyde dehydrogenase—the enzymes involved in alcohol metabolism—and influence liability to alcohol use disorders (AUDs).^2,3 Researchers are exploring ways in which genes might impact SUD risk (Box 1).^1,4,5

Genetic influences on substance use may be less important during adolescence than adulthood. In a study of 1,796 male twins’ alcohol, nicotine, and cannabis use from early adolescence to middle adulthood, genetic variations had little or no influence on substance use in early adolescence. The influence of genetic factors gradually increased with age.⁶

Familial environmental factors, by contrast, were important in early adolescence and gradually decreased in effect with increasing age. During adolescence, the family’s influence on substance use apparently operates more through environmental characteristics than through heritable factors.⁶

Familial influences. Parents with ongoing SUDs model problematic substance use and create environments of child maltreatment and inadequate supervision.

Child maltreatment. Children of parents with SUDs are more likely to suffer sexual abuse, physical abuse, or neglect.⁷ The effects of sexual abuse on the child may vary by abuse severity and the child’s gender, developmental stage, and relationship to the perpetrator. Maltreatment may cause the child difficulties in psychological regulation and social development, leading to related psychopathology; these characteristics may contribute to later SUDs.⁸

Inadequate supervision. Adolescents who report that their parents do not effectively monitor their activities have an increased likelihood of developing SUDs. However, children/adolescents who exhibit difficulties with psychological regulation—such as impulsive behavior and irritability—are difficult to parent, and adolescents with early substance involvement may subvert parental supervision efforts.^9,10

Box 1

Predictive phenotypes

Predictive phenotypes—measurable individual characteristics that predict SUDs—may be considered risk factors but should not be viewed as causal influences akin to genetic and familial/environmental factors. Rather, predictive phenotypes may reflect propensities that are manifested by specific behaviors and other features according to developmental stage and environmental facilitation.

• specific psychiatric disorders
  
• specific personality traits that collectively are called psychological dysregulation
  
• early substance use.¹¹
  

Recent studies have demonstrated that this clustering of problems—including impulsive behavior, inattention, and negative affect—represents a single continuous dimension termed psychological dysregulation.¹² The construct of psychological dysregulation has origins in neuropathology and provides a conceptual link between childhood psychopathological characteristics known to predict SUD and neurobiological deficits.⁵ Childhood indices of psychological dysregulation—such as the Behavior Rating Inventory of Executive Function (BRIEF)¹⁴—complement other risk factors, such as parental SUDs and early substance use, in predicting accelerated substance use and SUDs.¹⁵

Neurobiological characteristics. Recent investigations have focused on relationships between variations in normal brain development and differences in psychological regulation.⁵ Several brain structures thought relevant to the development of psychological regulation—including the prefrontal cortex, limbic structures, and reward circuits—develop during adolescence. Delays or deficits in the development of these structures are called neurodevelopmental dysmaturation.⁵

Variation in genes that influence these brain areas may interact with environmental influences—including child maltreatment and early substance use—to produce neurodevelopmental dysmaturation that manifests as psychological dysregulation. Thus, genetic and environmental causes are hypothesized to lead to an endophenotype (neurodevelopmental dysmaturation) and developmentally specific phenotypes, such as:

• ADHD in childhood
  
• CD and accelerated substance use initiation in early adolescence
  
• SUDs involving alcohol and cannabis in late adolescence.⁵
  

Consuming small quantities of alcohol under parental supervision is culturally normative and does not predict problematic drinking.¹⁷ On the other hand, regularly consuming “standard drink” quantities of alcohol in late childhood typically occurs in unsupervised settings and predicts adolescent-onset AUDs.¹⁸

Problem-focused interview methods—including CAGE, TWEAK, and CRAFFT—have been developed and tested to screen adolescents for AUDs. None has been as consistently successful as the World Health Organization’s Alcohol Use Disorders Identification Test (AUDIT) questionnaire¹⁸ (see Related Resources).

Childhood cigarette smoking also predicts accelerated substance use and SUDs.¹⁵ Marijuana use predicts both cannabis use disorders and other illicit drug use.¹ This observation supports the controversial “gateway hypothesis,” which proposes that marijuana use accelerates the onset of other illicit drug use.^15,19,20 An alternate hypothesis proposes that use of marijuana and other illicit drugs is a developmentally specific manifestation of a more general liability for SUDs.¹

Identifying those at high risk

Screening for SUD risk factors makes it possible to identify children and adolescents who are very likely to develop problematic substance use. For example, in a study of 560 children age 10 to 12 at recruitment, this author (DBC) identified subjects as high risk if they had 2 parents with SUDs, tobacco or alcohol use by age 12, and high psychological dysregulation as measured by combined assessments of cognitive, emotional, and behavioral regulation. By age 18:

• three-quarters of these adolescents used tobacco daily
  
• more than one-half had alcohol problems
  
• nearly one-half had cannabis abuse or dependence.¹⁵
  

Recommendations. Children and adolescents receiving health care services—including primary care, ongoing treatment for chronic conditions, and treatment for psychiatric disorders—should be evaluated for SUD risk. Screening ideally occurs at the initial evaluation or early in the course of treatment. Family history determines genetic risk.

Direct questioning is needed because unstructured evaluations often fail to reveal the presence of important SUD risks.²¹ Explore possible child maltreatment by questioning the parent and child about physical abuse, sexual abuse, and neglect. Key mental disorders include CD, ADHD, and PTSD. Ask about use of tobacco, alcohol, cannabis, and other drugs. Follow acknowledgement of use with inquiries on frequency, quantity, and problems.

Prevention and early intervention

By identifying characteristics that confer risk for SUDs, you can target these characteristics in prevention and early treatment efforts. These efforts may involve parents as well as children. Many promising approaches have been developed, including universal or selective interventions based on family, school, community, or multi-component approaches.²²

Because parental SUDs are a prominent risk factor for children, interventions to reduce or eliminate parental substance use may be helpful, particularly for diminishing childhood psychological dysregulation.²³ Early treatment of childhood predictive phenotypes, including CD and ADHD, is another promising approach.¹² Community efforts to limit adolescents’ access to addictive substances have met with some success.²²

Parents, teachers, and children and adolescents can obtain a wealth of information from the Web sites of the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse (Box 2). The Centers for Disease Control and Prevention offers infomation about preventing smoking (see Related Resources.)

Box 2

• Alcohol Use Disorders Identification Test (AUDIT). World Health Organization. http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf.
  
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
  
• National Institute on Drug Abuse. www.nida.nih.gov.
  
• Centers for Disease Control and Prevention. Youth Tobacco Prevention. www.cdc.gov/tobacco/youth.
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Traditionally, clinicians have identified children at high risk for substance abuse disorders (SUDs) by their family history—such as “children of alcoholics.” Advances in etiology research, however, have led to the identification of other risks for SUDs seen during childhood (Table). The clustering of these SUD risk factors—genetic influences, family characteristics, and predictive phenotypes—makes it feasible to identify children and adolescents who are very likely to develop problematic substance use.

Table

Risk factors for substance abuse in children and adolescents

Nature vs nurture

Genetic influences. Heritable risk accounts for a substantial proportion of the variation in SUDs, as multiple genes differentially influence substance initiation, metabolism, and reinforcing properties.¹ For example, well-characterized genetic variations determine individual differences in alcohol dehydrogenase and aldehyde dehydrogenase—the enzymes involved in alcohol metabolism—and influence liability to alcohol use disorders (AUDs).^2,3 Researchers are exploring ways in which genes might impact SUD risk (Box 1).^1,4,5

Genetic influences on substance use may be less important during adolescence than adulthood. In a study of 1,796 male twins’ alcohol, nicotine, and cannabis use from early adolescence to middle adulthood, genetic variations had little or no influence on substance use in early adolescence. The influence of genetic factors gradually increased with age.⁶

Familial environmental factors, by contrast, were important in early adolescence and gradually decreased in effect with increasing age. During adolescence, the family’s influence on substance use apparently operates more through environmental characteristics than through heritable factors.⁶

Familial influences. Parents with ongoing SUDs model problematic substance use and create environments of child maltreatment and inadequate supervision.

Child maltreatment. Children of parents with SUDs are more likely to suffer sexual abuse, physical abuse, or neglect.⁷ The effects of sexual abuse on the child may vary by abuse severity and the child’s gender, developmental stage, and relationship to the perpetrator. Maltreatment may cause the child difficulties in psychological regulation and social development, leading to related psychopathology; these characteristics may contribute to later SUDs.⁸

Inadequate supervision. Adolescents who report that their parents do not effectively monitor their activities have an increased likelihood of developing SUDs. However, children/adolescents who exhibit difficulties with psychological regulation—such as impulsive behavior and irritability—are difficult to parent, and adolescents with early substance involvement may subvert parental supervision efforts.^9,10

Box 1

Predictive phenotypes

Predictive phenotypes—measurable individual characteristics that predict SUDs—may be considered risk factors but should not be viewed as causal influences akin to genetic and familial/environmental factors. Rather, predictive phenotypes may reflect propensities that are manifested by specific behaviors and other features according to developmental stage and environmental facilitation.

• specific psychiatric disorders
  
• specific personality traits that collectively are called psychological dysregulation
  
• early substance use.¹¹
  

Recent studies have demonstrated that this clustering of problems—including impulsive behavior, inattention, and negative affect—represents a single continuous dimension termed psychological dysregulation.¹² The construct of psychological dysregulation has origins in neuropathology and provides a conceptual link between childhood psychopathological characteristics known to predict SUD and neurobiological deficits.⁵ Childhood indices of psychological dysregulation—such as the Behavior Rating Inventory of Executive Function (BRIEF)¹⁴—complement other risk factors, such as parental SUDs and early substance use, in predicting accelerated substance use and SUDs.¹⁵

Neurobiological characteristics. Recent investigations have focused on relationships between variations in normal brain development and differences in psychological regulation.⁵ Several brain structures thought relevant to the development of psychological regulation—including the prefrontal cortex, limbic structures, and reward circuits—develop during adolescence. Delays or deficits in the development of these structures are called neurodevelopmental dysmaturation.⁵

Variation in genes that influence these brain areas may interact with environmental influences—including child maltreatment and early substance use—to produce neurodevelopmental dysmaturation that manifests as psychological dysregulation. Thus, genetic and environmental causes are hypothesized to lead to an endophenotype (neurodevelopmental dysmaturation) and developmentally specific phenotypes, such as:

• ADHD in childhood
  
• CD and accelerated substance use initiation in early adolescence
  
• SUDs involving alcohol and cannabis in late adolescence.⁵
  

Consuming small quantities of alcohol under parental supervision is culturally normative and does not predict problematic drinking.¹⁷ On the other hand, regularly consuming “standard drink” quantities of alcohol in late childhood typically occurs in unsupervised settings and predicts adolescent-onset AUDs.¹⁸

Problem-focused interview methods—including CAGE, TWEAK, and CRAFFT—have been developed and tested to screen adolescents for AUDs. None has been as consistently successful as the World Health Organization’s Alcohol Use Disorders Identification Test (AUDIT) questionnaire¹⁸ (see Related Resources).

Childhood cigarette smoking also predicts accelerated substance use and SUDs.¹⁵ Marijuana use predicts both cannabis use disorders and other illicit drug use.¹ This observation supports the controversial “gateway hypothesis,” which proposes that marijuana use accelerates the onset of other illicit drug use.^15,19,20 An alternate hypothesis proposes that use of marijuana and other illicit drugs is a developmentally specific manifestation of a more general liability for SUDs.¹

Identifying those at high risk

Screening for SUD risk factors makes it possible to identify children and adolescents who are very likely to develop problematic substance use. For example, in a study of 560 children age 10 to 12 at recruitment, this author (DBC) identified subjects as high risk if they had 2 parents with SUDs, tobacco or alcohol use by age 12, and high psychological dysregulation as measured by combined assessments of cognitive, emotional, and behavioral regulation. By age 18:

• three-quarters of these adolescents used tobacco daily
  
• more than one-half had alcohol problems
  
• nearly one-half had cannabis abuse or dependence.¹⁵
  

Recommendations. Children and adolescents receiving health care services—including primary care, ongoing treatment for chronic conditions, and treatment for psychiatric disorders—should be evaluated for SUD risk. Screening ideally occurs at the initial evaluation or early in the course of treatment. Family history determines genetic risk.

Direct questioning is needed because unstructured evaluations often fail to reveal the presence of important SUD risks.²¹ Explore possible child maltreatment by questioning the parent and child about physical abuse, sexual abuse, and neglect. Key mental disorders include CD, ADHD, and PTSD. Ask about use of tobacco, alcohol, cannabis, and other drugs. Follow acknowledgement of use with inquiries on frequency, quantity, and problems.

Prevention and early intervention

By identifying characteristics that confer risk for SUDs, you can target these characteristics in prevention and early treatment efforts. These efforts may involve parents as well as children. Many promising approaches have been developed, including universal or selective interventions based on family, school, community, or multi-component approaches.²²

Because parental SUDs are a prominent risk factor for children, interventions to reduce or eliminate parental substance use may be helpful, particularly for diminishing childhood psychological dysregulation.²³ Early treatment of childhood predictive phenotypes, including CD and ADHD, is another promising approach.¹² Community efforts to limit adolescents’ access to addictive substances have met with some success.²²

Parents, teachers, and children and adolescents can obtain a wealth of information from the Web sites of the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse (Box 2). The Centers for Disease Control and Prevention offers infomation about preventing smoking (see Related Resources.)

Box 2

• Alcohol Use Disorders Identification Test (AUDIT). World Health Organization. http://whqlibdoc.who.int/hq/2001/WHO_MSD_MSB_01.6a.pdf.
  
• National Institute on Alcohol Abuse and Alcoholism. www.niaaa.nih.gov.
  
• National Institute on Drug Abuse. www.nida.nih.gov.
  
• Centers for Disease Control and Prevention. Youth Tobacco Prevention. www.cdc.gov/tobacco/youth.
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Strong evidence for the efficacy of dialectical behavior therapy (DBT) for patients with borderline personality disorder (BPD) has brought hope to clinicians and patients alike. By including cognitive therapy, behavioral strategies, skills training, and exposure therapy, DBT addresses more than just self-harm and suicidal behavior (Box 1).^1-13 In fact, DBT’s primary interventions—such as skills training in emotion regulation and a straightforward approach to dysfunctional behaviors—could help many people.

Because DBT is so comprehensive and practical, clinicians might be tempted to refer almost anyone who seems even slightly “borderline” for DBT. But some patients—particularly those with mood and anxiety disorders—might benefit more from other treatments. To help you make appropriate evidence-based referrals for DBT and other psychological treatments, this article recommends 4 steps:

• Know what the treatment involves.
• Consider the evidence for the treatment in patients similar to yours.
• Consider why your patient—with unique characteristics and problems—would benefit from these specific interventions.
• Communicate to the patient your reasons for the referral.

Box 1

Step 1. What does DBT involve?

Difficulty with emotion regulation. DBT is based on a biosocial theory of BPD.¹ Within this framework, BPD is caused by the transaction (mutual interplay) of a biologically based vulnerability to emotions with an invalidating rearing environment. The patient with BPD typically experiences strong and long-lasting emotional reactions, often to seemingly small or insignificant events such as a slight look of disappointment on someone’s face or a minor daily hassle. Patients with BPD often are especially attuned to emotional reactions, particularly signs of rejection or disapproval.

Caregivers in an invalidating environment fail to provide the support a highly emotional child needs to learn to manage intense emotions. An invalidating environment:

• indiscriminately rejects the child’s communication of emotions and thoughts as invalid, independent of the validity of the child’s experience
• punishes emotional displays, then intermittently reinforces emotional escalation
• oversimplifies the ease of problem solving or coping.¹

As a result, the fledgling BPD individual learns to mistrust and fear emotions and does not learn how to manage them. A patient with BPD is like a car with a powerful “emotional engine” but lacking brakes.

Team treatment. The standard DBT treatment package is an outpatient program run by a team.¹ Therapists meet weekly for consultation to help them execute DBT according to the manual, prevent burn-out, and improve skills and motivation to treat patients with multiple, severe problems. The team also maintains the DBT program’s integrity and functioning and ensures that all treatment components—including individual therapy and skills training—are in place.

In individual therapy, the therapist and client collaborate to help the client reduce dysfunctional behaviors, increase motivation, and work toward goals. Because persons with BPD often present with many serious life problems, the therapist organizes session time to address 3 main priorities:

• Life-threatening behavior (intentional self-injury or imminent threat of intentional self-injury, including suicidal crises or threats, severe suicidal ideation or urges, suicide attempts, nonsuicidal self-injury or self-injury urges, or similar behaviors).
• Therapy-interfering behaviors (actions by the therapist or patient that interfere with progress, such as angry outbursts, missed sessions, or tardiness).
• Quality-of-life-interfering behavior (behaviors or problems—such as depression, eating disorders, or substance use disorders; homelessness or financial difficulties; or serious interpersonal discord—that make it hard for the patient to establish a reasonable quality of life).

Additional priorities include skills deficits and secondary targets.¹ Each week, the client monitors his or her behaviors, emotions, and actions using a diary card. The therapist uses this information to collaboratively prioritize the focus of each individual therapy session.

Skills training typically occurs weekly in group sessions of 1.5 to 2.5 hours with 1 or 2 therapists. This structured, psycho-educational training focuses on skills that persons with BPD often lack:

• mindfulness (paying attention to the experience of the present moment)
• emotion regulation (regulating or managing distressing emotions)
• distress tolerance (averting crises, tolerating or accepting distressing situations or emotions)
• interpersonal effectiveness (maintaining relationships and asserting needs or wishes).

Therapists often use the first half of group sessions to review each patient’s homework and to provide feedback and coaching on effective skill use. The remaining time is spent teaching new skills. The therapist then assigns homework to practice new skills and closes with a wind-down exercise, often involving relaxation training.

Step 2. Consider the evidence

Before you make a referral for DBT (or any psychological treatment), know what the research says about who is likely to benefit from it. For women with BPD, DBT is the only treatment that can be considered “well-established.”^3,14 The literature on DBT includes 10 randomized controlled trials (as well as many uncontrolled trials), and the strongest research supports its use in women with BPD.^2,4-13

Based on a detailed review of the literature on DBT, I recommend a basic, evidence-based priority list for referrals (Table 1).^3,12,13 Patient groups at the top are most likely to benefit from DBT—according to the most solid, rigorous research—and deserve your strongest consideration for referral. Patient groups further down the list—with fewer rigorous studies of DBT—merit less consideration of DBT as the treatment of choice. Of course to use this list, an accurate diagnosis of your patient’s problems is essential.

DBT’s treatment strategies—exposure therapy, skills training, cognitive therapy, emotion regulation training, and mindfulness—can work for other types of patients. I have noticed, however, that some clinicians refer patients with depression, anxiety disorders, or even bipolar disorder for DBT. Despite DBT’s intuitive appeal, sufficient evidence does not yet support its use in patients with these disorders. Other evidence-based treatments may be more suitable for patients with uncomplicated mood and anxiety disorders (Table 2).³

Table 1

Candidates for DBT: An evidence-based referral priority list*

	Women with BPD who are suicidal or who self-harm (without bipolar disorder, a psychotic disorder, or mental retardation). One randomized clinical trial with suicidal individuals with BPD included men. Two studies excluded participants with substance dependence, but the most recent, largest study13 did not.
	Women with BPD and substance use problems (without bipolar disorder, a psychotic disorder, or cognitive impairment)
	Women with bulimia nervosa or binge-eating disorder (without substance abuse, psychotic disorder, or suicidal ideation). Other empirically supported treatments exist for these patients (Table 2).
	Depressed older adults (age ≥60, without bipolar disorder, a psychotic disorder, or cognitive impairment). Investigated treatments included group DBT skills training, telephone consultation, selective serotonin reuptake inhibitor medications, and psychiatric clinical management.12
	Suicidal and nonsuicidal adolescentswith oppositional defiant disorder or bipolar disorder
	Incarcerated men and womenwith or without BPD, in high- and low-security forensic settings
	Couples and families where 1 member has BPDor where domestic violence occurs in an intimate relationship
* Persons at the top of the list are the ones for whom the most solid, rigorous research has demonstrated the efficacy of DBT. Fewer rigorous studies of DBT have been conducted in persons further down the list.
BPD: borderline personality disorder; DBT: dialectical behavior therapy
Source: References 3,12,13

Table 2

When not to refer a patient for DBT: Evidence is stronger for alternate treatments

Step 3: Would this patient benefit?

Would your patient, with unique struggles and characteristics, benefit from DBT? Consider to what degree DBT’s interventions would solve some of your patient’s problems and whether DBT fits your patient’s needs.

DBT’s target problems. In controlled trials, DBT’s pragmatic approach outperforms comparator treatments in reducing suicidal behaviors and self-injury, and DBT therapists monitor and target these behaviors. Thus, because few treatments reduce self-injury,^15,16 you might consider DBT for patients who self-injure even if they do not have BPD.

DBT also includes a strong focus on emotions and emotion regulation. Therefore, if difficulty managing emotions is among your patient’s primary problems, DBT may offer some benefit. DBT also includes structured interpersonal skills training that might be useful for patients who lack assertiveness.

Finally, if you have a patient with multiple diagnoses and severe problems—but not psychosis—the DBT approach to organizing and prioritizing treatment targets may be beneficial. Some multi-diagnosis patients may struggle with aspects of DBT (such as learning new skills), but DBT is set up to incorporate other empirically supported treatment protocols for co-occurring Axis I and II disorders.

Does DBT ‘fit’ your patient? DBT is very structured and involves direct discussions of maladaptive behaviors. If your patient prefers or would benefit from a structured approach, you might consider a referral for DBT.

DBT is an outpatient behavioral treatment that focuses on the here and now. DBT might not be the best fit if your patient:

• views his or her problems as resulting primarily from childhood experiences or relationships with parents
• would prefer insight-oriented therapy.

If, however, your patient would like a practical approach focused on problem-solving, DBT could be an effective choice.

DBT is based in part on a dialectical philosophy, and DBT therapists often seek to bring together or synthesize polarized thinking. If your patient struggles with “black or white” thinking, this dialectical philosophy might be helpful. On the other hand, DBT might not be the best fit if your patient is particularly rigid in thinking or seems to require cognitive therapy to address his or her thought patterns.

DBT is not the treatment of choice for all personality disorders. Most of the evidence examines its use for BPD, and few studies have looked at any other personality disorder. Also, keep in mind that being interpersonally “difficult” does not mean that a patient is “borderline” or needs DBT.

Step 4: Communicate reasons for referral to your patient

Finally, communicate to your patient the reasons you are referring him or her for DBT. Patients often walk into my office for DBT, confused about why they are there. If patients understand why they have been referred for DBT and how it may help them, they may be more likely to follow through and realize its benefits.

A sample explanation of referral that I offer to guide this communication (Box 2) includes 3 main points:

• my diagnosis or conceptualization of the patient’s clinical problems
• a brief description of DBT
• a rationale for why DBT would be a good fit, and what kinds of benefits the patient might receive.

Box 2

Related Resources

• Chapman AL, Gratz KL. The borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications; 2007.
• National Education Alliance for Borderline Personality Disorder. Information for professionals, patients, and families. www.neabpd.org.
• Behavioral Tech, LLC, founded by Marsha Linehan, PhD. DBT training and resources, including a directory of DBT therapists. www.behavioraltech.org.
• Dialectical Behaviour Therapy Centre of Vancouver. www.dbtvancouver.com.

Disclosure

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

Strong evidence for the efficacy of dialectical behavior therapy (DBT) for patients with borderline personality disorder (BPD) has brought hope to clinicians and patients alike. By including cognitive therapy, behavioral strategies, skills training, and exposure therapy, DBT addresses more than just self-harm and suicidal behavior (Box 1).^1-13 In fact, DBT’s primary interventions—such as skills training in emotion regulation and a straightforward approach to dysfunctional behaviors—could help many people.

Because DBT is so comprehensive and practical, clinicians might be tempted to refer almost anyone who seems even slightly “borderline” for DBT. But some patients—particularly those with mood and anxiety disorders—might benefit more from other treatments. To help you make appropriate evidence-based referrals for DBT and other psychological treatments, this article recommends 4 steps:

• Know what the treatment involves.
• Consider the evidence for the treatment in patients similar to yours.
• Consider why your patient—with unique characteristics and problems—would benefit from these specific interventions.
• Communicate to the patient your reasons for the referral.

Box 1

Step 1. What does DBT involve?

Difficulty with emotion regulation. DBT is based on a biosocial theory of BPD.¹ Within this framework, BPD is caused by the transaction (mutual interplay) of a biologically based vulnerability to emotions with an invalidating rearing environment. The patient with BPD typically experiences strong and long-lasting emotional reactions, often to seemingly small or insignificant events such as a slight look of disappointment on someone’s face or a minor daily hassle. Patients with BPD often are especially attuned to emotional reactions, particularly signs of rejection or disapproval.

Caregivers in an invalidating environment fail to provide the support a highly emotional child needs to learn to manage intense emotions. An invalidating environment:

• indiscriminately rejects the child’s communication of emotions and thoughts as invalid, independent of the validity of the child’s experience
• punishes emotional displays, then intermittently reinforces emotional escalation
• oversimplifies the ease of problem solving or coping.¹

As a result, the fledgling BPD individual learns to mistrust and fear emotions and does not learn how to manage them. A patient with BPD is like a car with a powerful “emotional engine” but lacking brakes.

Team treatment. The standard DBT treatment package is an outpatient program run by a team.¹ Therapists meet weekly for consultation to help them execute DBT according to the manual, prevent burn-out, and improve skills and motivation to treat patients with multiple, severe problems. The team also maintains the DBT program’s integrity and functioning and ensures that all treatment components—including individual therapy and skills training—are in place.

In individual therapy, the therapist and client collaborate to help the client reduce dysfunctional behaviors, increase motivation, and work toward goals. Because persons with BPD often present with many serious life problems, the therapist organizes session time to address 3 main priorities:

• Life-threatening behavior (intentional self-injury or imminent threat of intentional self-injury, including suicidal crises or threats, severe suicidal ideation or urges, suicide attempts, nonsuicidal self-injury or self-injury urges, or similar behaviors).
• Therapy-interfering behaviors (actions by the therapist or patient that interfere with progress, such as angry outbursts, missed sessions, or tardiness).
• Quality-of-life-interfering behavior (behaviors or problems—such as depression, eating disorders, or substance use disorders; homelessness or financial difficulties; or serious interpersonal discord—that make it hard for the patient to establish a reasonable quality of life).

Additional priorities include skills deficits and secondary targets.¹ Each week, the client monitors his or her behaviors, emotions, and actions using a diary card. The therapist uses this information to collaboratively prioritize the focus of each individual therapy session.

Skills training typically occurs weekly in group sessions of 1.5 to 2.5 hours with 1 or 2 therapists. This structured, psycho-educational training focuses on skills that persons with BPD often lack:

• mindfulness (paying attention to the experience of the present moment)
• emotion regulation (regulating or managing distressing emotions)
• distress tolerance (averting crises, tolerating or accepting distressing situations or emotions)
• interpersonal effectiveness (maintaining relationships and asserting needs or wishes).

Therapists often use the first half of group sessions to review each patient’s homework and to provide feedback and coaching on effective skill use. The remaining time is spent teaching new skills. The therapist then assigns homework to practice new skills and closes with a wind-down exercise, often involving relaxation training.

Step 2. Consider the evidence

Before you make a referral for DBT (or any psychological treatment), know what the research says about who is likely to benefit from it. For women with BPD, DBT is the only treatment that can be considered “well-established.”^3,14 The literature on DBT includes 10 randomized controlled trials (as well as many uncontrolled trials), and the strongest research supports its use in women with BPD.^2,4-13

Based on a detailed review of the literature on DBT, I recommend a basic, evidence-based priority list for referrals (Table 1).^3,12,13 Patient groups at the top are most likely to benefit from DBT—according to the most solid, rigorous research—and deserve your strongest consideration for referral. Patient groups further down the list—with fewer rigorous studies of DBT—merit less consideration of DBT as the treatment of choice. Of course to use this list, an accurate diagnosis of your patient’s problems is essential.

DBT’s treatment strategies—exposure therapy, skills training, cognitive therapy, emotion regulation training, and mindfulness—can work for other types of patients. I have noticed, however, that some clinicians refer patients with depression, anxiety disorders, or even bipolar disorder for DBT. Despite DBT’s intuitive appeal, sufficient evidence does not yet support its use in patients with these disorders. Other evidence-based treatments may be more suitable for patients with uncomplicated mood and anxiety disorders (Table 2).³

Table 1

Candidates for DBT: An evidence-based referral priority list*

	Women with BPD who are suicidal or who self-harm (without bipolar disorder, a psychotic disorder, or mental retardation). One randomized clinical trial with suicidal individuals with BPD included men. Two studies excluded participants with substance dependence, but the most recent, largest study13 did not.
	Women with BPD and substance use problems (without bipolar disorder, a psychotic disorder, or cognitive impairment)
	Women with bulimia nervosa or binge-eating disorder (without substance abuse, psychotic disorder, or suicidal ideation). Other empirically supported treatments exist for these patients (Table 2).
	Depressed older adults (age ≥60, without bipolar disorder, a psychotic disorder, or cognitive impairment). Investigated treatments included group DBT skills training, telephone consultation, selective serotonin reuptake inhibitor medications, and psychiatric clinical management.12
	Suicidal and nonsuicidal adolescentswith oppositional defiant disorder or bipolar disorder
	Incarcerated men and womenwith or without BPD, in high- and low-security forensic settings
	Couples and families where 1 member has BPDor where domestic violence occurs in an intimate relationship
* Persons at the top of the list are the ones for whom the most solid, rigorous research has demonstrated the efficacy of DBT. Fewer rigorous studies of DBT have been conducted in persons further down the list.
BPD: borderline personality disorder; DBT: dialectical behavior therapy
Source: References 3,12,13

Table 2

When not to refer a patient for DBT: Evidence is stronger for alternate treatments

Step 3: Would this patient benefit?

Would your patient, with unique struggles and characteristics, benefit from DBT? Consider to what degree DBT’s interventions would solve some of your patient’s problems and whether DBT fits your patient’s needs.

DBT’s target problems. In controlled trials, DBT’s pragmatic approach outperforms comparator treatments in reducing suicidal behaviors and self-injury, and DBT therapists monitor and target these behaviors. Thus, because few treatments reduce self-injury,^15,16 you might consider DBT for patients who self-injure even if they do not have BPD.

DBT also includes a strong focus on emotions and emotion regulation. Therefore, if difficulty managing emotions is among your patient’s primary problems, DBT may offer some benefit. DBT also includes structured interpersonal skills training that might be useful for patients who lack assertiveness.

Finally, if you have a patient with multiple diagnoses and severe problems—but not psychosis—the DBT approach to organizing and prioritizing treatment targets may be beneficial. Some multi-diagnosis patients may struggle with aspects of DBT (such as learning new skills), but DBT is set up to incorporate other empirically supported treatment protocols for co-occurring Axis I and II disorders.

Does DBT ‘fit’ your patient? DBT is very structured and involves direct discussions of maladaptive behaviors. If your patient prefers or would benefit from a structured approach, you might consider a referral for DBT.

DBT is an outpatient behavioral treatment that focuses on the here and now. DBT might not be the best fit if your patient:

• views his or her problems as resulting primarily from childhood experiences or relationships with parents
• would prefer insight-oriented therapy.

If, however, your patient would like a practical approach focused on problem-solving, DBT could be an effective choice.

DBT is based in part on a dialectical philosophy, and DBT therapists often seek to bring together or synthesize polarized thinking. If your patient struggles with “black or white” thinking, this dialectical philosophy might be helpful. On the other hand, DBT might not be the best fit if your patient is particularly rigid in thinking or seems to require cognitive therapy to address his or her thought patterns.

DBT is not the treatment of choice for all personality disorders. Most of the evidence examines its use for BPD, and few studies have looked at any other personality disorder. Also, keep in mind that being interpersonally “difficult” does not mean that a patient is “borderline” or needs DBT.

Step 4: Communicate reasons for referral to your patient

Finally, communicate to your patient the reasons you are referring him or her for DBT. Patients often walk into my office for DBT, confused about why they are there. If patients understand why they have been referred for DBT and how it may help them, they may be more likely to follow through and realize its benefits.

A sample explanation of referral that I offer to guide this communication (Box 2) includes 3 main points:

• my diagnosis or conceptualization of the patient’s clinical problems
• a brief description of DBT
• a rationale for why DBT would be a good fit, and what kinds of benefits the patient might receive.

Box 2

Related Resources

• Chapman AL, Gratz KL. The borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications; 2007.
• National Education Alliance for Borderline Personality Disorder. Information for professionals, patients, and families. www.neabpd.org.
• Behavioral Tech, LLC, founded by Marsha Linehan, PhD. DBT training and resources, including a directory of DBT therapists. www.behavioraltech.org.
• Dialectical Behaviour Therapy Centre of Vancouver. www.dbtvancouver.com.

Disclosure

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

Strong evidence for the efficacy of dialectical behavior therapy (DBT) for patients with borderline personality disorder (BPD) has brought hope to clinicians and patients alike. By including cognitive therapy, behavioral strategies, skills training, and exposure therapy, DBT addresses more than just self-harm and suicidal behavior (Box 1).^1-13 In fact, DBT’s primary interventions—such as skills training in emotion regulation and a straightforward approach to dysfunctional behaviors—could help many people.

Because DBT is so comprehensive and practical, clinicians might be tempted to refer almost anyone who seems even slightly “borderline” for DBT. But some patients—particularly those with mood and anxiety disorders—might benefit more from other treatments. To help you make appropriate evidence-based referrals for DBT and other psychological treatments, this article recommends 4 steps:

• Know what the treatment involves.
• Consider the evidence for the treatment in patients similar to yours.
• Consider why your patient—with unique characteristics and problems—would benefit from these specific interventions.
• Communicate to the patient your reasons for the referral.

Box 1

Step 1. What does DBT involve?

Difficulty with emotion regulation. DBT is based on a biosocial theory of BPD.¹ Within this framework, BPD is caused by the transaction (mutual interplay) of a biologically based vulnerability to emotions with an invalidating rearing environment. The patient with BPD typically experiences strong and long-lasting emotional reactions, often to seemingly small or insignificant events such as a slight look of disappointment on someone’s face or a minor daily hassle. Patients with BPD often are especially attuned to emotional reactions, particularly signs of rejection or disapproval.

Caregivers in an invalidating environment fail to provide the support a highly emotional child needs to learn to manage intense emotions. An invalidating environment:

• indiscriminately rejects the child’s communication of emotions and thoughts as invalid, independent of the validity of the child’s experience
• punishes emotional displays, then intermittently reinforces emotional escalation
• oversimplifies the ease of problem solving or coping.¹

As a result, the fledgling BPD individual learns to mistrust and fear emotions and does not learn how to manage them. A patient with BPD is like a car with a powerful “emotional engine” but lacking brakes.

Team treatment. The standard DBT treatment package is an outpatient program run by a team.¹ Therapists meet weekly for consultation to help them execute DBT according to the manual, prevent burn-out, and improve skills and motivation to treat patients with multiple, severe problems. The team also maintains the DBT program’s integrity and functioning and ensures that all treatment components—including individual therapy and skills training—are in place.

In individual therapy, the therapist and client collaborate to help the client reduce dysfunctional behaviors, increase motivation, and work toward goals. Because persons with BPD often present with many serious life problems, the therapist organizes session time to address 3 main priorities:

• Life-threatening behavior (intentional self-injury or imminent threat of intentional self-injury, including suicidal crises or threats, severe suicidal ideation or urges, suicide attempts, nonsuicidal self-injury or self-injury urges, or similar behaviors).
• Therapy-interfering behaviors (actions by the therapist or patient that interfere with progress, such as angry outbursts, missed sessions, or tardiness).
• Quality-of-life-interfering behavior (behaviors or problems—such as depression, eating disorders, or substance use disorders; homelessness or financial difficulties; or serious interpersonal discord—that make it hard for the patient to establish a reasonable quality of life).

Additional priorities include skills deficits and secondary targets.¹ Each week, the client monitors his or her behaviors, emotions, and actions using a diary card. The therapist uses this information to collaboratively prioritize the focus of each individual therapy session.

Skills training typically occurs weekly in group sessions of 1.5 to 2.5 hours with 1 or 2 therapists. This structured, psycho-educational training focuses on skills that persons with BPD often lack:

• mindfulness (paying attention to the experience of the present moment)
• emotion regulation (regulating or managing distressing emotions)
• distress tolerance (averting crises, tolerating or accepting distressing situations or emotions)
• interpersonal effectiveness (maintaining relationships and asserting needs or wishes).

Therapists often use the first half of group sessions to review each patient’s homework and to provide feedback and coaching on effective skill use. The remaining time is spent teaching new skills. The therapist then assigns homework to practice new skills and closes with a wind-down exercise, often involving relaxation training.

Step 2. Consider the evidence

Before you make a referral for DBT (or any psychological treatment), know what the research says about who is likely to benefit from it. For women with BPD, DBT is the only treatment that can be considered “well-established.”^3,14 The literature on DBT includes 10 randomized controlled trials (as well as many uncontrolled trials), and the strongest research supports its use in women with BPD.^2,4-13

Based on a detailed review of the literature on DBT, I recommend a basic, evidence-based priority list for referrals (Table 1).^3,12,13 Patient groups at the top are most likely to benefit from DBT—according to the most solid, rigorous research—and deserve your strongest consideration for referral. Patient groups further down the list—with fewer rigorous studies of DBT—merit less consideration of DBT as the treatment of choice. Of course to use this list, an accurate diagnosis of your patient’s problems is essential.

DBT’s treatment strategies—exposure therapy, skills training, cognitive therapy, emotion regulation training, and mindfulness—can work for other types of patients. I have noticed, however, that some clinicians refer patients with depression, anxiety disorders, or even bipolar disorder for DBT. Despite DBT’s intuitive appeal, sufficient evidence does not yet support its use in patients with these disorders. Other evidence-based treatments may be more suitable for patients with uncomplicated mood and anxiety disorders (Table 2).³

Table 1

Candidates for DBT: An evidence-based referral priority list*

	Women with BPD who are suicidal or who self-harm (without bipolar disorder, a psychotic disorder, or mental retardation). One randomized clinical trial with suicidal individuals with BPD included men. Two studies excluded participants with substance dependence, but the most recent, largest study13 did not.
	Women with BPD and substance use problems (without bipolar disorder, a psychotic disorder, or cognitive impairment)
	Women with bulimia nervosa or binge-eating disorder (without substance abuse, psychotic disorder, or suicidal ideation). Other empirically supported treatments exist for these patients (Table 2).
	Depressed older adults (age ≥60, without bipolar disorder, a psychotic disorder, or cognitive impairment). Investigated treatments included group DBT skills training, telephone consultation, selective serotonin reuptake inhibitor medications, and psychiatric clinical management.12
	Suicidal and nonsuicidal adolescentswith oppositional defiant disorder or bipolar disorder
	Incarcerated men and womenwith or without BPD, in high- and low-security forensic settings
	Couples and families where 1 member has BPDor where domestic violence occurs in an intimate relationship
* Persons at the top of the list are the ones for whom the most solid, rigorous research has demonstrated the efficacy of DBT. Fewer rigorous studies of DBT have been conducted in persons further down the list.
BPD: borderline personality disorder; DBT: dialectical behavior therapy
Source: References 3,12,13

Table 2

When not to refer a patient for DBT: Evidence is stronger for alternate treatments

Step 3: Would this patient benefit?

Would your patient, with unique struggles and characteristics, benefit from DBT? Consider to what degree DBT’s interventions would solve some of your patient’s problems and whether DBT fits your patient’s needs.

DBT’s target problems. In controlled trials, DBT’s pragmatic approach outperforms comparator treatments in reducing suicidal behaviors and self-injury, and DBT therapists monitor and target these behaviors. Thus, because few treatments reduce self-injury,^15,16 you might consider DBT for patients who self-injure even if they do not have BPD.

DBT also includes a strong focus on emotions and emotion regulation. Therefore, if difficulty managing emotions is among your patient’s primary problems, DBT may offer some benefit. DBT also includes structured interpersonal skills training that might be useful for patients who lack assertiveness.

Finally, if you have a patient with multiple diagnoses and severe problems—but not psychosis—the DBT approach to organizing and prioritizing treatment targets may be beneficial. Some multi-diagnosis patients may struggle with aspects of DBT (such as learning new skills), but DBT is set up to incorporate other empirically supported treatment protocols for co-occurring Axis I and II disorders.

Does DBT ‘fit’ your patient? DBT is very structured and involves direct discussions of maladaptive behaviors. If your patient prefers or would benefit from a structured approach, you might consider a referral for DBT.

DBT is an outpatient behavioral treatment that focuses on the here and now. DBT might not be the best fit if your patient:

• views his or her problems as resulting primarily from childhood experiences or relationships with parents
• would prefer insight-oriented therapy.

If, however, your patient would like a practical approach focused on problem-solving, DBT could be an effective choice.

DBT is based in part on a dialectical philosophy, and DBT therapists often seek to bring together or synthesize polarized thinking. If your patient struggles with “black or white” thinking, this dialectical philosophy might be helpful. On the other hand, DBT might not be the best fit if your patient is particularly rigid in thinking or seems to require cognitive therapy to address his or her thought patterns.

DBT is not the treatment of choice for all personality disorders. Most of the evidence examines its use for BPD, and few studies have looked at any other personality disorder. Also, keep in mind that being interpersonally “difficult” does not mean that a patient is “borderline” or needs DBT.

Step 4: Communicate reasons for referral to your patient

Finally, communicate to your patient the reasons you are referring him or her for DBT. Patients often walk into my office for DBT, confused about why they are there. If patients understand why they have been referred for DBT and how it may help them, they may be more likely to follow through and realize its benefits.

A sample explanation of referral that I offer to guide this communication (Box 2) includes 3 main points:

• my diagnosis or conceptualization of the patient’s clinical problems
• a brief description of DBT
• a rationale for why DBT would be a good fit, and what kinds of benefits the patient might receive.

Box 2

Related Resources

• Chapman AL, Gratz KL. The borderline personality disorder survival guide: everything you need to know about living with BPD. Oakland, CA: New Harbinger Publications; 2007.
• National Education Alliance for Borderline Personality Disorder. Information for professionals, patients, and families. www.neabpd.org.
• Behavioral Tech, LLC, founded by Marsha Linehan, PhD. DBT training and resources, including a directory of DBT therapists. www.behavioraltech.org.
• Dialectical Behaviour Therapy Centre of Vancouver. www.dbtvancouver.com.

Disclosure

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

Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.¹ Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”²

This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.

The placebo effect

The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.³ Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.⁴

In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).⁵ Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.

Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect⁶—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.

Table 1

Correcting misconceptions about the placebo effect

Clinical strategies to enhance the placebo effect

CASE REPORT: Predicting positive results

Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.

Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.

The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.

Conditioned responses

Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.^7-10 Conditioned responses—as demonstrated in glycemia regulation¹⁰ and with psychopharmacology¹¹—also can enhance the desirable results of pharmacotherapy.

CASE REPORT: A soothing drink

Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.

Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.

I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.

Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.

Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.

The power of suggestion

The power of suggestion has been shown to positively or negatively affect treatment outcomes.^12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.

CASE REPORT: Predicting improvement

Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.

Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.

When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.

This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.

The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).

Box

Participatory pharmacotherapy

Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.

CASE REPORT: All in the family

Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.

I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.

I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.

• a successful therapeutic alliance
  
• adherence with prescribed medications
  
• the best possible outcome with pharmacotherapy.
  

In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.

Table 3

Choosing patients for participatory pharmacotherapy

• Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
  
• Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
  
• Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
  

• Lithium • Eskalith, Lithobid
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.¹ Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”²

This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.

The placebo effect

The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.³ Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.⁴

In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).⁵ Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.

Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect⁶—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.

Table 1

Correcting misconceptions about the placebo effect

Clinical strategies to enhance the placebo effect

CASE REPORT: Predicting positive results

Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.

Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.

The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.

Conditioned responses

Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.^7-10 Conditioned responses—as demonstrated in glycemia regulation¹⁰ and with psychopharmacology¹¹—also can enhance the desirable results of pharmacotherapy.

CASE REPORT: A soothing drink

Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.

Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.

I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.

Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.

Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.

The power of suggestion

The power of suggestion has been shown to positively or negatively affect treatment outcomes.^12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.

CASE REPORT: Predicting improvement

Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.

Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.

When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.

This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.

The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).

Box

Participatory pharmacotherapy

Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.

CASE REPORT: All in the family

Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.

I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.

I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.

• a successful therapeutic alliance
  
• adherence with prescribed medications
  
• the best possible outcome with pharmacotherapy.
  

In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.

Table 3

Choosing patients for participatory pharmacotherapy

• Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
  
• Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
  
• Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
  

• Lithium • Eskalith, Lithobid
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Any medication’s therapeutic success depends on the interaction between its specific biochemical effects and nonspecific factors.¹ Thus, clinical trial designers may view the placebo effect as undesirable, but it can be a valuable response that improves treatment outcomes in clinical practice. As Freud stated, “Expectation colored by hope and faith is an effective force with which we have to reckon…in all our attempts at treatment and cure.”²

This article describes how experienced clinicians make use of the placebo effect and 3 other powerful, nonspecific elements of successful pharmacotherapy.

The placebo effect

The placebo effect is any effect attributable to a pill or potion that does not originate from its specific pharmacologic properties.³ Its clinical value has been trivialized, in part because of misconceptions (Table 1). For example, the placebo effect is commonly believed to be short-lived, whereas in fact it can last a long time.⁴

In clinical practice, our goal is to enhance the placebo effect to maximize a desirable therapeutic outcome (Table 2).⁵ Therefore, before I prescribe a medication, I tell my patient that I have selected a particular medication because I have had good results with it in many other patients and I believe it will work well for him or her, too.

Too often, doctors feel pessimistic about a medication’s potential therapeutic result and communicate this pessimism. What the patient hears is, “There’s nothing else I can do for you; why not try this medication, even though I don’t believe it’s going to work.” This may create a negative placebo effect⁶—termed the “nocebo” effect—which gives the patient a negative expectation about the treatment’s outcome. The patient internalizes the doctor’s words and lives out this negative expectation.

Table 1

Correcting misconceptions about the placebo effect

Clinical strategies to enhance the placebo effect

CASE REPORT: Predicting positive results

Mr. B, age 42, has a history of recurrent depression associated with severe insomnia, poor appetite, significant weight loss, and psychosocial withdrawal with feelings of hopelessness. After I take a detailed history and do a mental status examination, I suggest that he be treated with cognitive-behavioral therapy (CBT) and mirtazapine.

Even though studies of antidepressants rarely show mood improvements within the first 7 days, it is not unusual to hear patients report feeling less depressed within days after they start a new antidepressant. Although the drug’s specific chemical effects on the brain may not be sufficient to explain this phenomenon, the explanation probably lies in nonspecific effects—such as the patient expecting that this medication will make him feel better.

The placebo effect can occur as soon as a patient starts a medication. Experienced clinicians understand the placebo effect’s power and harness it to benefit their patients.

Conditioned responses

Many biological responses can be associated with visual, auditory, tactile, olfactory, or gustatory stimuli. Nonconditioned physiologic responses paired with conditioned stimuli induce the same biological effects of a drug. Evidence supporting this phenomenon includes successful conditioning of the immune system.^7-10 Conditioned responses—as demonstrated in glycemia regulation¹⁰ and with psychopharmacology¹¹—also can enhance the desirable results of pharmacotherapy.

CASE REPORT: A soothing drink

Ms. L, a 22-year-old college student, suffers from obsessive-compulsive disorder associated with anxiety and depression. She arrives at the appointment hurried and worried that she might be late. She is short of breath and looks stressed. The nurse offers Ms. L a cup of tea or water. She chooses a glass of water and is asked to bring it into her session.

Following a comprehensive interview and mental status examination, I recommend CBT plus medication. Considering Ms. L’s medication history, we agree to start treatment with sertraline. We review its potential benefits and expectations that it will reduce her anxiety, alleviate her ruminating obsessive worries, and improve her mood. I give her a 50-mg sample and inform her that some patients experience positive effects soon after taking the medication. I then ask her to take the first pill, using her glass of water. She does so and thanks me for being attentive to her needs.

I instruct her to call within 1 week and report on her condition, even if she feels better. Seven days later she reports that she is feeling better and is looking forward to her next appointment. She reports no side effects.

Often patients come to my office feeling thirsty. My staff or I offer them a glass of water or a cup of tea. As patients sip from the cup, they swallow and incorporate the liquid into their bodies. At the same time, I use verbal interventions to make them feel listened to and understood. They internalize this emotional experience in connection with swallowing the liquid.

Later, when swallowing the new medication as instructed, the patient re-experiences the positive therapeutic effect that was internalized in the doctor’s office.

The power of suggestion

The power of suggestion has been shown to positively or negatively affect treatment outcomes.^12,13 In practice, most clinicians give unintentional suggestions by how and what they communicate to the patient.

CASE REPORT: Predicting improvement

Mrs. J, age 48, has had dysthymic disorder and fibromyalgia for many years. She describes how various specialists have tried to alleviate her depression and chronic pain. Follow-up questions reveal that whenever she received a new prescription the physician would alert her to all the possible side effects and instruct her to call the office if she developed a problem with the new medication.

Invariably, Mrs. J would call as instructed and describe side effects she developed with the new medication. Often the doctor would discontinue the medication, depriving Mrs. J of benefits she might have derived later.

When Mrs. J calls to report on her status, she mentions that she is sleeping better and has begun to feel better during the day. She says that her husband told her she has started to smile again.

This vignette illustrates the importance of suggesting to the patient a positive outcome of pharmacotherapy associated with a particular action (calling the doctor’s office to report results). When the patient promised to call, she internalized the suggestion that calling would be associated with feeling better—and that is what happened. This intervention contrasts with saying to the patient, “Call me if you have a problem with any of these side effects,” which gives the patient a suggestion to call and report a problem.

The suggestion effect also can be used to reframe a predictable side effect as a positive sign that indicates the beginning of change leading to recovery (Box).

Box

Participatory pharmacotherapy

Many patients seek ownership in making decisions about their treatment and medications. In participatory pharmacotherapy, patients provide you with data and valuable information—such as family history, personal medical history, and experience with treatment—and inform you about which medications worked best and which did not work. You invite patients to predict how they see themselves getting better and into recovery.

CASE REPORT: All in the family

Mr. A, age 28 and single, has been diagnosed with a bipolar mood disorder. As part of a detailed family history, he reports that his maternal grandfather, mother, and a maternal uncle were diagnosed with mood swings and were successfully treated with medications, specifically lithium. He states that he believes he has the same condition.

I compliment Mr. A for being so well informed about his grandfather and uncle and educate him about mood stabilizers’ benefits in bipolar disorder. I tell him about the finding that if lithium has helped his relatives, it will probably help him as well.

I also reassure Mr. A that, in deciding what medications to avoid and what medications to use, I will consider his experience with specific antidepressants that did not help him. He thanks me for considering his suggestion about what medication to use for him.

• a successful therapeutic alliance
  
• adherence with prescribed medications
  
• the best possible outcome with pharmacotherapy.
  

In patients with a defiant-oppositional personality, consider framing the treatment decision as a choice between 2 equally efficacious medications. This gives the patient the sense of control in choosing his or her own medication, which is jointly monitored.

Table 3

Choosing patients for participatory pharmacotherapy

• Brody H. The placebo response: how you can release the body’s inner pharmacy for better health. New York, NY: HarperCollins Publishers; 2000.
  
• Spiro H. The power of hope: a doctor’s perspective. New Haven, CT: Yale University Press; 1998.
  
• Ernst E. Placebo: new insights into an old enigma. Drug Discov Today 2007;12:413-8.
  

• Lithium • Eskalith, Lithobid
  
• Mirtazapine • Remeron
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

Dr. Torem reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI), with nearly 3 million new cases diagnosed annually in the United States.¹ In July 2007 the U.S. Preventive Services Task Force (USPSTF) updated its recommendation on Chlamydia screening of sexually active female adolescents and adults ( Table 1 ).² Routine screening is not recommended for men because there is not enough data to determine the benefits and risks of screening.

Although the USPSTF recommendation targets the general population, it is important to assess each patient’s sexual behavior. Women exhibiting impulsivity caused by bipolar mania, substance abuse, or personality disorders or who exchange sex for food, shelter, substances, or money are at high risk of infection ( Table 2 ).^1,2

The new guideline introduces a screening cutoff at age 25 because women age <25 years are 5 times more likely than women age >30 to have chlamydial infection.² In women age ≥25, yearly screening is recommended only for those at high risk as indicated by:

• previous chlamydial infection or other STIs
• new or multiple sexual partners
• inconsistent condom use
• being a sex worker ( Table 2 ).²

Chlamydia screening reduces the incidence of pelvic inflammatory disease (PID) in nonpregnant adolescent and adult women, which can cause infertility, ectopic pregnancy, and chronic pelvic pain.² If untreated, the risk of PID approaches 40%.¹ In pregnant women, Chlamydia treatment significantly improves birth outcomes. Pregnant women should be screened during the first prenatal visit and in the third trimester if at continued risk.

Psychological implications of screening. Address possible themes of guilt and shame with patients to clarify and alleviate the burden they may feel about STI screening and treatment. Compared with men, women experience more stigmatization, blame, and denial about the source of infection. Women also report being more concerned about potential threats to their relationships.¹

Table 1

U.S. Preventive Services Task Force
screening recommendations for chlamydial infection

Table 2

Risks for chlamydial infection

Screening test. The Centers for Disease Control and Prevention (CDC) recommends screening with nucleic acid amplification tests (NAATs), which have high specificity (>95%) and sensitivity (80% to 93%) for chlamydial infections. Urine specimens are comparable to cervical and urethral specimens and avert the cost and patient discomfort associated with speculum exams.³ NAATs do not exclude other infections, such as trichomonas, however, and are not sufficient in patients with active urinary or vaginal symptoms.

Clinical presentation and treatment. Most persons with Chlamydia are asymptomatic and may infect new sexual partners. In women, chlamydial infection may cause cervicitis, urethritis, PID, chronic pelvic pain, ectopic pregnancy, miscarriage, preterm labor, and infertility. In men, chlamydial infection may cause urethritis, urethral strictures, and epididymis. In both genders, chlamydial infection increases the risk of acquiring other STIs, such as human immunodeficiency virus.⁴

The CDC recommends treating chlamydial infection with azithromycin, 1 g/d PO for pregnant and nonpregnant women. Alternatives include amoxicillin, 500 mg tid for 7 days for pregnant women, or doxycycline, 100 mg bid for 7 days for nonpregnant women. Sexual partners of an infected individual should be treated presumptively or tested and then treated. Because Chlamydia NAAT is highly sensitive, patients with a negative test do not need treatment. Patients who test positive for gonorrhea and receive a negative non-NAAT (antigen-based tests that are less sensitive than NAATs) for Chlamydia should be treated for both.⁵

Related resources

• Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. www.cdc.gov/std/treatment.
• U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. Preventive Services. www.preventiveservices.ahrq.gov.

Drug brand names

• Amoxicillin • Amoxil, others
• Azithromycin • Zithromax
• Doxycycline • Vibramycin

Disclosure

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI), with nearly 3 million new cases diagnosed annually in the United States.¹ In July 2007 the U.S. Preventive Services Task Force (USPSTF) updated its recommendation on Chlamydia screening of sexually active female adolescents and adults ( Table 1 ).² Routine screening is not recommended for men because there is not enough data to determine the benefits and risks of screening.

Although the USPSTF recommendation targets the general population, it is important to assess each patient’s sexual behavior. Women exhibiting impulsivity caused by bipolar mania, substance abuse, or personality disorders or who exchange sex for food, shelter, substances, or money are at high risk of infection ( Table 2 ).^1,2

The new guideline introduces a screening cutoff at age 25 because women age <25 years are 5 times more likely than women age >30 to have chlamydial infection.² In women age ≥25, yearly screening is recommended only for those at high risk as indicated by:

• previous chlamydial infection or other STIs
• new or multiple sexual partners
• inconsistent condom use
• being a sex worker ( Table 2 ).²

Chlamydia screening reduces the incidence of pelvic inflammatory disease (PID) in nonpregnant adolescent and adult women, which can cause infertility, ectopic pregnancy, and chronic pelvic pain.² If untreated, the risk of PID approaches 40%.¹ In pregnant women, Chlamydia treatment significantly improves birth outcomes. Pregnant women should be screened during the first prenatal visit and in the third trimester if at continued risk.

Psychological implications of screening. Address possible themes of guilt and shame with patients to clarify and alleviate the burden they may feel about STI screening and treatment. Compared with men, women experience more stigmatization, blame, and denial about the source of infection. Women also report being more concerned about potential threats to their relationships.¹

Table 1

U.S. Preventive Services Task Force
screening recommendations for chlamydial infection

Table 2

Risks for chlamydial infection

Screening test. The Centers for Disease Control and Prevention (CDC) recommends screening with nucleic acid amplification tests (NAATs), which have high specificity (>95%) and sensitivity (80% to 93%) for chlamydial infections. Urine specimens are comparable to cervical and urethral specimens and avert the cost and patient discomfort associated with speculum exams.³ NAATs do not exclude other infections, such as trichomonas, however, and are not sufficient in patients with active urinary or vaginal symptoms.

Clinical presentation and treatment. Most persons with Chlamydia are asymptomatic and may infect new sexual partners. In women, chlamydial infection may cause cervicitis, urethritis, PID, chronic pelvic pain, ectopic pregnancy, miscarriage, preterm labor, and infertility. In men, chlamydial infection may cause urethritis, urethral strictures, and epididymis. In both genders, chlamydial infection increases the risk of acquiring other STIs, such as human immunodeficiency virus.⁴

The CDC recommends treating chlamydial infection with azithromycin, 1 g/d PO for pregnant and nonpregnant women. Alternatives include amoxicillin, 500 mg tid for 7 days for pregnant women, or doxycycline, 100 mg bid for 7 days for nonpregnant women. Sexual partners of an infected individual should be treated presumptively or tested and then treated. Because Chlamydia NAAT is highly sensitive, patients with a negative test do not need treatment. Patients who test positive for gonorrhea and receive a negative non-NAAT (antigen-based tests that are less sensitive than NAATs) for Chlamydia should be treated for both.⁵

Related resources

• Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. www.cdc.gov/std/treatment.
• U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. Preventive Services. www.preventiveservices.ahrq.gov.

Drug brand names

• Amoxicillin • Amoxil, others
• Azithromycin • Zithromax
• Doxycycline • Vibramycin

Disclosure

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Chlamydia trachomatis is the most common bacterial sexually transmitted infection (STI), with nearly 3 million new cases diagnosed annually in the United States.¹ In July 2007 the U.S. Preventive Services Task Force (USPSTF) updated its recommendation on Chlamydia screening of sexually active female adolescents and adults ( Table 1 ).² Routine screening is not recommended for men because there is not enough data to determine the benefits and risks of screening.

Although the USPSTF recommendation targets the general population, it is important to assess each patient’s sexual behavior. Women exhibiting impulsivity caused by bipolar mania, substance abuse, or personality disorders or who exchange sex for food, shelter, substances, or money are at high risk of infection ( Table 2 ).^1,2

The new guideline introduces a screening cutoff at age 25 because women age <25 years are 5 times more likely than women age >30 to have chlamydial infection.² In women age ≥25, yearly screening is recommended only for those at high risk as indicated by:

• previous chlamydial infection or other STIs
• new or multiple sexual partners
• inconsistent condom use
• being a sex worker ( Table 2 ).²

Chlamydia screening reduces the incidence of pelvic inflammatory disease (PID) in nonpregnant adolescent and adult women, which can cause infertility, ectopic pregnancy, and chronic pelvic pain.² If untreated, the risk of PID approaches 40%.¹ In pregnant women, Chlamydia treatment significantly improves birth outcomes. Pregnant women should be screened during the first prenatal visit and in the third trimester if at continued risk.

Psychological implications of screening. Address possible themes of guilt and shame with patients to clarify and alleviate the burden they may feel about STI screening and treatment. Compared with men, women experience more stigmatization, blame, and denial about the source of infection. Women also report being more concerned about potential threats to their relationships.¹

Table 1

U.S. Preventive Services Task Force
screening recommendations for chlamydial infection

Table 2

Risks for chlamydial infection

Screening test. The Centers for Disease Control and Prevention (CDC) recommends screening with nucleic acid amplification tests (NAATs), which have high specificity (>95%) and sensitivity (80% to 93%) for chlamydial infections. Urine specimens are comparable to cervical and urethral specimens and avert the cost and patient discomfort associated with speculum exams.³ NAATs do not exclude other infections, such as trichomonas, however, and are not sufficient in patients with active urinary or vaginal symptoms.

Clinical presentation and treatment. Most persons with Chlamydia are asymptomatic and may infect new sexual partners. In women, chlamydial infection may cause cervicitis, urethritis, PID, chronic pelvic pain, ectopic pregnancy, miscarriage, preterm labor, and infertility. In men, chlamydial infection may cause urethritis, urethral strictures, and epididymis. In both genders, chlamydial infection increases the risk of acquiring other STIs, such as human immunodeficiency virus.⁴

The CDC recommends treating chlamydial infection with azithromycin, 1 g/d PO for pregnant and nonpregnant women. Alternatives include amoxicillin, 500 mg tid for 7 days for pregnant women, or doxycycline, 100 mg bid for 7 days for nonpregnant women. Sexual partners of an infected individual should be treated presumptively or tested and then treated. Because Chlamydia NAAT is highly sensitive, patients with a negative test do not need treatment. Patients who test positive for gonorrhea and receive a negative non-NAAT (antigen-based tests that are less sensitive than NAATs) for Chlamydia should be treated for both.⁵

Related resources

• Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. www.cdc.gov/std/treatment.
• U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. Preventive Services. www.preventiveservices.ahrq.gov.

Drug brand names

• Amoxicillin • Amoxil, others
• Azithromycin • Zithromax
• Doxycycline • Vibramycin

Disclosure

Dr. Xiong reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.