Bipolar Disorder

Significant deficits in social cognition were found in patients with schizophrenia spectrum disorders (SSDs), but not in patients with bipolar disorder (BD), Dr. George C. Nitzburg and his associates reported.

In a study of 537 SSD patients, 85 BD patients with psychotic features, 37 BD patients without psychotic features, and 309 controls, SSD patients had significant social cognition deficits, compared with controls. Bipolar patients did not have these deficits, the investigators reported (F (2,964) = 24.85, P < .001). Social cognition was assessed using scores on the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT).

The results of this study “highlight the importance of developing standardized social-cognitive batteries for use across BD and SSD and emphasize the need for future work on social brain development in clinical populations,” Dr. Nitzburg and his coauthors wrote in the report.

Read the full article here: doi:10.1016/j.scog.2014.12.003.

Significant deficits in social cognition were found in patients with schizophrenia spectrum disorders (SSDs), but not in patients with bipolar disorder (BD), Dr. George C. Nitzburg and his associates reported.

In a study of 537 SSD patients, 85 BD patients with psychotic features, 37 BD patients without psychotic features, and 309 controls, SSD patients had significant social cognition deficits, compared with controls. Bipolar patients did not have these deficits, the investigators reported (F (2,964) = 24.85, P < .001). Social cognition was assessed using scores on the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT).

The results of this study “highlight the importance of developing standardized social-cognitive batteries for use across BD and SSD and emphasize the need for future work on social brain development in clinical populations,” Dr. Nitzburg and his coauthors wrote in the report.

Read the full article here: doi:10.1016/j.scog.2014.12.003.

Significant deficits in social cognition were found in patients with schizophrenia spectrum disorders (SSDs), but not in patients with bipolar disorder (BD), Dr. George C. Nitzburg and his associates reported.

In a study of 537 SSD patients, 85 BD patients with psychotic features, 37 BD patients without psychotic features, and 309 controls, SSD patients had significant social cognition deficits, compared with controls. Bipolar patients did not have these deficits, the investigators reported (F (2,964) = 24.85, P < .001). Social cognition was assessed using scores on the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT).

The results of this study “highlight the importance of developing standardized social-cognitive batteries for use across BD and SSD and emphasize the need for future work on social brain development in clinical populations,” Dr. Nitzburg and his coauthors wrote in the report.

Read the full article here: doi:10.1016/j.scog.2014.12.003.

Manic episodes, by definition, are associated with significant social or occupational impairment.¹ Some manic patients are violent or engage in reckless behaviors that can harm themselves or others, such as speeding, disrupting traffic, or playing with fire. When these patients present to a psychiatrist’s outpatient practice, involuntary hospitalization might be justified.

However, some manic patients, in spite of their elevated, expansive, or irritable mood state, never behave dangerously and might not meet legal criteria for involuntary hospitalization, although these criteria differ from state to state. These patients might see a psychiatrist because manic symptoms such as irritability, talkativeness, and impulsivity are bother­some to their family members but pose no serious danger (Box). In this situation, the psychiatrist can strongly encourage the patient to seek voluntary hospitalization or attend a partial hospitalization program. If the patient declines, the psychiatrist is left with 2 choices: initiate treatment in the outpatient setting or refuse to treat the patient and refer to another provider.

Treating “non-dangerous” mania in the outpatient setting is fraught with challenges:
   • the possibility that the patient’s condition will progress to dangerousness
   • poor adherence to treatment because of the patient’s limited insight
   • the large amount of time required from the psychiatrist and care team to adequately manage the manic episode (eg, time spent with fam­ily members, frequent patient visits, and managing communications from the patient).

There are no guidelines to assist the office-based practitioner in treating mania in the outpatient setting. When considering dosing and optimal medication combina­tions for treating mania, clinical trials may be of limited value because most of these studies only included hospitalized manic patients.

Because of this dearth of knowledge, we provide recommendations based on our review of the literature and from our expe­rience working with manic patients who refuse voluntary hospitalization and could not be hospitalized against their will. These recommendations are organized into 3 sec­tions: diagnostic approach, treatment strat­egy, and family involvement.

Diagnostic approach
Making a diagnosis of mania might seem straightforward for clinicians who work in inpatient settings; however, mania might not present with classic florid symptoms among outpatients. Patients might have a chief concern of irritability, dysphoria, anxiety, or “insomnia,” which may lead clinicians to focus initially on non-bipolar conditions.²

During the interview, it is important to assess for any current DSM-5 symptoms of a manic episode, while being careful not to accept a patient’s denial of symptoms. Patients with mania often have poor insight and are unaware of changes from their base­line state when manic.³ Alternatively, manic patients may want you to believe that they are well and could minimize or deny all symptoms. Therefore, it is important to pay attention to mental status examination find­ings, such as hyperverbal speech, elated affect, psychomotor agitation, a tangential thought process, or flight of ideas.

Countertransference feelings of diagnos­tic confusion or frustration after long patient monologues or multiple interruptions by the patient should be incorporated into the diagnostic assessment. Family members or friends often can provide objective obser­vations of behavioral changes necessary to secure the diagnosis.

Treatment strategy
Decision points. When treating manic out­patients, assess the need for hospitalization at each visit. Advantages of the inpatient setting include:
   • the possibility of rapid medication adjustments
   • continuous observation to ensure the patient’s safety
   • keeping the patient temporarily removed from his community to prevent irrevers­ible social and economic harms.

However, a challenge with hospitaliza­tion is third-party payers’ influence on a patient’s length of stay, which may lead to rapid medication changes that may not be clinically ideal.

At each outpatient visit, explore with the patient and family emerging symptoms that could justify involuntary hospitaliza­tion. Document whether you recommended inpatient hospitalization, the patient’s response to the recommendation, that you are aware and have considered the risks associated with outpatient care, and that you have discussed these risks with the patient and family.

For patients well-known to the psychia­trist, a history of dangerous mania may lead him (her) to strongly recommend hos­pitalization, whereas a pre-existing thera­peutic alliance and no current or distant history of dangerous mania may lead the clinician to look for alternatives to inpatient care. Concomitant drug or alcohol use may increase the likelihood of mania becoming dangerous, making outpatient treatment ill-advised and riskier for everyone involved.

In exchange for agreeing to provide out­patient care for mania, it often is helpful to negotiate with the patient and family a threshold level of symptoms or behavior that will result in the patient agreeing to voluntary hospitalization (Table 1). Such an agreement can include stopping outpatient treatment if the patient does not improve significantly after 2 or 3 weeks or develops psychotic symptoms. The negotiation also can include partial hospitalization as an option, so long as the patient’s mania con­tinues to be non-dangerous.

Obtaining pretreatment blood work can help a clinician determine whether a medication is safe to prescribe and establish causality if laboratory abnormalities arise after treatment begins. Ideally, the psychia­trist should follow consensus guidelines developed by the International Society for Bipolar Disorders⁴ or the American Psychiatric Association (APA)⁵ and order appropriate laboratory tests before prescrib­ing anti-manic medications. Determine the pregnancy status of female patients of child-bearing age before prescribing a potentially teratogenic medication, especially because mania is associated with increased libido.⁶

Manic patients might be too disorga­nized to follow up with recommendations for laboratory testing, or could wait sev­eral days before completing blood work. Although not ideal, to avoid delaying treat­ment, a clinician might need to prescribe medication at the initial office visit, without pretreatment laboratory results. When the patient is more organized, complete the blood work. Keeping home pregnancy tests in the office can help rule out pregnancy before prescribing medication.

Medication. Meta-analyses have estab­lished the efficacy of mood stabilizers and antipsychotics for treating mania,^7,8 and sev­eral consensus guidelines have incorporated these findings into treatment algorithms.⁹

For a patient already taking medications recommended by the guidelines, assess treatment adherence during the initial inter­view by questioning the patient and family. When the logistics of phlebotomy permit, obtaining the blood level of psychotropics can show the presence of any detectable drug concentration, which demonstrates that the patient has taken the medication recently.

If there is no evidence of nonadherence, an initial step might be to increase the dos­age of the antipsychotic or mood stabilizer that the patient is already taking, ensuring that the dosage is optimized based on FDA indications and clinical trials data. The rec­ommended rate of dosage adjustments dif­fers among medications; however, optimal dosing should be reached quickly because a World Federation of Societies of Biological Psychiatry task force recommends that a mania treatment trial not exceed 2 weeks.¹⁰

Dosage increases can be made at weekly visits or sooner, based on treatment response and tolerability. If there is no ben­efit after optimizing the dosage, the next step would be to add a mood stabilizer to a second-generation antipsychotic (SGA), or vice versa to promote additive or syn­ergistic medication effects.¹¹ Switching one medication for the other should be avoided unless there are tolerability concerns.

For a patient who is not taking any medi­cations, select a treatment that balances rapid stabilization with long-term efficacy and tolerability. Table 2 lists FDA-approved treatments for mania. Lamotrigine provides prophylactic efficacy with few associated risks, but it has no anti-manic effects and would be a poor choice for most actively manic patients. Most studies indicate that antipsychotics work faster than lithium at the 1-week mark; however, this may be a function of the lithium titration schedule followed in the protocols, the severity of mania among enrolled patients, the inclu­sion of typically non-responsive manic patients (eg, mixed) in the analysis, and the antipsychotic’s sedative potential rela­tive to lithium. Although the anti-manic and prophylactic potential of lithium and valproate might make them an ideal first-line option, antipsychotics could stabilize a manic patient faster, especially if agitation is present.^12,13

Breaking mania quickly is important when treating patients in the outpatient set­ting. In these situations, a reasonable choice is to prescribe a SGA, because of their rapid onset of effect, low potential for switch to depression, and utility in treating classic, mixed, or psychotic mania.¹⁰ Oral loading of valproate (20 mg/kg) is another option. An inpatient study that used an oral-loading strategy demonstrated a similar time to response as olanzapine,¹⁴ in contrast to an inpatient¹⁵ and an outpatient study¹⁶ that employed a standard starting dosage for each patient and led to slower improve­ment compared with olanzapine.

SGAs should be dosed moderately and lower than if the patient were hospitalized, to avoid alienating the patient from treat­ment by causing intolerable side effects. In particular, patients and their families should be warned about immediate risks, such as orthostasis or extrapyramidal symptoms. Although treatment guidelines recommend combination therapy as a possible first-line option,⁹ in the outpatient setting, monother­apy with an optimally dosed, rapid-acting agent is preferred to promote medication adherence and avoid potentially danger­ous sedation. Manic patients experience increased distractibility and verbal memory and executive function impairments that can interfere with medication adherence.¹⁷ Therefore, patients are more likely to fol­low a simpler regimen. If SGA or valpro­ate monotherapy does not control mania, begin combination treatment with a mood stabilizer and SGA. If the patient experi­ences remission with SGA monotherapy, the risks and benefits of maintaining the SGA vs switching to a mood stabilizer can be discussed.

Provide medication “as needed” for agitation—additional SGA dosing or a benzodiazepine—and explain to fam­ily members when their use is warranted. Benzodiazepines can provide short-term benefits for manic patients: anxiety relief, sedation, and anti-manic efficacy as mono­therapy^18-20 and in combination with other medications.²¹ Studies showing mono­therapy efficacy employed high dosages of benzodiazepines (lorazepam mean dos­age, 14 mg/d; clonazepam mean dosage, 13 mg/d)¹⁹ and high dosages of antipsy­chotics as needed,^18,20 and often were associ­ated with excessive sedation and ataxia.^18,19 This makes benzodiazepine monotherapy a potentially dangerous approach for out­patient treatment of mania. IM lorazepam treated manic agitation less quickly than IM olanzapine, suggesting that SGAs are preferable in the outpatient setting because rapid control of agitation is crucial.²² If pre­scribed, a trusted family member should dispense benzodiazepines to the patient to minimize misuse because of impulsivity, distractibility, desperation to sleep, or plea­sure seeking.

SGAs have the benefit of sedation but occasionally additional sleep medica­tions are required. Benzodiazepine recep­tor agonists (BzRAs), such as zolpidem, eszopiclone, and zaleplon, should be used with caution. Although these medicines are effective in treating insomnia in indi­viduals with primary insomnia²³ and major depression,²⁴ they have not been studied in manic patients. The decreased need for sleep in mania is phenomenologically²⁵ and perhaps biologically different than insomnia in major depression.²⁶ Therefore, mania-associated sleep disturbance might not respond to BZRAs. BzRAs also might induce somnambulism and other parasom­nias,²⁷ especially when used in combination with psychotropics, such as valproate²⁸; it is unclear if the manic state itself increases this risk further. Sedating antihistamines with anticholinergic blockade, such as diphenhydramine and low dosages (<100 mg/d) of quetiapine, are best used only in combination with anti-manic medi­cations because of putative link between anticholinergic blockade and manic induc­tion.²⁹ Less studied but safer options include novel anticonvulsants (gabapen­tin, pregabalin), melatonin, and melatonin receptor agonists. Sedating antidepressants, such as mirtazapine and trazodone, should be avoided.²⁵

Important adjunctive treatment steps include discontinuing all pro-manic agents, including antidepressants, stimulants, and steroids, and discouraging use of caffeine, energy drinks, illicit drugs, and alcohol. The patient should return for office visits at least weekly, and possibly more frequently, depending on severity. Telephone check-in calls between scheduled visits may be nec­essary until the mania is broken.

Psychotherapy. Other than supportive therapy and psychoeducation, other forms of psychotherapy during mania are not indicated. Psychotherapy trials in bipolar disorder do not inform anti-manic efficacy because few have enrolled acutely manic patients and most report long-term benefits rather than short-term efficacy for the index manic episode.³⁰ Educate patients about the importance of maintaining regular social rhythms and taking medication as pre­scribed. Manic patients might not be aware that they are acting differently during manic episodes, therefore efforts to improve the patient’s insight are unlikely to succeed. More time should be spent emphasizing the importance of adherence to treatment and taking anti-manic medications as pre­scribed. This discussion can be enhanced by focusing on the medication’s potential to reduce the unpleasant symptoms of mania, including irritability, insomnia, anxiety, and racing thoughts. At the first visit, dis­cuss setting boundaries with the patient to reduce mania-driven, intrusive phone calls. A patient might develop insight after mania has resolved and he (she) can appre­ciate social or economic harm that occurred while manic. This discussion might foster adherence to maintenance treatment. Advise your patient to limit activities that may increase stimulation and perpetuate the mania, such as exercise, parties, concerts, or crowded shopping malls. Also, recommend that your patient stop working temporarily, to reduce stress and prevent any manic-driven interactions that could result in job loss.

If your patient has an established relationship with a psychotherapist, discuss with the therapist the plan to initiate mania treatment in the outpatient setting and work as a collaborative team, assuming that the patient has granted permission to share information. Encourage the therapist to increase the frequency of sessions with the patient to enable greater monitoring of changes in the patient’s manic symptoms. 

Family involvement
Family support is crucial when treating mania in the outpatient setting. Lacking insight and organization, manic patients require the “auxiliary” judgment of trusted family members to ensure treatment suc­cess. The family should identify a single person to act as the liaison between the family and the psychiatrist. The psychiatrist should instruct this individual to accom­pany the patient to each clinic visit and provide regular updates on the patient’s adherence to treatment, changes in symp­toms, and any new behaviors that would justify involuntary hospitalization. The treatment plan should be clearly communi­cated to this individual to ensure that it is implemented correctly. Ideally, this individ­ual would be someone who understands that bipolar disorder is a mental illness, who can tolerate the patient’s potential resentment of them for taking on this role, and who can influence the patient and the other family members to adhere to the treat­ment plan.

This family member also should watch the patient take medication to rule out nonadherence if the patient’s condition does not improve.

Provide extensive psychoeducation to the family (Table 3). Discuss these teaching points and their implications at length during the first visit and reinforce them at subsequent visits. Advise spouses that the acute manic period is not the time to make major decisions about their mar­riage or to engage in couple’s therapy. These options are better explored after the patient recovers from the manic episode.

These interventions can be challenging for the entire family system because they place family members in a paternalistic role and reduce the patient’s autonomy within the family. This is problematic when these role changes occur between spouses or between a patient-parent and his (her) children. Such changes typically need to be reversed over time and may require the help of a family or couple’s therapist. To support the psychological health of the patient’s family, refer them to the National Alliance on Mental Illness for family support groups or to individual psychotherapists.

Outpatient management can be rewarding
For “non-dangerous” manic patients who cannot be hospitalized involuntarily and refuse full or partial hospitalization, a psychiatrist must choose between beginning treatment in the clinic and referring the patient to another provider. The latter option is consistent with the APA’s ethical guidelines,³¹ but must be done appropriately to avoid legal liability.³² This decision may disappoint a family desperate to see their loved one recover quickly and may leave them feeling betrayed by the mental health system. On the other hand, choosing to treat mania in the outpatient setting can be rewarding when resolution of mania restores the family’s homeostasis.

To achieve this outcome, the outpatient psychiatrist must engage the patient’s fam­ily to ensure that the patient adheres to the treatment plan and monitor for potentially dangerous behavior. The psychiatrist also must use his knowledge of mood symp­toms, cognitive impairments, and the psy­chological experience of manic patients to create a safe and effective treatment strategy that the patient and family can implement.

Because of mania’s unpredictability and destructive potential, psychiatrists who agree to treat manic patients as outpatients should be familiar with their state’s statutes and case law that pertain to the refusal to accept a new patient, patient abandonment, involuntary hospitalization, confidentiality, and mandatory reporting. They also should seek clinical or legal consultation if they feel overwhelmed or uncertain about the safest and most legally sound approach.

Bottom Line
Treating mania in the outpatient setting is risky but can be accomplished in select patients with the help of the patient’s family and a strategy that integrates evidence-based pharmacotherapeutic and psychotherapeutic strategies. Because manic patients could display dangerous behavior, be familiar with your state’s laws regarding involuntary commitment, patient abandonment, and mandatory reporting.

Related Resources
• National Alliance on Mental Illness. www.NAMI.org.
• Depression and Bipolar Support Alliance. www.DBSAlliance.org.

Drug Brand Names
Aripiprazole • Abilify                                      Mirtazapine • Remeron
Asenapine • Saphris                                      Olanzapine • Zyprexa
Carbamazepine • Equetro, Tegretol                Pregabalin • Lyrica
Chlorpromazine • Thorazine                           Quetiapine • Seroquel
Clonazepam • Klonopin                                  Risperidone • Risperdal
Diphrenhydramine • Benadryl                         Trazodone • Desyrel
Eszopiclone • Lunesta                                    Valproate • Divalproex
Gabapentin • Neurontin                                  Zaleplon • Sonata
Lamotrigine • Lamictal                                    Ziprasidone •  Geodon
Lithium • Eskalith, Lithobid                              Zolpidem •  Ambien
Lorazepam • Ativan

Acknowledgement
The authors thank Peter Ash, MD, for carefully reviewing this manuscript and providing feedback.

Disclosures
Dr. Rakofsky receives research or grant support from Takeda. Dr. Dunlop receives research or grant support from Forest, GlaxoSmithKline, and Otsuka.

Manic episodes, by definition, are associated with significant social or occupational impairment.¹ Some manic patients are violent or engage in reckless behaviors that can harm themselves or others, such as speeding, disrupting traffic, or playing with fire. When these patients present to a psychiatrist’s outpatient practice, involuntary hospitalization might be justified.

However, some manic patients, in spite of their elevated, expansive, or irritable mood state, never behave dangerously and might not meet legal criteria for involuntary hospitalization, although these criteria differ from state to state. These patients might see a psychiatrist because manic symptoms such as irritability, talkativeness, and impulsivity are bother­some to their family members but pose no serious danger (Box). In this situation, the psychiatrist can strongly encourage the patient to seek voluntary hospitalization or attend a partial hospitalization program. If the patient declines, the psychiatrist is left with 2 choices: initiate treatment in the outpatient setting or refuse to treat the patient and refer to another provider.

Treating “non-dangerous” mania in the outpatient setting is fraught with challenges:
   • the possibility that the patient’s condition will progress to dangerousness
   • poor adherence to treatment because of the patient’s limited insight
   • the large amount of time required from the psychiatrist and care team to adequately manage the manic episode (eg, time spent with fam­ily members, frequent patient visits, and managing communications from the patient).

There are no guidelines to assist the office-based practitioner in treating mania in the outpatient setting. When considering dosing and optimal medication combina­tions for treating mania, clinical trials may be of limited value because most of these studies only included hospitalized manic patients.

Because of this dearth of knowledge, we provide recommendations based on our review of the literature and from our expe­rience working with manic patients who refuse voluntary hospitalization and could not be hospitalized against their will. These recommendations are organized into 3 sec­tions: diagnostic approach, treatment strat­egy, and family involvement.

Diagnostic approach
Making a diagnosis of mania might seem straightforward for clinicians who work in inpatient settings; however, mania might not present with classic florid symptoms among outpatients. Patients might have a chief concern of irritability, dysphoria, anxiety, or “insomnia,” which may lead clinicians to focus initially on non-bipolar conditions.²

During the interview, it is important to assess for any current DSM-5 symptoms of a manic episode, while being careful not to accept a patient’s denial of symptoms. Patients with mania often have poor insight and are unaware of changes from their base­line state when manic.³ Alternatively, manic patients may want you to believe that they are well and could minimize or deny all symptoms. Therefore, it is important to pay attention to mental status examination find­ings, such as hyperverbal speech, elated affect, psychomotor agitation, a tangential thought process, or flight of ideas.

Countertransference feelings of diagnos­tic confusion or frustration after long patient monologues or multiple interruptions by the patient should be incorporated into the diagnostic assessment. Family members or friends often can provide objective obser­vations of behavioral changes necessary to secure the diagnosis.

Treatment strategy
Decision points. When treating manic out­patients, assess the need for hospitalization at each visit. Advantages of the inpatient setting include:
   • the possibility of rapid medication adjustments
   • continuous observation to ensure the patient’s safety
   • keeping the patient temporarily removed from his community to prevent irrevers­ible social and economic harms.

However, a challenge with hospitaliza­tion is third-party payers’ influence on a patient’s length of stay, which may lead to rapid medication changes that may not be clinically ideal.

At each outpatient visit, explore with the patient and family emerging symptoms that could justify involuntary hospitaliza­tion. Document whether you recommended inpatient hospitalization, the patient’s response to the recommendation, that you are aware and have considered the risks associated with outpatient care, and that you have discussed these risks with the patient and family.

For patients well-known to the psychia­trist, a history of dangerous mania may lead him (her) to strongly recommend hos­pitalization, whereas a pre-existing thera­peutic alliance and no current or distant history of dangerous mania may lead the clinician to look for alternatives to inpatient care. Concomitant drug or alcohol use may increase the likelihood of mania becoming dangerous, making outpatient treatment ill-advised and riskier for everyone involved.

In exchange for agreeing to provide out­patient care for mania, it often is helpful to negotiate with the patient and family a threshold level of symptoms or behavior that will result in the patient agreeing to voluntary hospitalization (Table 1). Such an agreement can include stopping outpatient treatment if the patient does not improve significantly after 2 or 3 weeks or develops psychotic symptoms. The negotiation also can include partial hospitalization as an option, so long as the patient’s mania con­tinues to be non-dangerous.

Obtaining pretreatment blood work can help a clinician determine whether a medication is safe to prescribe and establish causality if laboratory abnormalities arise after treatment begins. Ideally, the psychia­trist should follow consensus guidelines developed by the International Society for Bipolar Disorders⁴ or the American Psychiatric Association (APA)⁵ and order appropriate laboratory tests before prescrib­ing anti-manic medications. Determine the pregnancy status of female patients of child-bearing age before prescribing a potentially teratogenic medication, especially because mania is associated with increased libido.⁶

Manic patients might be too disorga­nized to follow up with recommendations for laboratory testing, or could wait sev­eral days before completing blood work. Although not ideal, to avoid delaying treat­ment, a clinician might need to prescribe medication at the initial office visit, without pretreatment laboratory results. When the patient is more organized, complete the blood work. Keeping home pregnancy tests in the office can help rule out pregnancy before prescribing medication.

Medication. Meta-analyses have estab­lished the efficacy of mood stabilizers and antipsychotics for treating mania,^7,8 and sev­eral consensus guidelines have incorporated these findings into treatment algorithms.⁹

For a patient already taking medications recommended by the guidelines, assess treatment adherence during the initial inter­view by questioning the patient and family. When the logistics of phlebotomy permit, obtaining the blood level of psychotropics can show the presence of any detectable drug concentration, which demonstrates that the patient has taken the medication recently.

If there is no evidence of nonadherence, an initial step might be to increase the dos­age of the antipsychotic or mood stabilizer that the patient is already taking, ensuring that the dosage is optimized based on FDA indications and clinical trials data. The rec­ommended rate of dosage adjustments dif­fers among medications; however, optimal dosing should be reached quickly because a World Federation of Societies of Biological Psychiatry task force recommends that a mania treatment trial not exceed 2 weeks.¹⁰

Dosage increases can be made at weekly visits or sooner, based on treatment response and tolerability. If there is no ben­efit after optimizing the dosage, the next step would be to add a mood stabilizer to a second-generation antipsychotic (SGA), or vice versa to promote additive or syn­ergistic medication effects.¹¹ Switching one medication for the other should be avoided unless there are tolerability concerns.

For a patient who is not taking any medi­cations, select a treatment that balances rapid stabilization with long-term efficacy and tolerability. Table 2 lists FDA-approved treatments for mania. Lamotrigine provides prophylactic efficacy with few associated risks, but it has no anti-manic effects and would be a poor choice for most actively manic patients. Most studies indicate that antipsychotics work faster than lithium at the 1-week mark; however, this may be a function of the lithium titration schedule followed in the protocols, the severity of mania among enrolled patients, the inclu­sion of typically non-responsive manic patients (eg, mixed) in the analysis, and the antipsychotic’s sedative potential rela­tive to lithium. Although the anti-manic and prophylactic potential of lithium and valproate might make them an ideal first-line option, antipsychotics could stabilize a manic patient faster, especially if agitation is present.^12,13

Breaking mania quickly is important when treating patients in the outpatient set­ting. In these situations, a reasonable choice is to prescribe a SGA, because of their rapid onset of effect, low potential for switch to depression, and utility in treating classic, mixed, or psychotic mania.¹⁰ Oral loading of valproate (20 mg/kg) is another option. An inpatient study that used an oral-loading strategy demonstrated a similar time to response as olanzapine,¹⁴ in contrast to an inpatient¹⁵ and an outpatient study¹⁶ that employed a standard starting dosage for each patient and led to slower improve­ment compared with olanzapine.

SGAs should be dosed moderately and lower than if the patient were hospitalized, to avoid alienating the patient from treat­ment by causing intolerable side effects. In particular, patients and their families should be warned about immediate risks, such as orthostasis or extrapyramidal symptoms. Although treatment guidelines recommend combination therapy as a possible first-line option,⁹ in the outpatient setting, monother­apy with an optimally dosed, rapid-acting agent is preferred to promote medication adherence and avoid potentially danger­ous sedation. Manic patients experience increased distractibility and verbal memory and executive function impairments that can interfere with medication adherence.¹⁷ Therefore, patients are more likely to fol­low a simpler regimen. If SGA or valpro­ate monotherapy does not control mania, begin combination treatment with a mood stabilizer and SGA. If the patient experi­ences remission with SGA monotherapy, the risks and benefits of maintaining the SGA vs switching to a mood stabilizer can be discussed.

Provide medication “as needed” for agitation—additional SGA dosing or a benzodiazepine—and explain to fam­ily members when their use is warranted. Benzodiazepines can provide short-term benefits for manic patients: anxiety relief, sedation, and anti-manic efficacy as mono­therapy^18-20 and in combination with other medications.²¹ Studies showing mono­therapy efficacy employed high dosages of benzodiazepines (lorazepam mean dos­age, 14 mg/d; clonazepam mean dosage, 13 mg/d)¹⁹ and high dosages of antipsy­chotics as needed,^18,20 and often were associ­ated with excessive sedation and ataxia.^18,19 This makes benzodiazepine monotherapy a potentially dangerous approach for out­patient treatment of mania. IM lorazepam treated manic agitation less quickly than IM olanzapine, suggesting that SGAs are preferable in the outpatient setting because rapid control of agitation is crucial.²² If pre­scribed, a trusted family member should dispense benzodiazepines to the patient to minimize misuse because of impulsivity, distractibility, desperation to sleep, or plea­sure seeking.

SGAs have the benefit of sedation but occasionally additional sleep medica­tions are required. Benzodiazepine recep­tor agonists (BzRAs), such as zolpidem, eszopiclone, and zaleplon, should be used with caution. Although these medicines are effective in treating insomnia in indi­viduals with primary insomnia²³ and major depression,²⁴ they have not been studied in manic patients. The decreased need for sleep in mania is phenomenologically²⁵ and perhaps biologically different than insomnia in major depression.²⁶ Therefore, mania-associated sleep disturbance might not respond to BZRAs. BzRAs also might induce somnambulism and other parasom­nias,²⁷ especially when used in combination with psychotropics, such as valproate²⁸; it is unclear if the manic state itself increases this risk further. Sedating antihistamines with anticholinergic blockade, such as diphenhydramine and low dosages (<100 mg/d) of quetiapine, are best used only in combination with anti-manic medi­cations because of putative link between anticholinergic blockade and manic induc­tion.²⁹ Less studied but safer options include novel anticonvulsants (gabapen­tin, pregabalin), melatonin, and melatonin receptor agonists. Sedating antidepressants, such as mirtazapine and trazodone, should be avoided.²⁵

Important adjunctive treatment steps include discontinuing all pro-manic agents, including antidepressants, stimulants, and steroids, and discouraging use of caffeine, energy drinks, illicit drugs, and alcohol. The patient should return for office visits at least weekly, and possibly more frequently, depending on severity. Telephone check-in calls between scheduled visits may be nec­essary until the mania is broken.

Psychotherapy. Other than supportive therapy and psychoeducation, other forms of psychotherapy during mania are not indicated. Psychotherapy trials in bipolar disorder do not inform anti-manic efficacy because few have enrolled acutely manic patients and most report long-term benefits rather than short-term efficacy for the index manic episode.³⁰ Educate patients about the importance of maintaining regular social rhythms and taking medication as pre­scribed. Manic patients might not be aware that they are acting differently during manic episodes, therefore efforts to improve the patient’s insight are unlikely to succeed. More time should be spent emphasizing the importance of adherence to treatment and taking anti-manic medications as pre­scribed. This discussion can be enhanced by focusing on the medication’s potential to reduce the unpleasant symptoms of mania, including irritability, insomnia, anxiety, and racing thoughts. At the first visit, dis­cuss setting boundaries with the patient to reduce mania-driven, intrusive phone calls. A patient might develop insight after mania has resolved and he (she) can appre­ciate social or economic harm that occurred while manic. This discussion might foster adherence to maintenance treatment. Advise your patient to limit activities that may increase stimulation and perpetuate the mania, such as exercise, parties, concerts, or crowded shopping malls. Also, recommend that your patient stop working temporarily, to reduce stress and prevent any manic-driven interactions that could result in job loss.

If your patient has an established relationship with a psychotherapist, discuss with the therapist the plan to initiate mania treatment in the outpatient setting and work as a collaborative team, assuming that the patient has granted permission to share information. Encourage the therapist to increase the frequency of sessions with the patient to enable greater monitoring of changes in the patient’s manic symptoms. 

Family involvement
Family support is crucial when treating mania in the outpatient setting. Lacking insight and organization, manic patients require the “auxiliary” judgment of trusted family members to ensure treatment suc­cess. The family should identify a single person to act as the liaison between the family and the psychiatrist. The psychiatrist should instruct this individual to accom­pany the patient to each clinic visit and provide regular updates on the patient’s adherence to treatment, changes in symp­toms, and any new behaviors that would justify involuntary hospitalization. The treatment plan should be clearly communi­cated to this individual to ensure that it is implemented correctly. Ideally, this individ­ual would be someone who understands that bipolar disorder is a mental illness, who can tolerate the patient’s potential resentment of them for taking on this role, and who can influence the patient and the other family members to adhere to the treat­ment plan.

This family member also should watch the patient take medication to rule out nonadherence if the patient’s condition does not improve.

Provide extensive psychoeducation to the family (Table 3). Discuss these teaching points and their implications at length during the first visit and reinforce them at subsequent visits. Advise spouses that the acute manic period is not the time to make major decisions about their mar­riage or to engage in couple’s therapy. These options are better explored after the patient recovers from the manic episode.

These interventions can be challenging for the entire family system because they place family members in a paternalistic role and reduce the patient’s autonomy within the family. This is problematic when these role changes occur between spouses or between a patient-parent and his (her) children. Such changes typically need to be reversed over time and may require the help of a family or couple’s therapist. To support the psychological health of the patient’s family, refer them to the National Alliance on Mental Illness for family support groups or to individual psychotherapists.

Outpatient management can be rewarding
For “non-dangerous” manic patients who cannot be hospitalized involuntarily and refuse full or partial hospitalization, a psychiatrist must choose between beginning treatment in the clinic and referring the patient to another provider. The latter option is consistent with the APA’s ethical guidelines,³¹ but must be done appropriately to avoid legal liability.³² This decision may disappoint a family desperate to see their loved one recover quickly and may leave them feeling betrayed by the mental health system. On the other hand, choosing to treat mania in the outpatient setting can be rewarding when resolution of mania restores the family’s homeostasis.

To achieve this outcome, the outpatient psychiatrist must engage the patient’s fam­ily to ensure that the patient adheres to the treatment plan and monitor for potentially dangerous behavior. The psychiatrist also must use his knowledge of mood symp­toms, cognitive impairments, and the psy­chological experience of manic patients to create a safe and effective treatment strategy that the patient and family can implement.

Because of mania’s unpredictability and destructive potential, psychiatrists who agree to treat manic patients as outpatients should be familiar with their state’s statutes and case law that pertain to the refusal to accept a new patient, patient abandonment, involuntary hospitalization, confidentiality, and mandatory reporting. They also should seek clinical or legal consultation if they feel overwhelmed or uncertain about the safest and most legally sound approach.

Bottom Line
Treating mania in the outpatient setting is risky but can be accomplished in select patients with the help of the patient’s family and a strategy that integrates evidence-based pharmacotherapeutic and psychotherapeutic strategies. Because manic patients could display dangerous behavior, be familiar with your state’s laws regarding involuntary commitment, patient abandonment, and mandatory reporting.

Related Resources
• National Alliance on Mental Illness. www.NAMI.org.
• Depression and Bipolar Support Alliance. www.DBSAlliance.org.

Drug Brand Names
Aripiprazole • Abilify                                      Mirtazapine • Remeron
Asenapine • Saphris                                      Olanzapine • Zyprexa
Carbamazepine • Equetro, Tegretol                Pregabalin • Lyrica
Chlorpromazine • Thorazine                           Quetiapine • Seroquel
Clonazepam • Klonopin                                  Risperidone • Risperdal
Diphrenhydramine • Benadryl                         Trazodone • Desyrel
Eszopiclone • Lunesta                                    Valproate • Divalproex
Gabapentin • Neurontin                                  Zaleplon • Sonata
Lamotrigine • Lamictal                                    Ziprasidone •  Geodon
Lithium • Eskalith, Lithobid                              Zolpidem •  Ambien
Lorazepam • Ativan

Acknowledgement
The authors thank Peter Ash, MD, for carefully reviewing this manuscript and providing feedback.

Disclosures
Dr. Rakofsky receives research or grant support from Takeda. Dr. Dunlop receives research or grant support from Forest, GlaxoSmithKline, and Otsuka.

Manic episodes, by definition, are associated with significant social or occupational impairment.¹ Some manic patients are violent or engage in reckless behaviors that can harm themselves or others, such as speeding, disrupting traffic, or playing with fire. When these patients present to a psychiatrist’s outpatient practice, involuntary hospitalization might be justified.

However, some manic patients, in spite of their elevated, expansive, or irritable mood state, never behave dangerously and might not meet legal criteria for involuntary hospitalization, although these criteria differ from state to state. These patients might see a psychiatrist because manic symptoms such as irritability, talkativeness, and impulsivity are bother­some to their family members but pose no serious danger (Box). In this situation, the psychiatrist can strongly encourage the patient to seek voluntary hospitalization or attend a partial hospitalization program. If the patient declines, the psychiatrist is left with 2 choices: initiate treatment in the outpatient setting or refuse to treat the patient and refer to another provider.

Treating “non-dangerous” mania in the outpatient setting is fraught with challenges:
   • the possibility that the patient’s condition will progress to dangerousness
   • poor adherence to treatment because of the patient’s limited insight
   • the large amount of time required from the psychiatrist and care team to adequately manage the manic episode (eg, time spent with fam­ily members, frequent patient visits, and managing communications from the patient).

There are no guidelines to assist the office-based practitioner in treating mania in the outpatient setting. When considering dosing and optimal medication combina­tions for treating mania, clinical trials may be of limited value because most of these studies only included hospitalized manic patients.

Because of this dearth of knowledge, we provide recommendations based on our review of the literature and from our expe­rience working with manic patients who refuse voluntary hospitalization and could not be hospitalized against their will. These recommendations are organized into 3 sec­tions: diagnostic approach, treatment strat­egy, and family involvement.

Diagnostic approach
Making a diagnosis of mania might seem straightforward for clinicians who work in inpatient settings; however, mania might not present with classic florid symptoms among outpatients. Patients might have a chief concern of irritability, dysphoria, anxiety, or “insomnia,” which may lead clinicians to focus initially on non-bipolar conditions.²

During the interview, it is important to assess for any current DSM-5 symptoms of a manic episode, while being careful not to accept a patient’s denial of symptoms. Patients with mania often have poor insight and are unaware of changes from their base­line state when manic.³ Alternatively, manic patients may want you to believe that they are well and could minimize or deny all symptoms. Therefore, it is important to pay attention to mental status examination find­ings, such as hyperverbal speech, elated affect, psychomotor agitation, a tangential thought process, or flight of ideas.

Countertransference feelings of diagnos­tic confusion or frustration after long patient monologues or multiple interruptions by the patient should be incorporated into the diagnostic assessment. Family members or friends often can provide objective obser­vations of behavioral changes necessary to secure the diagnosis.

Treatment strategy
Decision points. When treating manic out­patients, assess the need for hospitalization at each visit. Advantages of the inpatient setting include:
   • the possibility of rapid medication adjustments
   • continuous observation to ensure the patient’s safety
   • keeping the patient temporarily removed from his community to prevent irrevers­ible social and economic harms.

However, a challenge with hospitaliza­tion is third-party payers’ influence on a patient’s length of stay, which may lead to rapid medication changes that may not be clinically ideal.

At each outpatient visit, explore with the patient and family emerging symptoms that could justify involuntary hospitaliza­tion. Document whether you recommended inpatient hospitalization, the patient’s response to the recommendation, that you are aware and have considered the risks associated with outpatient care, and that you have discussed these risks with the patient and family.

For patients well-known to the psychia­trist, a history of dangerous mania may lead him (her) to strongly recommend hos­pitalization, whereas a pre-existing thera­peutic alliance and no current or distant history of dangerous mania may lead the clinician to look for alternatives to inpatient care. Concomitant drug or alcohol use may increase the likelihood of mania becoming dangerous, making outpatient treatment ill-advised and riskier for everyone involved.

In exchange for agreeing to provide out­patient care for mania, it often is helpful to negotiate with the patient and family a threshold level of symptoms or behavior that will result in the patient agreeing to voluntary hospitalization (Table 1). Such an agreement can include stopping outpatient treatment if the patient does not improve significantly after 2 or 3 weeks or develops psychotic symptoms. The negotiation also can include partial hospitalization as an option, so long as the patient’s mania con­tinues to be non-dangerous.

Obtaining pretreatment blood work can help a clinician determine whether a medication is safe to prescribe and establish causality if laboratory abnormalities arise after treatment begins. Ideally, the psychia­trist should follow consensus guidelines developed by the International Society for Bipolar Disorders⁴ or the American Psychiatric Association (APA)⁵ and order appropriate laboratory tests before prescrib­ing anti-manic medications. Determine the pregnancy status of female patients of child-bearing age before prescribing a potentially teratogenic medication, especially because mania is associated with increased libido.⁶

Manic patients might be too disorga­nized to follow up with recommendations for laboratory testing, or could wait sev­eral days before completing blood work. Although not ideal, to avoid delaying treat­ment, a clinician might need to prescribe medication at the initial office visit, without pretreatment laboratory results. When the patient is more organized, complete the blood work. Keeping home pregnancy tests in the office can help rule out pregnancy before prescribing medication.

Medication. Meta-analyses have estab­lished the efficacy of mood stabilizers and antipsychotics for treating mania,^7,8 and sev­eral consensus guidelines have incorporated these findings into treatment algorithms.⁹

For a patient already taking medications recommended by the guidelines, assess treatment adherence during the initial inter­view by questioning the patient and family. When the logistics of phlebotomy permit, obtaining the blood level of psychotropics can show the presence of any detectable drug concentration, which demonstrates that the patient has taken the medication recently.

If there is no evidence of nonadherence, an initial step might be to increase the dos­age of the antipsychotic or mood stabilizer that the patient is already taking, ensuring that the dosage is optimized based on FDA indications and clinical trials data. The rec­ommended rate of dosage adjustments dif­fers among medications; however, optimal dosing should be reached quickly because a World Federation of Societies of Biological Psychiatry task force recommends that a mania treatment trial not exceed 2 weeks.¹⁰

Dosage increases can be made at weekly visits or sooner, based on treatment response and tolerability. If there is no ben­efit after optimizing the dosage, the next step would be to add a mood stabilizer to a second-generation antipsychotic (SGA), or vice versa to promote additive or syn­ergistic medication effects.¹¹ Switching one medication for the other should be avoided unless there are tolerability concerns.

For a patient who is not taking any medi­cations, select a treatment that balances rapid stabilization with long-term efficacy and tolerability. Table 2 lists FDA-approved treatments for mania. Lamotrigine provides prophylactic efficacy with few associated risks, but it has no anti-manic effects and would be a poor choice for most actively manic patients. Most studies indicate that antipsychotics work faster than lithium at the 1-week mark; however, this may be a function of the lithium titration schedule followed in the protocols, the severity of mania among enrolled patients, the inclu­sion of typically non-responsive manic patients (eg, mixed) in the analysis, and the antipsychotic’s sedative potential rela­tive to lithium. Although the anti-manic and prophylactic potential of lithium and valproate might make them an ideal first-line option, antipsychotics could stabilize a manic patient faster, especially if agitation is present.^12,13

Breaking mania quickly is important when treating patients in the outpatient set­ting. In these situations, a reasonable choice is to prescribe a SGA, because of their rapid onset of effect, low potential for switch to depression, and utility in treating classic, mixed, or psychotic mania.¹⁰ Oral loading of valproate (20 mg/kg) is another option. An inpatient study that used an oral-loading strategy demonstrated a similar time to response as olanzapine,¹⁴ in contrast to an inpatient¹⁵ and an outpatient study¹⁶ that employed a standard starting dosage for each patient and led to slower improve­ment compared with olanzapine.

SGAs should be dosed moderately and lower than if the patient were hospitalized, to avoid alienating the patient from treat­ment by causing intolerable side effects. In particular, patients and their families should be warned about immediate risks, such as orthostasis or extrapyramidal symptoms. Although treatment guidelines recommend combination therapy as a possible first-line option,⁹ in the outpatient setting, monother­apy with an optimally dosed, rapid-acting agent is preferred to promote medication adherence and avoid potentially danger­ous sedation. Manic patients experience increased distractibility and verbal memory and executive function impairments that can interfere with medication adherence.¹⁷ Therefore, patients are more likely to fol­low a simpler regimen. If SGA or valpro­ate monotherapy does not control mania, begin combination treatment with a mood stabilizer and SGA. If the patient experi­ences remission with SGA monotherapy, the risks and benefits of maintaining the SGA vs switching to a mood stabilizer can be discussed.

Provide medication “as needed” for agitation—additional SGA dosing or a benzodiazepine—and explain to fam­ily members when their use is warranted. Benzodiazepines can provide short-term benefits for manic patients: anxiety relief, sedation, and anti-manic efficacy as mono­therapy^18-20 and in combination with other medications.²¹ Studies showing mono­therapy efficacy employed high dosages of benzodiazepines (lorazepam mean dos­age, 14 mg/d; clonazepam mean dosage, 13 mg/d)¹⁹ and high dosages of antipsy­chotics as needed,^18,20 and often were associ­ated with excessive sedation and ataxia.^18,19 This makes benzodiazepine monotherapy a potentially dangerous approach for out­patient treatment of mania. IM lorazepam treated manic agitation less quickly than IM olanzapine, suggesting that SGAs are preferable in the outpatient setting because rapid control of agitation is crucial.²² If pre­scribed, a trusted family member should dispense benzodiazepines to the patient to minimize misuse because of impulsivity, distractibility, desperation to sleep, or plea­sure seeking.

SGAs have the benefit of sedation but occasionally additional sleep medica­tions are required. Benzodiazepine recep­tor agonists (BzRAs), such as zolpidem, eszopiclone, and zaleplon, should be used with caution. Although these medicines are effective in treating insomnia in indi­viduals with primary insomnia²³ and major depression,²⁴ they have not been studied in manic patients. The decreased need for sleep in mania is phenomenologically²⁵ and perhaps biologically different than insomnia in major depression.²⁶ Therefore, mania-associated sleep disturbance might not respond to BZRAs. BzRAs also might induce somnambulism and other parasom­nias,²⁷ especially when used in combination with psychotropics, such as valproate²⁸; it is unclear if the manic state itself increases this risk further. Sedating antihistamines with anticholinergic blockade, such as diphenhydramine and low dosages (<100 mg/d) of quetiapine, are best used only in combination with anti-manic medi­cations because of putative link between anticholinergic blockade and manic induc­tion.²⁹ Less studied but safer options include novel anticonvulsants (gabapen­tin, pregabalin), melatonin, and melatonin receptor agonists. Sedating antidepressants, such as mirtazapine and trazodone, should be avoided.²⁵

Important adjunctive treatment steps include discontinuing all pro-manic agents, including antidepressants, stimulants, and steroids, and discouraging use of caffeine, energy drinks, illicit drugs, and alcohol. The patient should return for office visits at least weekly, and possibly more frequently, depending on severity. Telephone check-in calls between scheduled visits may be nec­essary until the mania is broken.

Psychotherapy. Other than supportive therapy and psychoeducation, other forms of psychotherapy during mania are not indicated. Psychotherapy trials in bipolar disorder do not inform anti-manic efficacy because few have enrolled acutely manic patients and most report long-term benefits rather than short-term efficacy for the index manic episode.³⁰ Educate patients about the importance of maintaining regular social rhythms and taking medication as pre­scribed. Manic patients might not be aware that they are acting differently during manic episodes, therefore efforts to improve the patient’s insight are unlikely to succeed. More time should be spent emphasizing the importance of adherence to treatment and taking anti-manic medications as pre­scribed. This discussion can be enhanced by focusing on the medication’s potential to reduce the unpleasant symptoms of mania, including irritability, insomnia, anxiety, and racing thoughts. At the first visit, dis­cuss setting boundaries with the patient to reduce mania-driven, intrusive phone calls. A patient might develop insight after mania has resolved and he (she) can appre­ciate social or economic harm that occurred while manic. This discussion might foster adherence to maintenance treatment. Advise your patient to limit activities that may increase stimulation and perpetuate the mania, such as exercise, parties, concerts, or crowded shopping malls. Also, recommend that your patient stop working temporarily, to reduce stress and prevent any manic-driven interactions that could result in job loss.

If your patient has an established relationship with a psychotherapist, discuss with the therapist the plan to initiate mania treatment in the outpatient setting and work as a collaborative team, assuming that the patient has granted permission to share information. Encourage the therapist to increase the frequency of sessions with the patient to enable greater monitoring of changes in the patient’s manic symptoms. 

Family involvement
Family support is crucial when treating mania in the outpatient setting. Lacking insight and organization, manic patients require the “auxiliary” judgment of trusted family members to ensure treatment suc­cess. The family should identify a single person to act as the liaison between the family and the psychiatrist. The psychiatrist should instruct this individual to accom­pany the patient to each clinic visit and provide regular updates on the patient’s adherence to treatment, changes in symp­toms, and any new behaviors that would justify involuntary hospitalization. The treatment plan should be clearly communi­cated to this individual to ensure that it is implemented correctly. Ideally, this individ­ual would be someone who understands that bipolar disorder is a mental illness, who can tolerate the patient’s potential resentment of them for taking on this role, and who can influence the patient and the other family members to adhere to the treat­ment plan.

This family member also should watch the patient take medication to rule out nonadherence if the patient’s condition does not improve.

Provide extensive psychoeducation to the family (Table 3). Discuss these teaching points and their implications at length during the first visit and reinforce them at subsequent visits. Advise spouses that the acute manic period is not the time to make major decisions about their mar­riage or to engage in couple’s therapy. These options are better explored after the patient recovers from the manic episode.

These interventions can be challenging for the entire family system because they place family members in a paternalistic role and reduce the patient’s autonomy within the family. This is problematic when these role changes occur between spouses or between a patient-parent and his (her) children. Such changes typically need to be reversed over time and may require the help of a family or couple’s therapist. To support the psychological health of the patient’s family, refer them to the National Alliance on Mental Illness for family support groups or to individual psychotherapists.

Outpatient management can be rewarding
For “non-dangerous” manic patients who cannot be hospitalized involuntarily and refuse full or partial hospitalization, a psychiatrist must choose between beginning treatment in the clinic and referring the patient to another provider. The latter option is consistent with the APA’s ethical guidelines,³¹ but must be done appropriately to avoid legal liability.³² This decision may disappoint a family desperate to see their loved one recover quickly and may leave them feeling betrayed by the mental health system. On the other hand, choosing to treat mania in the outpatient setting can be rewarding when resolution of mania restores the family’s homeostasis.

To achieve this outcome, the outpatient psychiatrist must engage the patient’s fam­ily to ensure that the patient adheres to the treatment plan and monitor for potentially dangerous behavior. The psychiatrist also must use his knowledge of mood symp­toms, cognitive impairments, and the psy­chological experience of manic patients to create a safe and effective treatment strategy that the patient and family can implement.

Because of mania’s unpredictability and destructive potential, psychiatrists who agree to treat manic patients as outpatients should be familiar with their state’s statutes and case law that pertain to the refusal to accept a new patient, patient abandonment, involuntary hospitalization, confidentiality, and mandatory reporting. They also should seek clinical or legal consultation if they feel overwhelmed or uncertain about the safest and most legally sound approach.

Bottom Line
Treating mania in the outpatient setting is risky but can be accomplished in select patients with the help of the patient’s family and a strategy that integrates evidence-based pharmacotherapeutic and psychotherapeutic strategies. Because manic patients could display dangerous behavior, be familiar with your state’s laws regarding involuntary commitment, patient abandonment, and mandatory reporting.

Related Resources
• National Alliance on Mental Illness. www.NAMI.org.
• Depression and Bipolar Support Alliance. www.DBSAlliance.org.

Drug Brand Names
Aripiprazole • Abilify                                      Mirtazapine • Remeron
Asenapine • Saphris                                      Olanzapine • Zyprexa
Carbamazepine • Equetro, Tegretol                Pregabalin • Lyrica
Chlorpromazine • Thorazine                           Quetiapine • Seroquel
Clonazepam • Klonopin                                  Risperidone • Risperdal
Diphrenhydramine • Benadryl                         Trazodone • Desyrel
Eszopiclone • Lunesta                                    Valproate • Divalproex
Gabapentin • Neurontin                                  Zaleplon • Sonata
Lamotrigine • Lamictal                                    Ziprasidone •  Geodon
Lithium • Eskalith, Lithobid                              Zolpidem •  Ambien
Lorazepam • Ativan

Acknowledgement
The authors thank Peter Ash, MD, for carefully reviewing this manuscript and providing feedback.

Disclosures
Dr. Rakofsky receives research or grant support from Takeda. Dr. Dunlop receives research or grant support from Forest, GlaxoSmithKline, and Otsuka.

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I appreciate Dr. McInnis’s article and his recommendation to monitor the comprehensive metabolic profile, including the calcium level, before and during lithium treatment. There is an association among lithium treatment, hypercalcemia, and hyperparathyroid­ism.^1,2 This can occur by lithium reduc­ing parathyroid hormone suppression or stimulating parathyroid glands.³

Surprisingly, many guidelines do not include a recommendation to monitor the calcium level; however, the International Society for Bipolar Disorders and other experts do rec­ommend obtaining a calcium level before initiating lithium therapy and at least annually thereafter.^1,4 If hyper­calcemia is present, assessing lithium and the parathyroid hormone level is recommended.³

Clinicians can continue lithium and monitor calcium if treatment is beneficial, hypercalcemia is mild, and the patient is asymptomatic.² For a symptomatic patient or one who has significant hypercalcemia, clinicians should consider discon­tinuing lithium and monitoring for a normalizing calcium level.² For patients with significant hypercalce­mia who need lithium therapy, con­sultation with an endocrinologist is advised.³

Jonathan R. Scarff, MD
VA Outpatient Clinic
Spartanburg, South Carolina

Dr. McInnis responds
Generally, calcium is included in the com­prehensive biochemistry panel (Table 1). Typically, magnesium or phosphorus is overlooked, and therefore was specifi­cally included in the table of recommen­dations. There is a complex relationship between lithium and calcium; Dr. Scarff’s points highlight this. It is noteworthy that lithium normalizes the calcium ampli­tude during action potentials in neurons derived from induced pluripotent stem cells from persons with BD¹; this sug­gests that there might be a direct mode of action in BD involving lithium and calcium. This finding further emphasizes the importance of monitoring calcium, and the wise clinician will verify that it is included in the comprehensive bio­chemistry panel.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

I was astonished that Dr. Melvin G. McInnis’ article on using lithium to treat bipolar disorder (BD) (Current Psychiatry, June 2014, p. 38-44; [http://bit.ly/1sszAUr]) did not address all the potential hazards of the medication. He discussed side effects, but only how to manage them so that patients will adhere to treatment.

I have used lithium for patients with BD, and often it is efficacious, although hazardous in overdose. Lithium toxicity can cause cardiac arrhythmias, and must be monitored closely. In addition, the effects of hydration and exercise on the lithium level, especially during summer, often are ignored.

Two of my patients, an adolescent and an adult, were well-maintained on lithium, adhered to treatment, and had no concurrent medical problems, but developed significant toxicity for no reason that I could determine. The adult had a lithium level of 2.0 mEq/L in the emergency room; the adoles­cent had a lithium level of 1.8 mEq/L. Levels this high are considered poten­tially lethal, and because it happened without warning and without a cause that I could determine, I consider lithium to be one of the riskier mood stabilizers. I still prescribe it, but with great caution.

Dr. McInnis also did not mention the possibility of lithium-induced diabetes insipidus, a condition in which the kid­neys are no longer able to concentrate urine and that is marked by excessive urination, concomitant water intake, and low urine specific gravity. It is uncommon, but I have seen it 3 times in 30 years, in a practice that special­izes in psychotherapy and does not see a high percentage of patients with BD. I consider it a condition that must be kept in mind as we follow our patients in long-term treatment.

Mary Davis, MD
Lancaster, Pennsylvania

Dr. McInnis responds
Dr. Davis raises the issue of lithium toxic­ity and provides examples of 2 patients who developed levels of 2.0 mEq/L and 1.8 mEq/L. These levels clearly are well beyond the toxicity threshold of 1.3 mEq/L, and the patients wisely sought urgent care. These scenarios exemplify the need for regular monitoring of the lithium level—in particular, when there is any change in physical or mental health status. Development of significant tox­icity generally has some lead-time with emerging short-term side effects (out­lined in Table 2 of my article), which underscores the importance of discussing the nature of emerging side effects with your patient.

Dr. Davis is correct in noting that the practitioner must be aware of long-term side effects of lithium. I find it helpful to discuss these effects with the patient in the context of short-term (days or weeks), intermediate (weeks or months), and long-term (months or years) time frames (Table 2). Diabetes insipidus is listed as an intermediate side effect.

I am grateful to Dr. Davis for raising the issue of hydration and summer heat, a con­cern among parents and coaches when student athletes practice strenuously for extended hours.¹ Miller et al² found that the concentration of lithium was between 1.2- and 4.6-fold in forearm sweat compared with serum levels, with the implication that heat-induced sweating may lower lithium levels. Jefferson et al³ studied 4 athletes after a 20-km race and found that all had become dehydrated but had a decrease in the serum lithium level. This is contrary to the widely held belief that excessive sweating predis­poses to lithium toxicity. 

BD is among the more lethal psychi­atric disorders, and lithium is among the few medications shown to mitigate sui­cidal behavior.⁴ As with any medication, lithium is not without risk, and there is a clear need for informed medical manage­ment. Any notable change in health sta­tus or physical activity in a patient taking lithium is worthy of review, with recom­mendations based on knowledge of the patient and medical science.

HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

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HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

[email protected]

On Twitter @whitneymcknight

HOLLYWOOD, FLA. – Because there is no clinically significant difference in bipolar spectrum symptom relief offered by either lithium or quetiapine, which mood stabilizer clinicians choose to prescribe should largely depend on what side effects patients can tolerate.

That’s the conclusion of a panel of experts who presented data from the Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder) clinical trial at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

By randomly assigning the study’s 482 participating outpatient adults to either lithium or quetiapine, while allowing clinicians to prescribe adjunctive treatment as necessary; and by using a broader-than-usual set of inclusion criteria, the investigators hoped to provide clinicians with "real world" data on how the respective mood stabilizers perform.

"To my knowledge, this is the first randomized comparative effectiveness study of regular, expert care that looks at lithium versus quetiapine strategies of treatment, both with adjunctive personalized treatment when necessary," study coauthor Dr. Andrew A. Nierenberg told the audience in a well-attended session.

"We tortured the data to get a P value to pop out," said Dr. Nierenberg, who is the director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston. "The bottom line was that the treatment strategies, based on either lithium or quetiapine, were very similar. I think the clinical implication is that the choice of treatment really depends on someone’s tolerability. This may resurrect lithium as something [clinicians] should at least consider, because its use has gone down dramatically in the last 20 years or so."

Side effects such as metabolic or sleep disturbances were slightly less frequent in the lithium group, although the difference was not statistically significant; rates of suicidality and discontinuation of medication due to side effects were also similar across the two groups, according to Dr. David E. Kemp of the psychiatry department at Case Western Reserve University, Cleveland, and a study coauthor who also presented data during the session. Changes from baseline in mood stabilization were also virtually the same across the groups.

‘Rules of engagement’

The study enrolled adults aged 18-68 years who were at least mildly ill with either bipolar disorder I (68%) or II, with a Clinical Global Impression (CGI) score of at least 3, although the average CGI score was 4.5 (standard deviation of plus or minus 0.9). Of the 482 enrolled, 364 completed the study.

The so-called rules of engagement for clinicians from the 11 participating centers were that "they do everything they could to get their patients well," with the caveat that the lithium patient group not receive any antipsychotic, and the quetiapine patient group not receive lithium or any other antipsychotic.

"But they could get anything else that they needed," Dr. Nierenberg said.

At the time of enrollment, subjects were, in the estimation of their treating physician, experiencing symptoms that warranted a change in treatment, and that either lithium or quetiapine would be viable therapeutic options. Patients did not need to be lithium- or quetiapine-naive, but they could not have been treated with either drug in the previous 30 days. If they were already taking a second-generation antipsychotic, participants had to be willing to discontinue that medication and to be randomly assigned to either of the study drugs.

This strict adherence to one mood stabilizer, combined with adjunctive personalized treatments such as antidepressants or benzodiazepines, prescribed at the discretion of the treating clinician, ensured that the study tested the strategy of using either lithium or quetiapine as the base of treatment, Dr. Nierenberg said.

‘Similar’ results

Clinicians also were instructed to use the maximum tolerated dose of the respective mood stabilizer. For the 240 patients in the lithium group, the mean maximum tolerated dose was 1,007.5 mg, with the median dose being a "perfectly reasonable 900 mg," Dr. Nierenberg said. Blood lithium levels were taken at weeks 2, 16, and 24 and also were all found to be "reasonable," with most patients getting to at least 0.6 mEq/L by week 24.

For the 242 members of the quetiapine group, the maximum tolerated dose was 344.9 mg, with a median tolerated dose of 300 mg, which Dr. Nierenberg said was "what you would expect."

The overall result was that regardless of which mood stabilizer was prescribed along with adjunctive personalized treatment, the coprimary outcomes of the benefits and harms ratio from treatment effects over time (the CGI efficacy index), and the number of necessary clinical adjustments (changes in medication excluding titrations according to scale), were virtually parallel: For each primary outcome, the P value for the estimated change in baseline was less than .0001 for both lithium plus adjunctive treatment, and quetiapine plus adjunctive treatment.

Further, Dr. Nierenberg reported the "unexpected" result that at 6 months, about a quarter of each group was observed to be doing well without any adjunctive personalized treatments (23.8% of the lithium group; 27.3% of the quetiapine group; P = .14). "We thought that everybody would be on multiple things," Dr. Nierenberg said.

There was also no real difference in the time to discontinuation. "We were actually surprised that at 6 months, about three-quarters of the patients were still on the study drug, which was pretty good considering that this was a very ill population," Dr. Nierenberg said.

Using a CGI bipolar severity scale rating of up to 2, maintained for at least 8 weeks, the investigators found that overall, 20% were considered doing "really well"; it was also about 20% for the lithium plus adjunctive therapy group and the quetiapine and adjunctive therapy group (P = .14 for all three).

Because the Agency for Healthcare Research and Quality–funded study mandated that researchers end their investigation at precisely 36 months, Dr. Nierenberg said the study sites "randomized the 482 patients to 6 months of treatment within 36 months from start to finish," but he added that the investigators would have preferred to conduct a full 2-year study of participants.

"The good news was that most of the patients actually did improve substantially; the bad news is that while maybe a quarter did really well by the end of 6 months, we don’t know whether if we were to extend the study out further, we would see a difference between the two groups, whether they would continue to improve, or whether they would relapse," he said.

Adverse effects, predictors of response

Because study participants were followed for only 6 months, the long-term adverse effects of many years of exposure to either mood stabilizer, such as renal impairment with lithium or type II diabetes with quetiapine, were not considered, Dr. Kemp said. The adverse-effect profile for lithium generally includes a narrow therapeutic index; nausea, vomiting, and diarrhea; renal impairment; and hypothyroidism. Although Dr. Kemp said that the long-term adverse effects of quetiapine are understudied, known short-term side effects include the potential for sedation or somnolence, and weight gain.

Changes in baseline on the Frequency and Intensity of Side Effects Ratings for the quetiapine plus adjunctive personalized treatment arm were slightly more adverse than for the lithium and additional treatment arm. For the lithium plus adjunctive treatment group, the mean frequency of side effects was –1.41 (–1.78, –1.04 SD); the mean intensity of side effects was –1.48 (–1.80, –1.15 SD); and the mean level of impairment was –1.13 (–1.43, –0.82 SD). For the quetiapine and adjunctive treatment group, the mean frequency measure was –1.08 (–1.45, –0.72 SD); the intensity was –1.12 (–1.44, –0.79 SD); and the impairment was –0.77 (–1.07, –0.47 SD). For all scores in both groups, P was less than .001.

The changes from baseline on the Bipolar Index Severity Scale (BISS) overall for the quetiapine plus adjunctive treatment group was –28.56 (–10.91, –26.21 SD; P less than .0001). For the lithium plus adjunctive treatment group, it was –27.61 (–29.99, –25.24 SD; P less than .0001). The overall difference between the two groups was 0.94 (–2.10, 3.99 SD; P = .54).

Scores on the Longitudinal Interval Follow-up Evaluation Range of Impaired Functioning Tool also slightly favored lithium: –3.74 (–4.29, –3.19 SD) vs. –3.6 (–4.15, –3.07 SD) for quetiapine (P less than .0001 for all).

To the investigators’ surprise, among those with comorbid anxiety, the lithium plus adjunctive treatment group had fewer necessary clinical adjustments per month than did the quetiapine plus adjunctive treatment group, according to Dr. Nierenberg: –0.83 vs. 1.11 (P = .02).

"That seemed counterintuitive, and this difference was only with anxiety, not with any other comorbid psychiatric conditions," Dr. Nierenberg said. He hypothesized that it was possible benzodiazepines were used more frequently and easily with lithium than with quetiapine, but said future analyses would give a clearer answer. "We have a detailed database of every other medication used: when it was started, when it was stopped, and the reason why everything was done."

Not having current anxiety disorder was predictive of a better outcome (odds ratio, 1.81; P = .02), as was employment (OR, 1.67; P = .04). Those with bipolar II disorder responded better to treatment than those with bipolar disorder I, having an OR of response to treatment of nearly 1.8 P = .03). "That was a surprise to us, too," Dr. Nierenberg said.

Just over a quarter (27%) of the study population had metabolic syndrome, according to Dr. Kemp, who said this was not found to influence treatment outcomes.

Nearly half of the overall population was obese (48%), and slightly less than half (44%) had adipose. Prospective analysis indicated that patients with either obesity or adiposity tended to show less improvement in their CGI scores in a statistically significant way, regardless of which mood stabilizer they were on.

"Part of that might be due to overlapping pathophysiology between bipolar disorder and obesity," Dr. Kemp said. "Much of that is centered around inflammation in the central nervous system, as well as alterations in adipokines receptor levels and mitochondrial dysfunction."

"A key issue is to take care of obesity," said panel discussant Dr. Mauricio Tohen, chairman of psychiatry at the University of New Mexico in Albuquerque. "Regardless of the treatment, when there is obesity, the outcome will not be as good."

Efficacy vs. ‘generalizability’

Adjunctive personalized treatment was measured to help minimize the lack of assay sensitivity and internal validity typically inherent in comparative effectiveness trials, while also achieving more broadly applicable results.

"The right study depends on the right question," Dr. Tohen said. "If the question is whether a particular treatment has efficacy and is safe, then of course, we need an efficacy study. The problem with efficacy studies is that they limit the generalizability."

Instead, Dr. Tohen, who disclosed he spent more than a decade evaluating efficacy studies for both Eli Lily and AstraZeneca (makers of quetiapine), praised the metric of the adjunctive personalized treatments, and said a study should answer the question, "Of all the patients in my clinic, who will do better on which treatment? With efficacy studies you cannot answer that question because of the exclusion criteria that need to be taken into account."

In addition, Dr. Tohen said the metric likely would increase in importance under the Affordable Care Act, where efficacy is not the only consideration. "For example, if a patient relapses earlier, it might not be reimbursed, so asking what other outcomes we need to measure in [these kinds of] comparative effectiveness studies is very important."

In the CHOICE study, which had no placebo group, participating physicians were asked to track each patient’s dosage changes, missed doses, new medications added, discontinued medications, and the specific reasons for any of these changes. Changes that were made because of lack of effectiveness or intolerance were measured; however, planned dosage titrations according to normal scales were not considered necessary clinical adjustments but simply the regular course of treatment.

This heterogeneity of adjunctive treatment was seen by the investigators as a way to reflect "real world" practice, although they also noted it could be seen as a limitation to the study.

Another way the study was designed to reflect real-world practice was the inclusion of a broader-than-usual group of participants, and asking them for their feedback at the end of the study period.

"Before we put together these data, we held a stakeholder summit," Dr. Nierenberg said. "We invited patients and their advocates to help us interpret the study. They felt strongly that this was a reasonably positive study, because they thought that people really did get better. You could report these data toward the negative or the positive, but we reported toward the positive because that is what the stakeholders asked us to do." Dr. Tohen said that this kind of feedback in a comparative effectiveness study was another way these kinds of studies could help guide practice in the era of the Affordable Care Act.

As for who was actually admitted to the study, "exclusions were minimal," said Dr. Edward S. Friedman of the psychiatry department at the University of Pittsburgh. Those with a history of drug or alcohol dependence in the previous 30 days, a demonstrated intolerance to either study drug, or severe cardiovascular or renal disease were excluded, as were those with unstable thyroid disease, and pregnant or breastfeeding women.

Overall, the group was multiethnic, although nearly three-quarters were white and 20% were black. Roughly a third of the entire study population was employed, a third unemployed, and the rest were students, retirees, or those on disability.

The overall BISS score at enrollment averaged 56.1 (SD plus or minus 18.8). The average BISS depression score was 37.6 (SD plus or minus 14.0), and the average BISS mania score was 18.5 (SD plus or minus 12.1).

There were many comorbid psychiatric conditions, ranging from panic disorder to agoraphobia, although substance use was highest (61.4%). Current anxiety disorder also was prevalent at 58%.

"The CHOICE sample was similar in age and gender to previous efficacy studies," Dr. Friedman said. "It was more representative of the U.S. population than efficacy studies such as STEP-BD or LITMUS."

The 283 women (59% of the study) were more likely to report having spent a greater percentage of time depressed in the previous year, although the percentage of time spent in manic or hypomanic states was equal across both genders.

"This study was composed of sick individuals who had been sick for a considerable period of time," Dr. Friedman said.

For example, in the CHOICE study, 47% had been hospitalized for their bipolar disorder previously, vs. 43% in the LITMUS study. CHOICE participants had an attempted suicide rate of 36%, which fell between the 41% in the LITMUS trial and the 33.3% in an efficacy study conducted by Dr. Joseph R. Calabrese and his colleagues (J. Clin. Psychiatry 1999;60:79-88).

The average age for the first depressive episode for CHOICE participants was 16.4 years; the first manic episode tended to be at 20 years; and the first mood episode tended to be around 15.5 years. These data were similar to those in the LITMUS study, but differed from data in several efficacy studies such as the one by Dr. Calabrese, where the average age was 31.3 years.

"You might anticipate that in these specialty clinics we would have very few medication-naive patients, and yet we did," Dr. Friedman said during a postpanel audience participation session. "Looking for patients with a low threshold, we brought in patients who were very sick. They were also older, with lots of previous episodes. Maybe we missed younger patients who didn’t have as many previous episodes."

"These are the patients you would see in your practice," Dr. Nierenberg said before asking the audience what they think should be studied next in a comparative effectiveness trial. "We could look at the use of different antipsychotics, the combinations we use, with or without lamotrigine," he said.

"Most of the decisions that are made in medicine are made without evidence. Most of the things that are done are done without evidence. You have combinations that were never studied before or never even used before, and it’s across all medicine." Because medicine needs to be learning more, he said the audience needed to participate. "What are the questions that need to be asked?"

[email protected]

On Twitter @whitneymcknight

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.

As psychiatrists, we are particularly attuned to the value of face-to-face contact with patients. After all, so much is communicated nonverbally.

Fortunately, telepsychiatry has the capacity to give us the information we need to provide effective interventions for patients with mental illness. Even patients with serious mental illness can benefit from these interventions.

Take, for example, a literature review of 390 studies using terms that included "schizophrenia" and/or "telepsychiatry," "telemedicine," or "telepsychology" (Clin. Schizophr. Relat. Psychoses 2014 [doi:10.3371/CSRP.KAFE.021513]). The review, conducted by Dr. John Kasckow of the Veterans Affairs Pittsburgh Health Care System, found that modalities involving the telephone, the Internet, and videoconferencing "appear to be feasible in patients with schizophrenia." Furthermore, they found that those modalities appear to improve patient outcomes, although they acknowledge that more research is needed.

A subset of patients that can benefit from telepsychiatry is those in correctional facilities. Another literature review that looked at the implementation of telepsychiatry in correctional facilities in seven states, including my own state of California, and found that the modality "may improve living conditions and safety inside correctional facilities" (Perm. J. 2013 Summer;17:80-6). This review, conducted by Stacie Anne Deslich of the Marshall University in South Charleston, W.Va., and her colleagues, also found that using telepsychiatry improved access and saved those facilities $12,000 to more than $1 million.

These researchers also called for more study, particularly a case-control examination of the cost of providing psychiatric care through telemedicine vs. face-to-face psychiatric treatment. Using telepsychiatry for this population of patients is particularly important in light of depth and breadth of untreated mental illness in correctional facilities, such as depression, anxiety, bipolar disorders, and schizophrenia. "In addition, costs for providers traveling to distant facilities have been a deterrent to providing adequate care to inmates," Ms. Deslich wrote.

Yet another population of patients that can benefit from telepsychiatry is those with mental illness who come to emergency departments. A program implemented in Elizabeth City, N.C., connected patients in the ED with psychiatric providers who were at remote locations using telemedicine carts that were equipped with wireless technology (ED Manag. 2013;25:121-4). The program’s administrators reported that almost 30% of the patients who had involuntary commitment orders were stabilized to the extent that those orders could be rescinded and they were discharged to outpatient care. Furthermore, the researchers reported, the average length of stay for ED patients who were discharged to inpatient treatment facilities dropped by more than half, from 48 hours to 22.5 hours.

Not so surprisingly, telepsychiatry also is establishing a solid track record among young patients. A study of the perspectives of psychiatrists who provide consultation services to schools found "students were more likely to disclose clinical information via video, compared with face-to-face contact" (Telemed. J.E. Health 2013; 19;794-9). However, the psychiatrists did express concerns about technological difficulties, logistics, and information sharing.

Telepsychiatry also is gaining a foothold in other areas, such as in geriatric and consultation psychiatry. In other settings, telepsychiatry is being introduced, and evidence is still accumulating.

The primary driver of telepsychiatry is the psychiatrist shortage. In 2009, a total of 77% of U.S. counties reported a shortage. Additionally, recent increases in coverage for mental health care create a demand for more psychiatrist time. These factors, coupled with an aging psychiatry workforce, led to a growing imbalance between supply and demand that telepsychiatry can help to alleviate. Telepsychiatry can increase the efficiency of psychiatric care by allowing one psychiatrist to serve patients in multiple settings without burdensome travel. Although telepsychiatry was first used more than 30 years ago, only recently have demographic, economic, and cultural trends led to its rapid expansion.

Opportunities for telepsychiatry implementation exist across the spectrum of psychiatric care. So far, research has shown little or no difference between the outcomes yielded by traditional care and telepsychiatry. Work remains to be done, but clearly telepsychiatry is here to stay.

Dr. Kornbluh is assistant medical director for program improvement and telepsychiatry at the California Department of State Hospitals.