Questions and Answers About the STEP-BD Depression Psychosocial Treatment Trial

Posted on July 12, 2016 by JmaC

1. Q. What was the goal of the STEP-BD depression psychosocial treatment trial and how did it fit into STEP-BD?

A. The study reported in the April 2007 issue of the Archives of General Psychiatry describes the results of a clinical trial examining the effectiveness of four psychosocial interventions for people with bipolar disorder who are experiencing a depressive episode. The clinical trial was part of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) research program, the largest, federally funded treatment trial ever conducted for bipolar disorder. STEP-BD enabled researchers to explore a range of treatment options related to bipolar disorder, including mood-stabilizing medications, antidepressants, atypical antipsychotic medications, and psychosocial interventions (talk therapies).

Once enrolled in the STEP-BD program, participants aged 15 or older received individualized care from their STEP-BD treatment provider that included the best available treatment options. This approach was called the Best Practice Pathway. Participants in the Best Practice Pathway who were age 18 or older and whose depression did not improve or who experienced a new depressive episode, could enter the randomized clinical trial that examined the effectiveness of different combinations of medication and psychosocial therapy for the depressive phase of bipolar disorder.

In this one-year randomized clinical trial, the goal of the psychosocial study was to determine if receiving intensive (and long-term) treatment with any one of the three psychosocial therapies offered in STEP-BD was more effective in relieving bipolar depression than receiving treatment with a brief, short-term talk therapy intervention.

2. Q. Why is the psychosocial treatment trial important?

A. Although various treatments currently are available for treating bipolar disorder, including medications and talk therapies, it is not known if psychosocial interventions, when received alongside medication, can help relieve bipolar-related depression and keep patients well in typical, real-world clinical settings. In addition, most previous clinical trials were conducted in single academic centers and included carefully selected groups of research participants who may be different from the people seeking care in everyday practice settings.

In this regard, the psychosocial treatment study in STEP-BD is unique because it included “real world” patients experiencing the early phases of a depressive episode, who were already receiving care for their bipolar disorder as part of STEP-BD. The therapists who delivered care in the psychosocial treatment study received STEP-BD training in the different psychosocial therapies by experts in the field. The training and ongoing supervision was of low intensity, consistent with what is typically available in clinical practice.

3. Q. How were participants selected for inclusion in the psychosocial treatment trial?

A. While enrolled in the STEP-BD Best Practice Pathway, participants were evaluated for depression at every follow-up visit. These clinic visits recorded and tracked participants’ treatment and assessed their symptoms and clinical status for the duration of participation in the study. If the study participants experienced a depressive episode, they could choose to leave the Best Practice Pathway and enter the randomized portion of STEP-BD; 366 participants did so.

The randomized acute depression study lasted 26 weeks and addressed the question of whether adding an antidepressant medication (buproprion or paroxetine) to an existing mood stabilizing medication is more effective for treating acute bipolar-related depression than adding a placebo pill. All participants in this portion were required to be on a mood stabilizing medication, such as lithium, valproate, carbamazepine or other mood stabilizer approved by the U.S. Food and Drug Administration.

These 366 participants also had the option of participating in the randomized psychosocial treatment study in which they would receive psychosocial treatment in addition to their medication treatment. Of the 366 participants who entered the randomized depression trial, 236 chose to enter the psychosocial portion. In addition, 57 STEP-BD participants who were enrolled in the Best Practice Pathway, but who were not part of the medication portion of the randomized depression trial, chose to enter the psychosocial study as well. Altogether, 293 participants took part in the psychosocial treatment study. Many of those who chose not to participate in the psychosocial portion of the study were already receiving psychotherapy on their own.

4. Q. What psychosocial interventions did participants receive?

A. Researchers randomly assigned participants to receive either a short-term collaborative care intervention or one of three longer-term intensive therapies that have been shown to help stabilize bipolar symptoms—cognitive-behavioral therapy (CBT), interpersonal and social rhythm therapy (IPSRT), or family-focused treatment (FFT). Collaborative care was considered the “control” intervention, meaning that the outcomes of this therapy were used as a baseline by which to compare the other three intensive therapies. All of these therapies focused on education about the illness, relapse prevention planning, and bipolar illness management interventions, and all but collaborative care consisted of up to 30, 50-minute sessions that took place over nine months.

Collaborative care, which consisted of three, 50-minute sessions over six weeks, provided participants with a workbook, an educational videotape and other information that aimed to help them understand and manage the illness, maintain adherence to medications, and develop a treatment contract geared toward preventing bipolar episodes.

In the CBT intervention group, participants received education about the illness. They learned to challenge negative thoughts or beliefs about bipolar disorder or its associated stressful life circumstances, developed schedules to stay active, and developed strategies to detect and cope with mood swings.

The focus of IPSRT was on attaining and maintaining regular social rhythms (daily routines and sleep/wake cycles) and the relationship of daily activities to mood and levels of social stimulation. IPSRT therapists encouraged participants to keep track of their daily routines (e.g., when they went to sleep, when they woke up, etc.) while working toward establishing stable social rhythms. Patients also worked to resolve key interpersonal problems related to grief, role transitions, interpersonal disputes, or interpersonal skill deficits.

In FFT, participants and their relatives (e.g., spouses and parents) were taught an understanding of bipolar illness, its course, treatment and management. Family members were taught how to recognize early warning signs that might predict an oncoming depressive or manic episode in the person with bipolar illness, and strategies to intervene when these warning signs occurred. Treatment included enhancing communication between the participants and their family members to improve the quality of family interactions, and problem-solving to manage conflicts related to the illness.

5. Q. What do the results from the STEP-BD psychosocial treatment trial tell us about the treatment of bipolar disorder?

A. The outcome measures that were used to evaluate success of the treatments were “time to recovery” (e.g., how quickly did people get well) and the total amount of time during the study year that participants remained “well” (measured by the probability of being well during any given month). To be considered “well” in the study, participants had to have no more than two symptoms of mild or moderate mania or depression.

Of the 293 STEP-BD participants in the psychosocial treatment study, 59 percent recovered from their depression; 41 percent either did not recover or left the study early.

Over the course of the study year, participants in the intensive psychotherapies (FFT, IPSRT, CBT) had a more successful recovery rate (64 percent) compared to the individuals in the collaborative care group (52 percent). Also, participants in the intensive psychotherapies who recovered did so faster (on average, after about 113 days) than those in the collaborative care group (after about 146 days). Furthermore, the participants in the intensive psychotherapies were one and a half times more likely to remain well during any given month of the study year than those in the collaborative care group.

The study also showed that in each of the four psychosocial treatment groups, participants who were also enrolled in the randomized medication portion of the trial got well faster than those who were not, even though all patients were receiving some type of medication. In addition, recovery time was faster in all four groups for those participants who had family supports available.

Differences among the three intensive psychosocial interventions were not statistically significant, but they are worth noting. Over the yearlong study, 77 percent of participants in the FFT recovered, compared to 65 percent of participants in IPSRT and 60 percent in CBT.

6. Q. What do the results mean for people with bipolar depression and the doctors who provide care for them?

A. This one-year study showed that, in conjunction with adequate mood stabilizing medications, intensive psychotherapy is more effective in helping people recover from a depressive episode, and stay well over a one-year period, than a brief collaborative care treatment. All three types of intensive psychosocial treatments had comparable benefits.

Overall, psychotherapy appears to be a vital part of the effort to stabilize episodes of depression in bipolar illness. These findings should help clinicians plan treatments for individuals recovering from an episode of bipolar depression.

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Management of Bipolar Disorder

Posted on July 12, 2016 by JmaC

This article exemplifies the AAFP 2000 Annual Clinical Focus on mental health.

Bipolar disorder most commonly is diagnosed in persons between 18 and 24 years of age. The clinical presentations of this disorder are broad and include mania, hypomania and psychosis. Frequently associated comorbid conditions include substance abuse and anxiety disorders. Patients with acute mania must be evaluated urgently. Effective mood stabilizers include lithium, valproic acid and carbamazepine. A comprehensive management program, including collaboration between the patient’s family physician and psychiatrist, should be implemented to optimize medical care.

Bipolar disorder is characterized by variations in mood, from elation and/or irritability to depression. This disorder can cause major disruptions in family, social and occupational life. Bipolar I disorder is defined as episodes of full mania alternating with episodes of major depression. Patients with mania often exhibit disregard for danger and engage in high-risk behaviors such as promiscuous sexual activity, increased spending, violence, substance abuse and driving while intoxicated.

Bipolar II disorder is characterized by recurrent episodes of major depression and hypomania. Hypomania is manifested by an elevated and expansive mood. The behaviors characteristic of hypomania are similar to those of mania but without gross lapses of impulse and judgment. Hypomania does not cause impairment of function and may actually enhance function in the short term.

Bipolar I disorder is typically diagnosed when patients are in their early 20s. Manic symptoms can rapidly escalate over a period of days and frequently follow psychosocial stressors. Some patients initially seek treatment for depression. Other patients may appear irritable, disorganized or psychotic. Differentiating true mania from mania resulting from secondary causes can be challenging (Table 1).1,2

TABLE 1
Causes of Secondary Mania

The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item, see the original print version of this publication.

Bipolar II disorder typically is brought to medical attention when the patient is depressed. A careful history will usually illuminate the diagnosis. Some depressed patients exhibit hypomania when given antidepressants.3 This variation is sometimes referred to as bipolar III disorder. The criteria for major depressive episode and manic episode, as described in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV), are summarized in Table 2.4

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TABLE 2

Criteria for Major Depressive Episode and Manic Episode

Major depressive episode

Five or more of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.

2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)

3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.

4. Insomnia or hypersomnia nearly every day

5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)

6. Fatigue or loss of energy nearly every day

7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)

8. Diminished ability to think or concentrate, or indeciseveness, nearly every day (either by subjective account or as observed by others)

9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

Manic episode

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)

B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:

1. Inflated self-esteem or grandiosity

2. Decreased need for sleep (e.g., feels rested after only 3 hours of sleep)

3. More talkative than usual or pressure to keep talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli)

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation

7. Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

Reprinted with permission from American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, D.C.: American Psychiatric Association, 1994:327,332. Copyright 1994.

Epidemiology

The lifetime prevalence of bipolar disorder is 1 percent, which compares to a lifetime prevalence of 6 percent for unipolar depression.5 The prevalence of bipolar disorder does not differ in males and females.6 The disorder affects persons of all ages. The epidemiologic catchment area study revealed the highest prevalence in the 18-to-24-year age group.7 In some patients, however, bipolar disorder does not become manifest until patients are older. One study reported new-onset bipolar disorder in patients older than 60 years.8

The incidence of bipolar disorder is increased in first-degree relatives of persons with the disorder, as is the incidence of other mood disorders.9 One study revealed a 13 percent risk of bipolar disorder among offspring of persons with the disorder.10 The risk of unipolar depression was 15 percent, and the risk of schizoaffective disorder was 1 percent.10 The mode of inheritance remains unclear, and no algorithm exists to predict the risk of bipolar disorder.11 Because of the familial association, genetic counseling should be offered to patients and their families as part of comprehensive educational and supportive approaches.

Clinical Presentations

Patients with symptoms of a mood disorder often do not meet the full criteria for bipolar disorder. Many patients with bipolar disorder are diagnosed as having depression. If agitation is prominent, hypomanic symptoms may be misunderstood as representing an anxiety state. Accurate diagnosis of bipolar disorder requires obtaining a comprehensive psychiatric history.

CHILDREN

Hyperactivity is the most common behavioral manifestation of mania in children.12 Manic children may exhibit irritability or temper tantrums.13 The differential psychiatric diagnoses include attention-deficit/hyperactivity disorder, conduct disorder and schizophrenia.14

ADOLESCENTS

Manic symptoms in adolescents are similar to those in adults. Florid psychosis can be a presentation of bipolar disorder in adolescents. Included in the differential diagnosis of mania in adolescents are substance abuse and schizophrenia, which may be challenging to distinguish from bipolar disorder. The normal risk-taking behavior in some adolescents must be distinguished from the reckless nature of manic symptoms.

DURING PREGNANCY

The course of bipolar disorder during pregnancy is variable. Management requires sustained collaboration between the patient’s family physician and her psychiatrist. A patient with bipolar disorder should be encouraged to plan pregnancy so that the dosage of her psychiatric medication can be slowly tapered. The risk of relapse is increased with abrupt discontinuation.15

Relapse during pregnancy must be treated aggressively with mood stabilizers. The patient should be admitted to the hospital. If lithium therapy is required, the patient should be counseled regarding the increased risk of cardiovascular malformations in fetuses exposed to lithium. Breast-feeding during lithium therapy is discouraged because lithium is excreted in breast milk.16

During the postpartum period, worsening of affective symptoms may occur, including rapid cycling, which is sometimes refractory to drug therapy.17 Women who have worsening of symptoms postpartum may have an increased risk of recurrence.

Comorbid Conditions

Studies of primary care patients with major depressive disorders have demonstrated a tendency toward certain comorbid conditions. In one study,18 more than 42 percent of patients meeting the criteria for a major depressive disorder (including bipolar disorder) had lifetime histories of substance abuse. In another study,19 the frequency of substance abuse was 39 percent in adolescents who had symptoms of bipolar disorder. Another study20 revealed a high prevalence of moderate to severe anxiety disorders in association with bipolar disorder, as well as a high prevalence of psychosocial morbidity.

While many patients with bipolar disorder show gradual improvement in the first several years after diagnosis, a substantial subgroup experiences poor adjustment in one or more areas of functioning.21 In a study of psychiatric patients who were evaluated 30 to 40 years after the index hospitalization for mania, 24 percent of the sample was considered to be occupationally incapacitated.22

Treatment

URGENT AND EMERGENT

If a patient with symptoms of acute mania presents to the office, a psychiatrist should be consulted, and the patient should be evaluated urgently. The family physician must know the legal requirements in the community for transferring a patient with acute mania from the office to the hospital. Often, police must be involved. It is inappropriate to expect family members to transport the patient from the office to the hospital, because family members may not appreciate the irrationality of manic thinking and the unpredictability of manic behavior.

The family physician and psychiatrist have the responsibility to inform, educate and support family members in terms of the possible need for the family to petition the court for the patient’s admission to a psychiatric unit. It is important to recognize, and to try to allay, the guilt and regret family members often feel in these circumstances.

Patients with newly diagnosed bipolar disorder require a medical evaluation along with a psychiatric evaluation. Table 323 lists the recommended laboratory tests for patients evaluated on an inpatient or an outpatient basis. Computed tomography or magnetic resonance imaging and electroencephalography are second-line options in the evaluation of treatment-resistant patients. These studies are not routinely required without a specific clinical reason. Similarly, the need for electrocardiography in patients younger than 40 years rests with the clinician’s judgment.

If necessary, and if the patient has been in good general health, mood stabilizers, as well as other drugs used in the treatment of bipolar disorder, can be started before the test results are available. If the need to begin treatment is urgent, medication can be given even before laboratory specimens are obtained.

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TABLE 3

Laboratory Evaluation of Patients Presenting with Bipolar Disorder

Inpatient

Complete physical examination

Serum levels of lithium, valproic acid (Depakene), carbamazepine (Tegretol) and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Electrocardiography in patients older than 40 years

Urine toxicology for substance abuse

Pregnancy test (if relevant)

Outpatient

Complete physical examination

Serum levels of lithium, valproic acid, carbamazepine and selected tricyclic antidepressants (if relevant)

Thyroid function tests

Complete blood count and general chemistry screening

Urinalysis if lithium therapy is initiated

Pregnancy test (if relevant)

Second-line tests: urine toxicology for substance abuse and electrocardiography in patients older than 40 years

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

COLLABORATIVE ONGOING CARE

Given the chronic nature of bipolar disorder and its impact on the entire family, it is important for the patient’s family physician and psychiatrist to develop an effective and collaborative relationship. Informed collaboration depends on an agreed method of communication in a frequency that meets the needs of each physician.24 A Canadian model brings psychiatrists and counselors into family practice offices for shared care.25

At the onset of bipolar disorder, the family physician might seek psychiatric consultation for differential diagnosis and treatment recommendations. Often, the psychiatrist assumes responsibility for initial management until the patient’s clinical pattern is determined. During follow-up, both physicians should monitor the patient for signs of psychosis, mood swings, violence and self-harmful behaviors. As the patient’s illness stabilizes and management becomes routine, the physicians can renegotiate, with each other and with the patient, responsibility for ongoing care.

When the patient’s condition has become stable, the psychiatrist may not need to see the patient as often, although the frequency of follow-up psychiatric visits depends on the course of the illness, the patient’s adherence to treatment, medication requirements, the need for ongoing psychotherapy and patterns of care in a particular geographic area. It is important for the patient’s family physician and psychiatrist to coordinate medication prescriptions and follow-up laboratory tests such as determination of serum drug levels. In addition, counseling and family therapy are important components of management and may be rendered by the family physician, psychiatrist and/or psychologist.

MEDICATION

Recommendations for drug therapy in patients with bipolar disorder are summarized in Table 4.23

Medication is the key to stabilizing bipolar disorder. Initial treatment of mania consists of lithium or valproic acid (Depakene). If the patient is psychotic, a neuroleptic medication is also given. Long-acting benzodiazepines may be used for treating agitation. However, in patients with a substance-abuse history, benzodiazepines should be used with caution because of the addictive potential of these agents.

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TABLE 4

Recommendations for Drug Therapy in Patients with Bipolar Disorder

Considerations for prescribing mood stabilizers

Lithium: For classic, euphoric mania; for mixed manic episode; when a mood stabilizer alone is used to treat depression; when the mood stabilizer must be given in a single evening dose; in patients with liver disease, excessive alcohol use or cocaine use; and in patients older than 65 years

Valproic acid (Depakene): For classic, euphoric mania; for mixed manic episode; for mania with rapid cycling; for long-term maintenance therapy in patients who do not tolerate lithium because of the “flat” feeling lithium causes; in patients with structural central nervous system disease, renal disease and cocaine use; and in patients older than 65 years

Carbamazepine (Tegretol): For mixed manic episode; for mania with rapid cycling; in patients with structural central nervous system disease or renal disease

An antipsychotic agent

High- or medium-potency antipsychotic agents are used as adjunctive treatment for mania with psychosis or psychotic depression.

A benzodiazepine

Sleep and sedation in mania or hypomania; insomnia in depression

The combination of a mood stabilizer, an antidepressant and an antipsychotic

Psychotic depression

The combination of a mood stabilizer and an antidepressant

Nonpsychotic depression

A mood stabilizer alone

Milder depression in bipolar I disorder

Bupropion (Wellbutrin)

Bipolar depression

Patient with high risk of manic switch or rapid cycling

A selective serotonin reuptake inhibitor

Bipolar depression

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

When the patient with bipolar disorder becomes depressed, a selective serotonin reuptake inhibitor (SSRI) or bupropion (Wellbutrin) is recommended.26 The use of tricyclic antidepressants should be avoided because of the possibility of inducing rapid cycling of symptoms.

Drug interactions are an important consideration when prescribing lithium (Table 5),27  valproic acid (Table 6)27  and a selective serotonin reuptake inhibitor (Table 7).27  Information about starting and maintenance dosages for lithium, valproic acid and carbamazepine (Tegretol) is summarized in Table 8.23

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TABLE 5

Drug Interactions with Lithium

DRUG EFFECT ON LITHIUM LEVEL MANAGEMENT

Thiazide diuretics

Increased lithium level

Avoid this combination or reduce dosage; monitor lithium level

Loop diuretics

Increased or decreased lithium level

Avoid this combination or alter either dosage as needed; monitor lithium level

Potassium-sparing diuretics

Decreased lithium level

Monitor lithium level and adjust dosage

Nonsteroidal anti-inflammatory drugs

Increased lithium level

Use lower dosage of lithium; consider aspirin or sulindac

Angiotensin-converting enzyme inhibitors

Increased lithium level; toxicity reported

Use lower dosage of lithium; monitor lithium level closely

Calcium channel blockers

Increased or decreased lithium level

Monitor lithium level closely

Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

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TABLE 6

Drug Interactions with Valproic Acid (Depakene)

DRUG INTERACTION MANAGEMENT

Phenobarbital

Increased phenobarbital level

Reduce dosage

Magnesium- and aluminum- containing antacids

Increased valproic acid level

Monitor valproic acid level; reduce dosage

Carbamazepine (Tegretol)

Decreased valproic acid level; possible increased carbamazepine level

Monitor valproic acid level; adjust dosage

Aspirin and naproxen (Naprosyn)

Increased valproic acid level

Avoid salicylates or other drugs bound to plasma albumin

Clonazepam (Klonopin)

Increased sedation

Use with caution

Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

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TABLE 7

Drug Interactions with Selective Serotonin Reuptake Inhibitors

DRUG INTERACTION MANAGEMENT

Alprazolam (Xanax)

Increased alprazolam levels

Monitor; reduce dosage

TCAs

Increased TCA level

Monitor TCA level

Warfarin (Coumadin)

Increased warfarin level with fluvoxamine (Luvox)

Monitor prothrombin time (INR); reduce fluvoxamine dosage

MAOIs

Serotonin syndrome

Combination of MAOI and SSRI is contraindicated

Clozapine (Clozaril)

Increased clozapine level with fluvoxamine

Monitor clozapine level

l-Tryptophan

Serotonin syndrome

Combination of L-tryptophan and SSRI is contraindicated

Phenytoin (Dilantin)

Possible phenytoin toxicity

Monitor phenytoin level

Carbamazepine (Tegretol)

Increased carbamazepine level with fluvoxamine and fluoxetine (Prozac)

Monitor carbamazpine level

Tolbutamide

Possible increased hypoglycemia

Monitor blood glucose level

Theophylline

Increased theophylline level with fluvoxamine

Monitor theophylline level

Cimetidine (Tagamet)

Increased SSRI levels

Monitor clinically

Type Ic antiarrhythmics

Increased antiarrhythmic level with fluoxetine, paroxetine (Paxil) and sertraline (Zoloft)

Monitor antiarrhythmic drug levels

Beta-adrenergic blockers

Increased beta-blocker level and enhanced effects

Use lower beta-blocker dosage

Codeine

Inhibited metabolism from fluoxetine, paroxetine and sertraline

Use different SSRI

St. John’s wort

Serotonin syndrome

Stop St. John’s wort before beginning SSRI therapy

SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; INR = International Normalized Ratio; MAOI = monoamine oxidase inhibitor.

Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions. Primary Psychiatry 1998;5:36–75.

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TABLE 8

Starting and Maintenance Dosages of Lithium, Valproic Acid and Carbamazepine and Common Side Effects

INITIAL DOSING STRATEGY* MAINTENANCE DOSAGE† COMMON SIDE EFFECTS‡ COST (GENERIC)§

Lithium

900 mg per day; increase by 300 to 600 mg every 2 to 3 days as tolerated

900 to 1,800 mg per day; 1,200 mg may be given as a single bedtime dose if tolerated; otherwise, prescribe twice-daily dosingTherapeutic blood level: 0.8 to 1.5 mEq per L

Thirst, polyuria, cognitive complaints, tremor,∥ weight gain, sedation, diarrhea, nausea (watch for dehydration, which can lead to toxicity), hypothyroidism (monitor TSH; give levothyroxine [Synthroid] if TSH is elevated)

One 300-mg capsule: $0.19 (0.06 to 0.10)

Valproic acid (Depakene)

20 mg per kg per day for mania; adjust dosage in 3 to 5 daysAn alternative is 500 to 750 mg daily; increase by 30 to 50 percent every 2 to 3 days as tolerated

1,000 to 3,000 mg per day. Lower dosages may be used in hypomania. Sometimes it is appropriate to give as a single bedtime dose; otherwise, prescribe twice-daily dosingTherapeutic blood level: 50 to 125 μg per mL

Tremor, ∥ sedation, diarrhea, nausea (use divalproex [Depakote]; give histamine H2-receptor blocker such as ranitidine [Zantac], 150 mg daily); weight gain, hair loss, mild elevation on liver function tests

One 250-mg capsule: $1.24

Carbamazepine (Tegretol)

200 to 400 per day; increase by 200 mg daily every 2 to 4 days

400 to 1,200 mg daily; in an occasional patient, it is appropriate to give a single bedtime dose; otherwise, prescribe twice-daily dosingTherapeutic blood level: 4 to 12 μg per mL; not well established

Headache, nystagmus, ataxia, sedation, rash, leukopenia (do not combine with clozapine [Clorazil]), mild elevation on liver function tests. Carbamazepine is associated with frequent drug–drug interactions related to induction of cytochrome P450 liver enzymes, resulting in lower drug levels of many other medications.

One 200-mg tablet: $0.44 (0.29 to 0.33)

TSH = thyroid-stimulating hormone.

*—When initiating therapy, consider lower dosages in patients with hypomania and in medically ill or elderly patients.

† —Consolidate doses to twice daily or once daily at bedtime if tolerated and efficacious.

‡ —Many of the side effects are dose related. Tolerance can be enhanced by tailoring the dosage to each patient’s tolerance and response.

§ —Estimated cost to the pharmacist for one tablet or capsule based on average wholesale prices rounded to the nearest dollar in Red book. Montvale, N.J.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescription filling fee.

∥—Tremor may be relieved with a beta-adrenergic blocker such as atenolol (Tenormin), in a dosage of 50 mg daily.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

MONITORING ISSUES

Treatment with mood stabilizers requires periodic laboratory tests to monitor the patient’s response to the drug (Table 9).23 In addition, preventive care includes surveillance for possible comorbidities. Screening for substance abuse and other mental health problems should be conducted routinely. If prodromal symptoms of depression or mania are noted, interventions may include more frequent office visits, crisis telephone calls and intensive outpatient programs.23 It is important that patients regulate their sleep. Insufficient and irregular hours of sleep often precipitate mood disturbance.

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TABLE 9

Recommended Laboratory Tests for Monitoring Response to Lithium, Valproic Acid and Carbamazepine

LITHIUM VALPROIC ACID (DEPAKENE) CARBAMAZEPINE (TEGRETOL)

First two months of therapy

Serum level every 1 to 2 weeks*†

Serum level every 1 to 2 weeks*CBC and liver function tests monthly

Serum level every 1 to 2 weeks*CBC and liver function tests monthly

Long-term therapy

Serum level every 3 to 6 months*†Thyroid function tests yearly (total T4, T4 uptake and TSH)†Renal function every 6 to 12 months (serum urea nitrogen, creatinine and electrolytes); 24-hour urine for volume and GFR only if specifically indicated, not routinely

Serum level every 3 to 6 months*†CBC and liver function tests every 6 to 12 months

Serum level every 3 to 6 months*CBC and liver function tests every 6 months

CBC = complete blood count; T4 = thyroxine; TSH = thyroid-stimulating hormone; GFR = glomerular filtration rate.

*—Serum levels of mood stabilizers should be obtained whenever the dosage or clinical situation changes.

†—Tests are strongly recommended by the committee that formulated the guidelines for treatment of bipolar disorder.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

Family and Psychosocial Issues

Significant issues for the patient and family members include the stigma that is frequently associated with mental illness and the need for support and education. Because patients with bipolar disorder lose judgment early in the course of the illness and often engage in high-risk behavior, family members may be interacting with the legal system, the police and the health care system simultaneously. Guilt, anger, grief and ambivalence are frequent feelings among family members as they cope with the difficulties.

Family members must be educated about possible relapses, what to look for and how to handle different situations. The recklessness that accompanies mania can have devastating consequences—including sexually transmitted diseases, financial ruin, traumatic injuries and accidents. Risk-taking causes significant distress to patients and families, and such behavior is a problem for which family physicians, psychiatrists and mental health professionals can intervene with appropriate medical, preventive, educational and social strategies (Table 10).23 Initial intervention includes education for the patient and family, including informational pamphlets, videos and involvement in support and patient advocacy groups.

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TABLE 10

Psychosocial Issues to Address in the Acute and Maintenance Phases of Bipolar Disorder

Acute phase

Monitor suicidality, mood, substance use, sleep patterns and medication compliance.

Educate patient and family members about features and biologic nature of the illness and the importance of compliance with therapy.

Encourage telephone contact and optimism regarding recovery. Set limits on impulsive behavior in patients with mania. Consider interpersonal or cognitive therapy for patients with depression. Hold family meetings to discuss issues.

Maintenance phase

Inquire about suicidality, mood, medication compliance, life events, substance use, sleep and activity.

Educate patient and family members about use of medication, warning signs of relapse, management of stress, sleep hygiene, eating and exercising regularly, limited caffeine and alcohol intake and management of work and leisure activities.

Long-range issues may include marital problems, employment and financial problems, peer relationships and modification of personality traits.

Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3–88.

Patients who are manic or depressed may attempt suicide or homicide. The risk is increased in patients who are psychotic and have severe depressive symptoms concurrent with mania.28 The lifetime suicide risk is 15 percent in patients with bipolar disorder; patients at highest risk are young men in an early phase of illness who have made previous suicide attempts or who abuse alcohol.29 Family members must learn the warning signs of suicide and must be able to distinguish between the signs of mania and those of depression.

Substance use should be discouraged. Even modest social drinking can lead to mood disturbance. In addition, substances such as alcohol can interact with medications, disinhibit patients and contribute to risky behaviors.

Guns should be removed from the house. Easy access to firearms can supply a ready means of suicide or accidental injury in a patient with impaired insight and judgment.

If the patient or family has concerns about sexually transmitted diseases, testing and counseling can be offered and preventive strategies explained and encouraged.

Legal intervention may be required in patients who exhibit violent behavior. Spouses should be informed of their legal rights, given crisis intervention information and access to safe houses.

If a patient is out of control in spending money, several avenues should be explored. Patients and family members may need referral to social services and/or to legal counsel. Precautions might include putting the house in the spouse’s name, limiting credit lines, creating trust funds and using financial planning services. Support groups are useful, as is family therapy.

Final Comment

Bipolar disorder can be well managed by family physicians in concert with psychiatrists. The consequences of the patient’s behavior on the patient’s life as well as the lives of family members must be explored. The family physician has a significant contribution to make in terms of education, support and follow-up. Both family physicians and psychiatrists have opportunities to intervene and help these patients and their families.

The Authors

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KIM S. GRISWOLD, M.D., M.P.H., is assistant professor of family medicine and psychiatry in the Department of Family Medicine at the State University of New York (SUNY) at Buffalo School of Medicine and Biomedical Sciences. She received a master’s degree in public health from Yale University, New Haven, Conn., and completed a faculty development fellowship in primary care at Michigan State University College of Human Medicine, East Lansing. After graduating from the SUNY–Buffalo School of Medicine and Biomedical Sciences, she completed a family practice residency at Buffalo (N.Y.) General Hospital.…

REFERENCES

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1. Krauthammer C, Klerman GL. Secondary mania. Arch Gen Psychiatry. 1978;35:1333–9.…

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Antipsychotics and bipolar disorder

Posted on July 12, 2016 by JmaC

Antipsychotic medicines are sometimes used together with mood stabilisers to help treat an episode of high mood (mania).

They are used as an initial treatment to help control the symptoms while the mood stabiliser begins to work.

Antipsychotic medicines can also treat mania with psychotic symptoms such as hallucinations, delusions or hearing voices.

The antipsychotic is usually stopped once the symptoms are under control, and treatment is continued with mood stabilisers.

However, some antipsychotics may also stabilise mood, and these medicines have a role as maintenance treatments to prevent episodes of ill health.

There are two types of antipsychotic medicine:

  • typical antipsychotics
  • atypical antipsychotics.

How do they work?

Antipsychotics are sometimes described as ‘major tranquillisers’, but this term is fairly misleading, as this type of medicine is not just a tranquilliser, and any tranquillising effect is not as important as the main way they work in psychiatric illness.

Recommended
Xanax (alprazolam)

Antipsychotic medicines work by affecting the activity of chemicals called neurotransmitters that are found in the brain. In particular, they decrease the activity of dopamine, a neurotransmitter that is involved in controlling mood and behaviour.

Levels of dopamine have been shown to be raised in the brains of people going through a manic episode, and blocking the activity of this dopamine is thought to be the main way in which antipsychotic medicines work to control manic symptoms.

How long do they take to work?

Antipsychotics work very quickly to control manic behaviour, particularly if they are given by injection.

Once the manic episode is controlled, the length of time the antipsychotic is continued for depends on individual circumstances, including whether the medicine will be continued long-term as a mood stabiliser. In any case, treatment should not usually be stopped abruptly as this could cause the manic symptoms to come back, or on rare occasions, withdrawal symptoms.

People who will be continuing treatment with other mood stabilisers may have their antipsychotic dose tapered down over a four week period. People who will not be continuing other mood stabilisers may need to reduce their antipsychotic more slowly – usually over three months – to avoid a relapse.

Typical antipsychotics

This is the older group of medicines that includes drugs such as haloperidol (eg Haldol) and chlorpromazine.

These medicines are very effective for controlling episodes of mania, but are less commonly used because they can have many unpleasant side effects. The most troublesome are abnormal involuntary facial and body movements that can occur after just a few doses.

Other side effects include:

  • drowsiness and sedation
  • muscle tremor and rigidity
  • agitation
  • insomnia
  • dry mouth
  • constipation
  • blurred vision
  • confusion
  • dizziness
  • effects on the heart
  • weight gain
  • impotence
  • increases in levels of the hormone prolactin that may result in development of breasts and milk production.

Atypical antipsychotics

Atypical antipsychotics are newer medicines that are more likely to be used than the older antipsychotics. They are better tolerated than the older antipsychotics because they have fewer troublesome side effects.

Atypicals include medicines such as aripiprazole (Abilify), clozapine (eg Clozaril),olanzapine (Zyprexa), quetiapine (Seroquel) and risperidone (Risperdal).

Aripiprazole, olanzapine, quetiapine and risperidone are all licensed to treat episodes of mania.

Aripiprazole and olanzapine are also licensed to prevent recurrence of mania in people whose manic episode responded to initial treatment with the medicine.

Quetiapine is licensed to prevent both manic and depressive relapses in people whose manic, depressive or mixed episode responded to initial treatment.

Clozapine is reserved for treating people with bipolar disorder who are highly unresponsive to other drugs, because it can cause serious side effects on the blood. It requires regular monitoring with blood tests.

Further research is ongoing into the use of atypical antipsychotics in bipolar disorder and particularly in bipolar depression.

Atypical antipsychotics cause less abnormal body and facial movements than the older drugs and have less effect on prolactin levels, though they still have the potential to cause these problems. Other side effects include:

  • sleepiness and sedation
  • weight gain
  • raised blood sugar levels and diabetes
  • raised cholesterol levels
  • sexual dysfunction
  • abnormal heart rhythms
  • dry mouth
  • constipation
  • blurred vision
  • drop in blood pressure and dizziness on standing up.

During long-term treatment with atypical antipsychotics your doctor will want you to have regular check-ups to monitor things such as the levels of glucose, lipids and prolactin in blood count.

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Antidepressants in Bipolar Disorder: The Controversies

Posted on July 12, 2016 by JmaC

Antidepressants in Bipolar Disorder: The Controversies

Updated 11/2014

Bottom line: there are at least 9 alternatives with at least as much evidence as antidepressants for effectiveness in bipolar depression, that don’t make bipolar disorder worse, as is clearly a risk with antidepressants. So most of these questions are nearly moot, in my opinion. Just skip the antidepressants unless you’re backed into them by not getting better on less potentially risky stuff.  But that’s not widely agreed upon, even after 10 years of direct study. Here are the specific areas of controversy.

  1. Do antidepressants even work in bipolar depression? Yes, but it’s not very well, except perhaps in Bipolar II, depending on who you listen to. 
  2. Can antidepressants trigger manic symptoms? Yes, that’s completely agreed upon. But how often? That’s not agreed upon at all.
  3. Are antidepressants “mood de-stabilizers” ? This is a crucial question, at least as important as #2. Answer: uh, it’s complicated?
  4. If you’re on an antidepressant and doing well, should you stay on or taper off?  First, don’t do anything without talking with whoever prescribed it.  If you have more than 4 mood episodes per year — then maybe taper off? Careful here!

1. Do antidepressants even work in bipolar depression?

No. Yes. Maybe. Only in Bipolar II. Depends on how long you watch — and how you define “work”.

Let’s try that again. There are two big lines of research about this. In one, which led to a formal study that took years and was supposed to answer this question directly, antidepressants were no better than placebos for bipolar depression.Sachs

But in a whole series of studies in Bipolar II (no Bipolar I patients in these studies), antidepressants not only worked better than placebo, they worked better than lithium! (The Amsterdam studies; more on those herein).

Overall, nearly everyone would agree: it’s suprising how little evidence we have in support of using antidepressants for bipolar depression, especially given how often they’re used. When there’s very little evidence to consider, it’s easy for controversies to persist. Thus there are loud voices on both sides of this issue.

But in 2013 the International Society for Bipolar Disorders (ISBD) issued a very clear set of recommendations.Pachiarotti Simplified: don’t use antidepressants, except in patients who’ve:

  1. done well on them before
  2. get worse when they’re stopped
  3. have bipolar II (noting even this is controversial)

And finally, in 2014 editorial entitled “Never without a mood stabilizer”, a highly respected researcher asks strongly why:

  • 35% of bipolar patients get antidepressants without mood stabilizers
  • antidepressants aren’t stopped when patients are manic
  • antidepressants are given when patients are in mixed states Vieta   

More on this controversy…

2. Can antidepressants trigger manic symptoms?

Yes. Almost universal agreement. But, how often does this happen? Some say 4% of the timeGjisman, some say 44% of the timeTruman in some circumstances. Yet it doesn’t really make much difference, you see:   yes, there is significant risk, at least 1 per 25 users, maybe more like 1 per 3 or even 1 per 2 for some people.  But because there are at least 9 alternativesto using an antidepressant to treat bipolar depression, most patients with bipolarity do not have to decide whether to take the pro-mania/hypomania risk of an antidepressant. They can just use something else.

Here are some groups of people who are at greater risk for having hypomanic or manic symptoms if they use an antidepressant:

  • Bipolar I
  • Female
  • Frequent mood shifts (e.g. monthly or more often)
  • It happened before
  • It happened to someone in your family
  • Someone in your family has bipolar disorder
  • Your first depression was between the ages of 18 and 24
  • You’ve had a post-partum depression
  • You’ve been psychotic without street drugs

More on this controversy…

But remember: there are at least 9 alternatives.

 

3. Are antidepressants “mood de-stabilizers” ?

Quoting from an editorial in the American Journal of Psychiatry, March 2008, by Nassir Ghaemi, one of the principal investigators in the STEP-BD, a large bipolar research trial (emphases mine):

Mood destabilization with antidepressants should be distinguished from an acute manic “switch.” Antidepressant-induced mania, or switch, is a short-term phenomenon; one might define it as happening within 2 months of the beginning of antidepressant treatment. Mood destabilization is a long-term phenomenon, reflecting more mood episodes over time than would have occurred by natural history.

Antidepressants may cause long-term mood destabilization without a short-term manic switch, and vice versa. Although some agents may have low rates of acute manic switch, especially when used with mood stabilizers, the data from STEP-BD suggest that even the new generation of antidepressants can produce long-term mood destabilization.

In that editorial, Dr. Ghaemi also emphasizes an approach I’ve been espousing for years: if a mood stabilizer is tried with an antidepressant also in use at the same time, and the mood stabilizer “doesn’t work”, that was an unfair trial of the mood stabilizer. It will need to be tried again later with no antidepressant in the picture.

If you’re skeptical about these conclusions I’ll show you some data I think supports them, but it’s pretty technical stuff.  Before I invite you there, does anyone think antidepressants have a stabilizing effect? Well, in Bipolar II,  Dr. Gordon Parker thinks so.Parker So do Drs. Amsterdam and Shults, whose 2013 study is similar but much bigger (however, read the Comments you’ll see linked at the bottom of their abstract; very telling, I think.)

I think they’re right, that antidepressants can have a stabilizing effect — for a while.  Consider two cases.

When people ask me “how long does it take for an antidepressant to cause manic or hypomanic symptoms?”, I answer with the experience of two patients. First, one guy told me “20 minutes after my first dose of Paxil I felt like I was shot out of a cannon.” So that’s the fastest it can happen, I figure.

The second I wrote up as a case report, it was so telling. Phelps One of my patients went 7 years on sertraline/Zoloft, doing really well, much better than on other antidepressants she’d tried. She’d “joined the human race”, she said, after years of depression. Then she developed anxiety. So her primary care provider increased her antidepressant (because antidepressants are used to treat anxiety; not an unreasonable move).

Ka-boom, she had horrible anxiety, agitation (like wanting to crawl out of her skin), suicidal ideation, terrible insomnia, and restlessness). This did not subside until she tapered off sertraline, despite desperate attempts with a bunch of medications including antipsychotics, anti-anxiety medications, and mood stabilizers. But the clincher was when she tried, about a year later, going back on sertraline, trying to get that “normal” feeling back.  One quarter of the dose she did so well on for 7 years produced the same agitated state within three days.

So, I think antidepressants can work quite well, for a while. Somewhere between 20 minutes and 7 years… But then they can cause mixed states and suicidal ideation, at least in some people. How many people? that’s a complete unknown. I don’t get to see the folks who are doing great years later, so I can’t judge by all the patients I see whose antidepressants seem like part of the problem. My colleague Dr. Manipod and I published a case series of 12 people who looked “unipolar”, i.e. not bipolar, but who got much better when their antidepressant was stopped.Phelps/Manipod 

Other colleagues have reported similar findings, e.g. 15 more cases.Sharma One has gone so far as to publish a couple of papers describing what he calls “tardive dysphoria” .  Short explanation of the term: he’s describing what happened to my patient above who did so well on sertraline for 7 years. El-Mallakh 

Want to see more data on this question? Dr. Ghaemi refers to two randomized trials.  More….

 

     (3b: Kindling and Long-term Worsening)

Could antidepressants cause kindling”? The phrase “kindling” is borrowed from neurology, where it has been used to describe forms of epilepsy, which appear to worsen with time. In this model, it is as though each episode of illness makes later episodes both more likely and more severe. It is clear that some patients’ bipolar disorder worsens as they get older, with more frequent and more severe episodes. Could this kind of pattern be triggered by antidepressants, at least in some susceptible patients?  This is hard to study, but some evidence supports kindling, at leastKemner; the antidepressant question is harder to nail down.

Here is good visual example of the phenomenon we’re talking about here. The graph shows the mood episodes of a man whose bipolar disorder seemed to clearly worsen with time (his age is shown at the bottom of the timeline; red means hospitalized, up is manic and down is depressed, of course):

contro8

Note the pattern: after each episode, the next episodes tend to come sooner and become more severe. This is the “kindling” pattern, though this man’s experience alone of course does not prove that the illness itself can do this. There could have been some other factors, such as alcohol or other drugs, etc.

However, suppose some forms of bipolar disorder really do “kindle” themselves. If that is so, then any worsening has the potential to be a “permanent” worsening. What if the patient above had been treated with psychotherapy at age 18, during that first depression? Compare what might have happened if he had been given an antidepressant, triggering a manic episode: might his graph have changed from the course we saw just above (a real patient’s experience):

course (1)

to this (a hypothetical example):

contro1

The difference, as you can see, is that this hypothetical patient lost 5 years of symptom free life. And he arrives at a nearly continuous course of illness by age 35, instead of age 40.

This “kindling” concern is very rarely raised in the bipolar literature, at least as regards the risks of antidepressants. Wouldn’t you think that if antidepressants could really cause or accelerate the course of bipolar disorders, that we should be freaked out about using them? and really careful to indentify anyone who might have that happen to them?  But no, it’s not a big deal in the literature.

So I invited people to tell their story, if it had happened to them. The good news is that over years, I received only a handful. Here’s one that seems to me a perfect example. But remember, he’s only one case and there were plenty of people who read that invitation.

Mr. B (direct quote from an email, used by permission):

Before my first use of an antidepressant, I had never suffered mania. I had been diagnosed with depression and anxiety, but not bipolar disorder. I was prescribed Lexapro for anxiety (I had never used psychiatric medication before) and used it for five or six days, taking a small dose (half tablet each day). It induced mania so I was hospitalized for a week or so.

 

Since then, I have steadily had irrational grandiose thoughts. In hindsight, I can see that I had some irrational grandiose thoughts before my Lexapro use, but since my Lexapro use they are far stronger. As far as permanence goes, so far I have not noticed any improvement at all coming simply from time passing (although therapy and other active approaches have been helpful). I had a second manic episode less than a year later (I was not on any medication at the time).

So there’s one case. There is also one published example of a patient given steroids for colitis, with a similar course.PiesHere’s another widely regarded expert expressing the same concern — in a different contex, but same resulting worry, from a 2008 New York Times article…

Kiki Chang, director of the pediatric bipolar-disorders program at Stanford, has embraced the kindling theory. “We are interested in looking at medication not just to treat and prevent future episodes, but also to get in early and — this is the controversial part — to prevent the manic episode,” he told me. “Once you’ve had a manic episode, you’ve already crossed the threshold, you’ve jumped off the bridge: it’s done. The chances that you’re going to have another episode are extremely high.”

More…

 

4. If you’re on an antidepressant and doing well, should you stay on or taper off?

Three studies address this issue directly — and they have different conclusions! Make sure you know about the second one, the results of which are a more reliable guidepost by standard criteria for judgement (randomized trials trump naturalistic studies).

  1. Altshuler et al , Am J Psych 2003 – naturalistic
  2. Ghaemi, STEP-BD – randomized
  3. Altshuler et al, J Clin Psych 2009 – randomized? no, even though it looks like it

Bottom line: the randomized trial says “if you have had rapid cycling (more than 4 mood episodes in a year), you should try tapering off.” For patients with more rare episodes, they actually did slightly better staying on (but not much, and it’s another long-term medication to carry, so I figure even those folks ought to try tapering off at least once, really really slowly).

For more, we’re digging into those studies, if you’re up to it: more….

 Conclusions

1. There are a lot of alternatives to antidepressants for the treatment of bipolar depression, most of which have at least as much evidence for their effectiveness in bipolar depression as antidepressants do. Use those alternatives first, all that are workable (some may not be) — especially if you’ve already had several antidepressants and you’re not better. Here’s a page with nine such alternatives.

2. Do not use antidepressants if rapid cycling or severe insomnia/agitation/irritability is already present.

3. Almost every patient with bipolar disorder who is taking an antidepressant deserves a trial off of that antidepressant to see if things are more stable (or at least, no worse). When trying this, taper off the antidepressant very slowly: four months, 25% per month, is a good rate (agreed upon in 31 ways by two psychiatrists!).

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Wrestling with Bipolar Disorder

Posted on July 12, 2016 by JmaC

It’s one of the most missed diagnoses in psychiatry. Bipolar disorder, involving moods that swing between the highs of mania and the lows of depression, is typically confused with everything from unipolar depression to schizophrenia to substance abuse, to borderline personality disorder, with just about all stops in between. Patients themselves often resist diagnosis, because they may not see as pathologic the surge in energy that accompanies the mania or hypomania that distinguishes the condition.

But on a few points consensus is emerging. Bipolar disorder is a chronically recurring illness. And the age of onset is dropping—in less than one generation it has gone from age 32 to 19. Whether there is a genuine increase in prevalence of the disorder is a matter of some debate, but there does seem to be a genuine increase among the young.

What’s more, the depression of manic-depression is emerging as a particularly thorny problem for both patients and their doctors.

“Depression is the bane of treatment of bipolar disorder,” says Robert M.A. Hirschfeld, M.D., head of psychiatry at the University of Texas Medical Branch in Galveston.

It’s what is most likely to motivate patients to accept care. People spend more time in the depression phase of the disorder. And unlike unipolar depression, the depression of bipolar illness tends to be treatment-resistant.

“Antidepressants don’t work very well in bipolar depression,” says Dr. Hirschfeld. “They are underwhelming in their ability to treat the depression.” In fact, a shift away from antidepressants is formally recognized in new treatment guidelines for bipolar disorder just released by the American Psychiatric Association.

As physicians gain experience in treating the disorder, they are discovering that antidepressants have two negative effects on the course of the disorder. Used by themselves, antidepressants can induce manic episodes. And over time they can accelerate mood cycling, increasing the frequency of episodes of depression or of mania followed by depression.

Instead, research points to the value of drugs that work as mood stabilizers for the depression of bipolar disorder, either alone or in combination with antidepressants. If antidepressants have any use at all in bipolar disorder, it may be as acute treatment for bouts of severe depression before mood stabilizers are added or substituted.

Even in cases of severe depression, the new guidelines favor increasing the dosage of mood stabilizers over other strategies.

Not so long ago, mood stabilizers could be summed up in a single word—lithium, in use since the 1960s to tame mania. But research has additionally demonstrated the effectiveness of divalproex sodium (Depakote) and lamotrigine (Lamictal), drugs that were initially developed for use as anticonvulsants in seizure disorders. Divalproex sodium has been approved for use as a mood stabilizer in bipolar disorder for several years, while lamotrigine is undergoing clinical trials for such an application.

“Optimizing the dose of lithium or divalproex has good antidepressant effects,” reports Dr. Hirschfeld. “We also now know that divalproex and lamotrigine are very good for preventing recurrence in bipolar patients.” A study showed that lamotrigine not only delays the time to any mood events but is notably effective against the depressive lows of bipolar illness.

No one knows for sure exactly how anticonvulsants work in bipolar disorder. For that matter, the condition has been described since the time of Hippocrates, but it is still not clear what goes awry in manic-depression.

Despite the unknowns, medications for treating the disorder are proliferating. In contrast to downplaying antidepressants in the depressive phase of the disorder, clinical research is ramping up the value of antipsychotic drugs for combating the manic phase, albeit a new generation of such drugs, collectively called atypical antipsychotics. Chief among them are olanzapine (Zyprexa) and risperidone (Risperdal). They are now considered a first-line approach to acute mania, and adjuncts for long-term therapy along with mood stabilizers.

In the long term, however, observes Nassir Ghaemi, M.D., assistant professor of psychiatry at Harvard and head of bipolar research at Cambridge Hospital, medication goes only so far. “Drugs are not effective enough. It may have to do with the overuse of antidepressants; they interfere with the benefits of mood stabilizers.

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“Medications don’t take you to the finish line.” There seem to be residual symptoms of depression that don’t clear. Even when patients stabilize into a normal, or euthymic, mood state, he says, some troubling signs can appear.

“Sometimes we see in euthymic patients cognitive dysfunction that we didn’t expect in the past—word-finding difficulties, trouble maintaining concentration,” Dr. Ghaemi explains. “Cumulative cognitive impairment seems to emerge with time. It may be related to findings of decreased size of the hippocampus, a brain structure that serves memory. We are on the verge of recognizing long-term cognitive impairment as a result of bipolar disorder.”

He believes there is a role for aggressive psychotherapy for keeping patients well, for keeping everyday ups and downs from becoming full-blown episodes. At the very least, he finds, psychotherapy can help patients resolve the work and relationship problems that often outlast symptoms.

In addition, psychotherapy can help patients learn new coping styles and interpersonal habits. “Many of the ways patients deal with their illness are not relevant when they are well,” explains Dr. Ghaemi.

For example, he says, many people develop the habit of staying up late as a way of coping with the manic symptoms. “What they couldn’t change before because of the illness needs to be changed after treatment if, for example, it bothers a spouse. People have to learn to change. But the longer one is ill, the harder it is to become completely well, because the harder it is to change the habits of one’s life.”

And for young people diagnosed with bipolar illness, he considers psychotherapy essential. “The younger patients are, the less convinced they are that they have bipolar disorder,” he says. “They have impaired insight. They’re especially concerned about the need to take medications. They should be in psychotherapy to get educated about the illness and medication.”

He also stresses the value of support groups, especially for young people. “It’s another, important layer of validation.”

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