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Pharmacological Management of

Bipolar Disorder

By :-Saurabh JaiswalPG-JR2, Psychiatry

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Mood is a pervasive and sustained feeling tone that is experienced internally and that influences a person's behaviour and perception of the world.

Affect is the external expression of mood. Mood can be normal, elevated, or depressed.

Mood disorders are a group of clinical conditions characterized by a loss of that sense of control and a subjective experience of great distress.

Patients with elevated mood demonstrate expansiveness, flight of ideas, decreased sleep, and grandiose ideas. Patients with depressed mood experience a loss of energy and interest, feelings of guilt, difficulty in concentrating, loss of appetite, and thoughts of death or suicide. Other signs and symptoms of mood disorders include change in activity level, cognitive abilities, speech, and vegetative functions .

Patients afflicted with only major depressive episodes are said to have major depressive disorder or unipolar depression. Patients with both manic and depressive episodes or patients with manic episodes alone are said to have bipolar disorder.

INTRODUCTION

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Bipolar I Disorder:

The DSM-IV-TR criteria for a manic episode requires the presence of a distinct period of abnormal mood lasting at least 1 week and includes separate bipolar I disorder diagnoses for a single manic episode and a recurrent episode, based on the symptoms of the most recent episode .

The designation bipolar I disorder is synonymous with what was formerly known as bipolar disorder, a syndrome in which a complete set of mania symptoms occurs during the course of the disorder.

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Bipolar II Disorder:The diagnostic criteria for bipolar II disorder is characterized by depressive episodes and hypomanic episodes during the course of the disorder, but the episodes of manic-like symptoms do not quite meet the diagnostic criteria for a full manic syndrome.

Evidence also indicates that patients with bipolar II disorder are at greater risk of both attempting and completing suicide than patients with bipolar I disorder and major depressive disorder.

Manic episodes clearly precipitated by antidepressant treatment (e.g., pharmacotherapy, electroconvulsive therapy [ECT]) indicate bipolar III disorder.

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Evolving Spectrum of Bipolar Disorders by Akiskal:

Bipolar 1/2: Schizobipolar disorder

Bipolar I: Core manic-depressive illness

Bipolar I1/2: Depression with protracted hypomania

Bipolar II: Depression with discrete spontaneous hypomanic episodes

Bipolar II1/2: Depression superimposed on cyclothymic temperament

Bipolar III: Depression plus induced hypomania (i.e., hypomania occurring solely in association with antidepressant or other somatic treatment)

Bipolar III1/2: Prominent mood swings occurring in the context of substance or alcohol use or abuse

Bipolar IV: Depression superimposed on a hyperthymic temperament

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Clinical Features Predictive of Bipolar Disorder :

Early age at onsetPsychotic depression before 25 years of agePostpartum depression, especially one with psychotic featuresRapid onset and offset of depressive episodes of short duration (<3 months)Recurrent depression (more than five episodes)Depression with marked psychomotor retardationAtypical features (reverse vegetative signs)SeasonalityBipolar family historyTrait mood lability (cyclothymia)Hyperthymic temperamentHypomania associated with antidepressantsRepeated (at least three times) loss of efficacy of antidepressants after initial response

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US Food and Drug Administration (FDA)-Approved Medications for the Treatment of Bipolar Disorders:

Agent Mania Maintenance

Aripiprazole Yes No

Carbamazepine Yes No

Divalproex Yes No

Lamotrigine No Yes

Lithium Yes Yes

Olanzapine Yes Yes

Risperidone Yes No

Quetiapine Yes No

Ziprasidone Yes No

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Lurasidone:

Lurasidone is an atypical antipsychotic started being used since 2013.

It is approved for treatment of depressive episodes associated with Bipolar I Disorder (bipolar depression) in adults both alone and in combination with Lithium or Valproate. Lurasidone is likely to deliver more efficacy without sacrificing tolerability according to current data.

Only 3 treatments are FDA-approved for the treatment of acute bipolar depression: Quetiapine, Olanzapine-Fluoxetine combination, and Lurasidone.

Only Quetiapine is approved for the treatment of bipolar II depression.

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Lithium Carbonate:

Lithium carbonate is considered the prototypical “mood stabilizer.†Yet, �because the onset of antimanic action with lithium can be slow, it usually is supplemented in the early phases of treatment by atypical antipsychotics, mood-stabilizing anticonvulsants, or high-potency benzodiazepines. Therapeutic lithium levels are between 0.6 and 1.2 mEq/L. The acute use of lithium has been limited in recent years by its unpredictable efficacy, problematic side effects, and the need for frequent laboratory tests. The introduction of newer drugs with more favorable side effects, lower toxicity, and less need for frequent laboratory testing has resulted in a decline in lithium use. For many patients, however, its clinical benefits can be remarkable

Pharmacotherapeutic Agents

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Valproate:

Valproate (valproic acid or divalproex sodium ) has surpassed lithium in use for acute mania. Unlike lithium, Valproate is only indicated for acute mania, although most experts agree it also has prophylactic effects. Typical dose levels of valproic acid are 750 to 2,500 mg per day, achieving blood levels between 50 and 120 µg/mL. Rapid oral loading with 15 to 20 mg/kg of divalproex sodium from day 1 of treatment has been well tolerated and associated with a rapid onset of response. A number of laboratory tests are required during valproate treatment.

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Carbamazepine and Oxcarbazepine:

Carbamazepine has been used worldwide for decades as a first-line treatment for acute mania, but has only gained approval in the United States in 2004. Typical doses of carbamazepine to treat acute mania range between 600 and 1,800 mg per day associated with blood levels of between 4 and 12 µg/mL. The keto congener of carbamazepine, oxcarbazepine, may possess similar antimanic properties. Higher doses than those of carbamazepine are required, because 1,500 mg of oxcarbazepine approximates 1,000 mg of carbamazepine

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Clonazepam and Lorazepam:

The high-potency benzodiazepine anticonvulsants used in acute mania include clonazepam and lorazepam . Both may be effective and are widely used for adjunctive treatment of acute manic agitation, insomnia, aggression, and dysphoria, as well as panic. The safety and the benign side effect profile of these agents render them ideal adjuncts to lithium, carbamazepine, or valproate.

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Atypical and Typical Antipsychotics:

All of the atypical antipsychotics :”olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole” have demonstrated antimanic efficacy and are FDA approved for this indication. Compared with older agents, such as haloperidol and chlorpromazine , atypical antipsychotics have a lesser liability for excitatory postsynaptic potential and tardive dyskinesia; many do not increase prolactin. However, they have a wide range of substantial to no risk for weight gain with its associated problems of insulin resistance, diabetes, hyperlipidemia, hypercholesteremia, and cardiovascular impairment. Some patients, however, require maintenance treatment with an antipsychotic medication.

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Treatment Options

Goals of Treatment• Control symptoms to allow a return to usual levels of psychosocialfunctioning.• Rapidly control agitation, aggression, and impulsivity.

1. Acute Manic or Mixed Episodes

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For patients not yet in treatment for bipolar disorder:

For severe mania or mixed episodes, initiate lithium incombination with an antipsychotic or valproate in combinationwith an antipsychotic.

For less ill patients, monotherapy with lithium, valproate, or anantipsychotic such as olanzapine may be sufficient.

• Short-term adjunctive treatment with a benzodiazepine mayalso be helpful.• For mixed episodes, valproate may be preferred over lithium.• Second-generation (atypical) antipsychotics are preferred overfirst-generation (typical) antipsychotics because of theirgenerally more tolerable side effect profile.• Alternatives include 1) carbamazepine or oxcarbazepine inlieu of lithium or valproate and 2) ziprasidone or quetiapine inlieu of another antipsychotic.

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For patients who suffer a “breakthrough” manic or mixedepisode while on maintenance treatment, optimize the medication dose.

• Ensure that serum levels are within the therapeutic range; insome instances, achieve a higher serum level (but still withinthe therapeutic range).

• Introduction or resumption of an antipsychotic is oftennecessary.

• Severely ill or agitated patients may also require short-termadjunctive treatment with a benzodiazepine.

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If symptoms are inadequately controlled within 10 to 14 days of treatment with optimized doses of the first-line medication regimen, add another first-line medication.

• Alternative treatment options include adding carbamazepine oroxcarbazepine in lieu of an additional first-line medication (lithium,valproate, antipsychotic), adding an antipsychotic if not alreadyprescribed, or changing from one antipsychotic to another.

• Clozapine may be particularly effective in refractory illness.

• Electroconvulsive therapy (ECT) may also be considered.

For psychosis during a manic or mixed episode, treat with anantipsychotic medication.• Second-generation antipsychotics are favoured because of theirgenerally more tolerable side effect profile.• ECT may also be considered.

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2. Acute Depression

Goals of Treatment:

• Achieve remission of the symptoms of major depression and returnthe patient to usual levels of psychosocial functioning.

• Avoid precipitating a manic or hypomanic episode.

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For patients not yet in treatment for bipolar disorder, initiateeither lithium or lamotrigine.

• As an alternative, especially for more severely ill patients,consider initiating treatment with both lithium and anantidepressant simultaneously

• Antidepressant monotherapy is not recommended.

• Consider ECT for- patients with life-threatening inanition, suicidality, orpsychosis or- severe depression during pregnancy.

• For patients who suffer a breakthrough depressive episode while on maintenance treatment, optimize the medication dosage.

• Ensure that serum levels are within the therapeutic range; in some instances, achieve a higher serum level

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If the patient fails to respond to optimized maintenance treatment, consider adding lamotrigine, bupropion, or paroxetine.• Alternative next steps include adding another newerantidepressant or a monoamine oxidaseinhibitor (MAOI).• Tricyclic antidepressants may carry a greater risk ofprecipitating a switch and are not recommended.• MAOIs may be difficult to use because of the risk of severedrug and dietary interactions.• Psychotic features during depression usually require adjunctivetreatment with an antipsychotic medication. Some evidencesuggests efficacy for antipsychotic medication (e.g.,olanzapine, quetiapine) in treating nonpsychotic bipolardepression.• Consider ECT for- severe or treatment-resistant depression,- psychotic features, or- catatonic features.• Clinicians may elect to use antidepressants earlier for bipolar IIdepression than for bipolar I depression because patients withbipolar II disorder probably have lower rates of antidepressant inducedswitching into hypomania or mania.

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MaintenanceGoals of Treatment:

• Prevent relapse and recurrence.• Reduce subthreshold symptoms.• Reduce suicide risk.• Reduce cycling frequency or milder degrees of mood instability.• Improve overall function.

Determine whether maintenance treatment is indicated.

• Maintenance medication is recommended following a manic ora depressive episode.• Although few maintenance studies of bipolar II disorder have beenconducted, maintenance treatment warrants strong considerationfor this form of the illness.

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Choose an initial treatment modality.

Recommended options

• Treatment options with the best empirical support includelithium or valproate. Possible alternatives include lamotrigine,carbamazepine, or oxcarbazepine.• If one of the above medications led to remission from the mostrecent depressive or manic episode, it generally should becontinued.• Maintenance ECT may also be considered for patients whorespond to ECT during an acute episode.• Treatment selection should be guided by illness severity,associated features such as rapid cycling or psychosis, and,where possible, patient preference.

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Role of antipsychotics:

• Antipsychotic medications should be discontinued unless theyare needed for control of persistent psychosis or prevention ofrecurrence of mood episodes.• Maintenance therapy with second-generation antipsychoticsmay be considered, but there is less evidence that theirefficacy in maintenance treatment is comparable to that of theother agents discussed above.

If the patient fails to respond (i.e., continues to experiencesubthreshold symptoms or breakthrough mood episodes), addanother maintenance medication, a second-generation antipsychotic, or an antidepressant.• There are insufficient data to support one combination overanother.• Maintenance ECT may also be considered for patients whorespond to ECT during an acute episode.

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