Pharmacologic Therapy

Appropriate medication depends on the stage of the bipolar disorder the patient is experiencing. Thus, a number of drugs are indicated for an acute manic episode, primarily the antipsychotics, valproate, and benzodiazepines (eg, lorazepam, clonazepam). The choice of agent depends on the presence of symptoms such as psychotic symptoms, agitation, aggression, and sleep disturbance. (See the list of medications for bipolar disorder in the Table below.) For patients with bipolar affective disorder in the depressed phase, the Medscape Reference article Depression provides antidepressant guidelines. Bauer and colleagues suggest 2 approaches. First, in a patient with bipolar depression who is not currently being treated with a mood-stabilizing agent (de novo depression, first or subsequent episode), options include quetiapine or olanzapine, with carbamazepine and lamotrigine as alternatives. Antidepressant are options for shortterm use, but it remains controversial if it is better to administer them in combination with mood-stabilizing agents or as monotherapy. Most clinicians use antidepressants and an antimanic agent in combination. Second, if the patient is already optimally treated with a mood-stabilizing agent (appropriate dose, good compliance) such as lithium, an option would be lamotrigine. No evidence suggests additional benefit from antidepressants if a patient is already being treated with a mood stabilizer, but this often tried in practice.[59] One cautionary note of interest, Post and colleagues have found that the more different antidepressant trials the patient with bipolar disorder has received, the less responsive they become to treatment.[60] Lithium is the drug commonly used for prophylaxis and treatment of manic episodes. A recent study suggests that lithium may also have a neuroprotective role.[61] However, it is also associated with increased risk of reduced urinary concentrating ability, hypothyroidism, hyperparathyroidism, and weight gain. The consistent finding of a high prevalence of hyperparathyroidism should prompt physicians to check patient calcium concentrations before and during treatment. Lithium is not associated with a significant reduction in renal function in most patients, and the risk of end-stage renal failure is low.[62] Lithium therapy may serve to protect and preserve the hippocampal volumes, in contrast to patients with major depression (ie, unipolar), who show diminished hippocampal volumes.[63] Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. The broad range of antidepressants and ECT are used for an acute depressive episode (ie, major depression). Ansari and Osser have developed a very useful algorithm to treat a bipolar patient in a depressed phase.[64] Finally, another set of medications is chosen for the maintenance and preventive phases of treatment. Diazgranados and colleagues have reported that for patients with treatment-resistant bipolar depression, impressive and swift antidepressant effects occurred when a single intravenous (IV) dose of an N -methyl-D -aspartate (NMDA) antagonist was

administered.[65] Increasingly, the role of glutamate in mood disorders is being researched, and experimental evidence shows that the NMDA receptor antagonist ketamine may be helpful in short-term treatment of depression, even in the context of bipolar disorder. Although antidepressant medications are most often prescribed for patients with bipolar disorder who are experiencing an acute depression, a study found that antidepressants were not statistically superior to placebo or other current standard treatment for bipolar depression.[66] Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs. These medications serve to stabilize the patients mood, as the name implies. They can also dampen extremes of mania or depression. Kessing et al found that, in general, lithium was superior to valproate.[67] Clinical experiences have shown that patients with bipolar disorder have fewer episodes of mania and depression when treated with mood-stabilizing drugs.[68]These medications serve to stabilize the patients mood, as the name implies. They also can dampen extremes of mania or depression. Atypical antipsychotics (including ziprasidone, quetiapine, risperidone, aripiprazole, olanzapine, and asenapine) are also now frequently used to stabilize acute mania, or even to treat bipolar depression in some cases. There have been concerns that ziprasidone may have adverse effects on body weight, fasting lipids, and fasting glucose. Pappadopulos et al looked at a comprehensive set of analyses of metabolic alternations in patients on this medication and found no significant differences between the ziprasidone and placebo groups in fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glucose in the controlled studies.[69] The role of mood stabilizers and antipsychotic medications in maintaining patients with bipolar disorder is well documented,[70] as is the use of long-acting antipsychotics to help with the maintenance phase. According to a multiple treatments meta-analysis of treatments for acute mania, haloperidol, risperidone, and olanzapine are the most efficacious treatments, significantly outperforming primary mood stabilizers and other antipsychotic medications.[71] In the treatment of depression associated with bipolar disorder II, Swartz and associates report that 95% of relevant trials were published later than 2005. They noted compelling evidence for the efficacy of quetiapine and preliminary support for the efficacy of lithium, antidepressants, and pramipexole. Mixed support was noted for lamotrigine. [72] As outlined in a clinical practice guideline from the American Psychiatric Association,[73] benzodiazepines have sedative effects, which may make them useful

adjunctive medications until antimanic medications take effect. Additionally, the guideline states that manic symptoms may be treated with chlorpromazine, which was deemed superior to placebo in a randomized trial and was deemed comparable to lithium (for controlling manic and psychotic symptoms) in acute treatment comparison trials. Children and adolescents who have bipolar disorder are particularly challenging to treat. Hamrin and Iennaco have conducted an extensive literature review using research findings on medication effectiveness in this population and have developed guidelines and recommendations for medications and management approaches.[74] The US Food and Drug Administration (FDA) has approved several bipolar treatment regimens (see the Table below).[75]

Caution in polyantipsychotic therapy in bipolar disorder

Brooks et al assessed the safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder.[76] The study sought to evaluate the safety and tolerability of second-generation antipsychotic (SGA) polytherapy compared with monotherapy in patients with bipolar disorder receiving open naturalistic treatment in the 22-site Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). After controlling for illness onset, age, baseline illness severity, and medication load, patients who were prescribed polytherapy compared with monotherapy had more dry mouth, sexual dysfunction, and constipation and were almost 3 times as likely to incur more psychiatric and medical care. No association with greater global functioning scores or percentage of days spent well was noted. The study concluded that although polytherapy was fairly common in bipolar disorder, it was associated with increased side effects and increased health service use but not with improved clinical status or function. Therefore, polytherapy in bipolar disorder may incur important disadvantages without clear benefit, warranting careful consideration before undertaking such interventions.