Understanding Bipolar Disorder:
A Treatment Update

U.S. Pharmacist Continuing Education
ACPE Program No. 430-000-00-005-H01
This program provides 2.0 hours of credit (0.2 CEU).
Lesson Expires: May 31, 2002

This CE article is supported by an unrestricted educational grant from Eli Lilly & Company.

Bipolar disorder is an episodic, long-term illness with a variable course. Target symptoms may include manic symptoms, such as an abnormally elevated, expansive, and irritable mood; hypersexuality; decreased need for sleep; pressured speech; racing thoughts; increased activity and agitation; persecutory and grandiose delusions; and/or depressive symptoms, such as excessive guilt; depressed mood; anhedonia (absence of pleasure); or thoughts of death.

A number of standardized rating scales have been used to evaluate the course of bipolar illness, especially during drug efficacy studies. The most common rating scales include the Young Mania Rating Scale (YMRS), most often used in clinical trials; the Depression and Mania Scale (DMS-D&M); the Schedule for Affective Disorders and Schizophrenia (SADS); the Hamilton Depression Scale (HAM-D); the Clinical Global Impression Scale (CGI); the Global Assessment Scale (GAS); and the Brief Psychiatric Rating Scale (BPRS).¹

The classification of mood disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) is shown in Table 1. In bipolar I, there has to be at least one manic or mixed episode with or without a depressive episode. Bipolar II must include a major depressive episode with at least one hypomanic episode.² Specifiers describing the course of episodes include rapid cycling (four or more episodes per year) and mixed states. These specifiers become important when selecting pharmacotherapy.

Epidemiology

Approximately 0.8% of the adult population is affected with bipolar I disorder (estimated range, 0.4%–1.6%), which is fairly gender-neutral. Bipolar II disorder affects approximately 0.5% of the population over the course of a lifetime³ and is more common in women. There do not appear to be significant differences in the prevalence of either disorder among racial groups.

According to the Epidemiologic Catchment Area study, the mean age of onset of bipolar disorder is 21 years.⁴ Studies that evaluate the age at onset classified by 5-year intervals find the peak age at onset of first symptoms to be between ages 15–19, closely followed by ages 20–24. In many cases, 5 to 10 years may elapse from the onset of illness to the first treatment or hospitalization. While once thought to occur rarely in childhood, bipolar disorder is gaining early recognition even in prepubertal children.⁵ The index episode in men is generally a manic episode (Table 2), while the first episode in women is likely to be a depressive episode. Patients may experience a number of episodes of depression before a manic episode occurs.⁶ Risk factors for bipolar disorder include a positive family history, seasonal changes, environmental stressors, history of electroconvulsive therapy (ECT), and antidepressant use.

Data strongly suggest that bipolar disorder is a genetic illness.⁷ Higher rates of mood disorder are found in first-degree relatives of patients with bipolar disorder than in relatives of non-psychiatrically ill control populations. However, the mechanism of transmission remains unclear, as is the effect of environmental stressors. Still, a positive family history of any mood disorder, and specifically bipolar disorder, adds strong evidence for the diagnosis of a mood disorder in a patient demonstrating mostly symptoms of psychosis.

Pathophysiology

The pathophysiology of bipolar disorder is not well understood. Alterations in neurotransmitters including norepinephrine, serotonin, and dopamine most likely play a critical role. Changes in activity of gamma aminobutyric acid and acetylcholine may also be involved. Other theories include behavioral sensitivity, electrophysiologic kindling, changes in electrolyte balance, alterations in membrane/secondary messenger systems, and circadian rhythm resynchronization.¹

Treatment Approach

Currently, there is no cure for bipolar disorder. However, treatment can decrease the associated morbidity and mortality. Goals of treatment are to decrease the frequency, severity, and psychosocial consequences of episodes and to improve psychosocial functioning between episodes. Some patients with severe and chronic impairments will need specific rehabilitative services. The treatment of bipolar disorder is complex, due to wide patient variability in clinical presentation, severity, and frequency of episodes. It is critical that treatment be individualized and consider both pharmacologic and nonpharmacologic approaches.^1,8-12
Drug Therapy: Generally, manic episodes are initially treated with lithium, valproate (VPA), or carbamazepine (CBZ). This list may now include olanzapine due to its recent FDA-approved indication. Adjunctive agents, such as benzodiazepines, may be useful for associated symptoms, such as insomnia or anxiety.^1,13,14 Lithium has been the most well-studied drug in both short-term and long-term trials. However, due to its side effect profile, narrow therapeutic window, and patient preference, the anticonvulsants (valproate in particular) have gained popularity.^15,16 Valproate may also be useful in manic patients who do not respond to lithium, patients with mixed mania (concurrent symptoms of mania and depression), or who cycle rapidly.¹⁶ Recurrent manic episodes can be treated with either lithium, CBZ, or VPA, along with adjunctive benzodiazepines for anxiety and insomnia.

More severe manic episodes associated with psychosis or agitation often require a mood stabilizer plus an antipsychotic or benzodiazepine until manic symptoms resolve. If the patient does not respond in 2–4 weeks, a second mood stabilizer may be added. If the patient remains unresponsive, an alternative mood stabilizer, or ECT may be useful to quickly reduce manic symptoms.^1,8

Once stabilized, most patients require long-term (or prophylactic) therapy to prevent or attenuate future episodes.⁹ Maintenance therapy with a mood stabilizer is recommended for any patient with at least two major episodes or after a particularly severe episode. Long-term treatment is also indicated in patients with a rapid onset of manic symptoms, patients with frequent episodes (more than one/year) and patients with a significant family history of bipolar disorder.¹ Lithium is the only FDA-approved maintenance treatment at this time.

Even when patients are continued on appropriate maintenance therapy, they can experience episodes of hypomania or depression. These may require short-term adjunctive treatment with antipsychotic or antidepressant agents.¹⁰ Patients maintained on lithium who show symptoms of depression should be evaluated for lithium-induced hypothyroidism.⁹ Rapid cyclers may have subclinical hypothyroidism and require thyroid supplements.¹⁷

Single drug therapy is preferred for patients requiring long-term treatment. Combinations of mood stabilizers (lithium plus VPA or CBZ, or VPA plus CBZ) may be indicated for certain patients, including those with mixed episodes and rapid cyclers.^11-12 Combinations of drugs may also be necessary to adequately treat refractory patients or continuous cyclers. Combination therapies may include mood stabilizers plus clonazepam, other benzodiazepines, or antispychotic agents. Discontinuing lithium therapy must be undertaken with great care, as stopping effective prophylaxis can increase the risk of relapse and may cause a more severe and nonresponsive type of disorder. It is not clear if the same risk applies to the discontinuation of other mood stabilizers.^1,15
Electroconvulsive Therapy: ECT is an effective alternative treatment for severe mania, psychotic depression, and mixed states with high suicidal risk. It may also be used in pregnant women who cannot take lithium, CBZ, or VPA.^8-9 ECT has approximately an 80% response rate. Preliminary data suggest that bilateral ECT may be more effective than unilateral treatment in mania.¹¹ Acute neurotoxicity and delirium have been reported in patients receiving ECT with lithium (even at reduced doses). Lithium should be withdrawn and discontinued at least two days before ECT and should not be resumed until 2–3 days after the last ECT.¹¹ Since CBZ, VPA, and benzodiazepines have anticonvulsant properties, these drugs should also be tapered down and discontinued prior to ECT.
Counseling: Because of the chronicity and recurrence of bipolar illness, patients (and family members) need education and supportive therapy. Bipolar disorder is most effectively treated with a combination of medications and adjunctive “supportive” or “insight-oriented” psychotherapy (individual, group, or family).¹³ After a manic episode, bipolar patients often feel ashamed of their behavior during the episode (e.g., inappropriate behavior, aggression, spending money, sexual indiscretions). They may lack self-confidence, question their judgment, and have difficulties with interpersonal relationships. Bipolar patients often worry about recurrent episodes and fear they will transmit the illness to their offspring. Patients should be educated about psychosocial or physical stressors that may precipitate episodes (e.g., changing jobs, moving, childbirth, sleep deprivation, jet lag, bereavement) and counseled about how to cope with stressful life events.¹⁴ They should be educated about recognizing the signs and symptoms of mania and depression and the importance of complying with treatment. Patients should be encouraged to chart target symptoms, to help them recognize mood changes, and to seek treatment as soon as possible.

Pharmacotherapy

Algorithms have been developed to guide the selection of mood stabilizers and combination therapies. The American Psychiatric Association (APA) published guidelines for the treatment of patients with bipolar I disorder in 1994.¹⁵ The guidelines include information on the diagnosis, clinical course, epidemiology, and treatment for bipolar disorder. However, the APA guidelines should not be considered the absolute standard of care due to the variability of bipolar disorder and the need to individualize therapy. Other treatment protocols and algorithms have also been published.^16,19,20
Lithium: Used for many years for the treatment of various mood disorders, lithium has been considered the drug of choice for bipolar disorder. However, its narrow therapeutic window requires an appropriate workup and monitoring to prevent avoidable toxicities (Table 3). The workup should be performed prior to initiating lithium therapy, or on admission while the patient is continuing to take lithium. It should be repeated one month after the patient stabilizes on the lithium regimen. After this, the complete laboratory assessment should be repeated at least annually. In general, the plasma concentrations during long-term therapy should be maintained in the range 0.8–1.0 mEq/L. Table 4 outlines lithium serum concentrations in relation to side effects. In addition to its adverse effect profile, lithium can be involved in a number of drug interactions. Approximately 20%–40% of patients cannot tolerate the adverse effects or do not respond to lithium despite therapeutic plasma concentrations.¹¹ Patients who experience rapid cycling, mixed episodes or severe manic stages are often resistant to monotherapy with lithium.^10,20

Valproic Acid: Valproic acid (VPA) was initially marketed as an anticonvulsant. It is manufactured as sodium valproate, valproic acid, and divalproex sodium. Valproate sodium is converted to VPA in the stomach, and divalproex sodium is converted to VPA in the small intestine. Divalproex sodium was approved by the FDA in 1995 as a mood stabilizer for the treatment of mania associated with bipolar disorder. It has been demonstrated to be equal in efficacy to lithium in patients with pure mania. It may be more effective than lithium in subtypes of bipolar disorder, including rapid cycling, mixed mania, secondary bipolar disorder and in patients with comorbid substance abuse.^23-29

A number of factors may predict a positive response to VPA. Patients who cycle rapidly, experience dysphoria or depression during the manic episode, or suffer concomitant panic attacks may respond to VPA. Patients whose mania is associated with abnormal EEG findings, organic mental disorders, head trauma, or mental retardation may also respond.^24,28-30 When VPA is administered with lithium, CBZ, antipsychotics or benzodiazepines, antimanic efficacy may be increased.²³ Cyclothymia (marked mood swings, within normal limits) and mood cycling in bipolar II disorder may respond to lower doses VPA (125–500 mg/d).³¹ VPA is usually well tolerated and has a relatively low incidence of adverse effects.²³ The most frequently reported adverse effects include GI effects and sedation. GI effects can include nausea, vomiting, epigastric cramping, dyspepsia, indigestion, and anorexia. These symptoms are usually temporary and can be offset by giving the drug with food, starting at a low dose and titrating slowly, and using the delayed-release product (divalproex sodium).

VPA may be associated with drowsiness, ataxia, lethargy, and a fine hand tremor. Other adverse effects can include alopecia, hair changes, pruritus, weight gain, inhibition of platelet aggregation, and transient elevations of liver enzymes.^23,24 Patients should be monitored for thrombocytopenia via platelet counts and physical examination for bleeding and bruising. Since thrombocytopenia usually occurs at higher doses and may be dose-related, this could be managed by reducing the dose and closely monitoring platelet counts. Hepatitis has been reported rarely (1 in 20,000 patients). Liver function tests should be obtained at baseline and at 6- to 12-month intervals. Younger patients, in particular, should be monitored for clinical signs of hepatic dysfunction. VPA should not be administered to patients with hepatic disease or significant hepatic dysfunction, or during the first trimester of pregnancy, as it has been associated with a 1%–2% risk of neural tube birth defects. It is excreted in human breast milk. To date, no adverse effects have been reported in nursing infants of mothers taking VPA.

VPA can be involved in numerous and complex drug-drug interactions. Additive CNS effects can occur when VPA is administered with other drugs that are CNS depressants. VPA can increase carbamazepine concentrations via displacement of CBZ from plasma protein-binding sites. CBZ, through induction of hepatic enzymes, can increase VPA metabolism and decrease VPA plasma concentrations. If CBZ and VPA are administered together, blood levels of both agents should be monitored closely.^8,10,23,32 The hematologic effects of VPA may potentiate the anticoagulant effects of warfarin and aspirin. Valproic acid can also cause abnormal thyroid function and false elevations in urine ketones.

Patients are initiated on VPA at a dose of 250–750 mg/day (5–10 mg/kg/day), given in divided doses. The dose can be titrated up by 250 mg every two or three days to a maximum of 60 mg/kg/day (750–3,000 mg/day).⁸ Higher initial doses of VPA (20 mg/kg/d or 1,200–1,500 mg/d in divided doses) have been used in acutely agitated manic patients to more rapidly achieve therapeutic serum concentration.³³

As therapeutic plasma concentrations for VPA in bipolar disorder have not been established, the anticonvulsant range of 50–125 mcg/mL, taken 12 hours after the last dose, is commonly used for monitoring. Patients with acute mania may require concentrations up to 150 mcg/mL. VPA concentrations up to 200 mcg/mL have been tried in some resistant bipolar cases but may increase the risk of adverse effects.¹¹
Carbamazepine: Carbamazepine (CBZ) was the first medication extensively studied as an alternative treatment for bipolar disorder.³⁴ It is most commonly used as an anticonvulsant and for syndromes such as trigeminal neuralgia. Studies have demonstrated that CBZ is effective for the acute treatment of manic episodes. Studies comparing CBZ to lithium show mixed results.^11,15 Some evidence suggests that patients with severe mania, rapid/continuous cycling, or mixed episodes may respond to CBZ versus lithium.^10,34 In most studies, approximately 60% of manic subjects who were first unresponsive to lithium responded to CBZ within the first several days of treatment.⁸ Although CBZ appears effective in treating the acute phase of bipolar disorder, some reports suggest that CBZ loses its effectiveness with time. Additional studies are needed to confirm its long-term efficacy compared to other mood stabilizers.³⁵ The addition of CBZ to lithium should be tried in rapid cycling patients or in those who fail on lithium therapy alone.¹¹ Once patients have responded, the lithium should be slowly withdrawn over several months (to minimize the risk of relapse), and the patient continued on CBZ therapy alone. CBZ is also beneficial in managing aggressive behavior and has been used for alcohol and benzodiazepine withdrawal syndrome. CBZ is recommended over lithium for patients with dementia and organic causes of mania (e.g., hypomania induced by levodopa, head trauma, CNS pathology, multiple sclerosis, myasthenia gravis).⁸ Other factors that may predict a positive response to CBZ include severe manic episodes, anxiety, dysphoria, schizoaffective/psychotic features, and brain damage (abnormal EEG). Patients with early onset manic episodes and a negative family history for mood disorders may also have a positive response to CBZ.³⁰

Central nervous system effects can occur in up to 60% of patients receiving CBZ and are the most common adverse effects reported.³⁶ These include drowsiness, dizziness, fatigue, clumsiness, ataxia, vertigo, blurred vision, diplopia, nystagmus, dysarthria, confusion, and headache. CNS side effects generally occur early in therapy, when plasma concentrations are >4 mcg/mL. These can be offset by starting with low doses and titrating the dose upward to achieve the desired therapeutic response. Side effects may also be alleviated rapidly by dose reduction or giving a larger bedtime dose. GI side effects, including nausea, vomiting, abdominal pain, diarrhea, constipation, and anorexia, are also common and can occur in up to 15% of patients.³⁶ They also occur early in therapy and may be minimized by administering the drug with food or reducing the daily dose.

Because bone marrow suppression is rare, the guidelines for monitoring hematologic changes with CBZ are now less extensive than previous recommendations.³⁷ However, patients should be monitored for the development of leukopenia. Patients with pre-existing low-normal or below-normal white blood cell (WBC) and neutrophil counts should be monitored even more closely (every two weeks for the first one to three months of treatment), as they may be at increased risk for developing leukopenia.^10,37 A transient decrease in WBC and platelets can occur during the first few months of treatment (affecting approximately 12% of children and 7% of adults) and does not require discontinuation of the drug.³⁷ CBZ-induced leukopenia has been reversed in some patients by adding lithium, which causes leukocytosis.³⁸ If symptoms of bone marrow suppression occur (sores, infections, fever, fatigue, pettechiae, or easy bruising), a CBC with differential, platelet count, and liver enzymes should be done to rule out aplastic anemia, agranulocytosis, or thrombocytopenia.⁸ If leukopenia occurs (defined as WBC <3,000/mm³ or neutrophil counts <1,000/mm³), the dose should be reduced or the drug discontinued.³⁷ It may be possible to restart CBZ at lower doses when WBC and neutrophil counts return to normal. The highest period of risk for hematologic reactions is during the first year of treatment, so patients should be monitored more closely during this time.

Carbamazepine can cause hypersensitivity reactions, dermatologic reactions, hyponatremia and mild temporary increases in liver enzymes. The safety of CBZ during pregnancy and lactation has not been established. CBZ has been considered an alternative for lithium during pregnancy, but caution should be used in prescribing it during the first trimester of pregnancy or during breast feeding.³⁶ CBZ is known to interact with numerous drugs because of its effect on the hepatic microsomal enzyme system.^39,40

Lithium and CBZ may be synergistic in the treatment of refractory bipolar patients (e.g., CBZ can be added to lithium therapy for nonresponsiveness and lithium may potentiate the antidepressant response for CBZ nonresponders). Neurotoxicity has been observed when lithium and CBZ are combined, despite therapeutic plasma concentrations of both drugs.⁴¹ Clinical symptoms included confusion, drowsiness, generalized weakness, lethargy, coarse tremor, hyperreflexia, and cerebellar signs. The neurotoxic syndrome usually resolves quickly when one or both agents are discontinued. Lithium and CBZ may have additive effects in suppressing thyroid function, so regular monitoring of thyroid indices is advisable during combination therapy.³⁸

In the majority of clinical trials, CBZ has been combined with antipsychotics or antidepressants with no adverse effects. Neurotoxicity has been reported with the combination of CBZ and haloperidol (e.g., lethargy, confusion, slurred speech, disorientation), but these symptoms usually clear quickly with discontinuation of the drugs. When CBZ is combined with lithium, VPA, or antipsychotics, lower doses and blood levels of CBZ should be used to minimize neurotoxicity. Concomitant drug therapies that inhibit the CYP450 3A4 isoenzyme system may result in CBZ toxicity. These include cimetidine, erythromycin, isoniazid, verapamil, diltiazem, propoxyphene, nefazodone, ketoconazole, itraconazole, and fluoxetine.^10,36,39-42 CBZ may increase the oxidative metabolism of other drugs (e.g., antipsychotics, antidepressants, phenytoin, VPA, benzodiazepines, doxycycline, warfarin, theophylline, oral contraceptives), and patients should be closely monitored for loss of efficacy of concomitant medications.

For an acute manic episode, CBZ should be initiated at a dose of 200–400 mg/day (divided doses) and then titrated up by 200 mg every three or five days, up to a dose of 600–1,200 mg/day in divided doses (two to four times daily). If the patient remains nonresponsive after two weeks, the dose can be slowly increased to achieve plasma concentrations of 6–12 mcg/mL.⁸ Patients who are treatment-resistant may require plasma concentrations up to 12–14 mcg/mL. Rapid cyclers or those who experience mixed episodes may also require higher doses. CBZ can be started at lower initial doses (e.g., 100–200 mg/day, and increased by 100–200 mg/day every three or five days) when the patient is not experiencing symptoms. When CBZ is discontinued, it should be tapered down to avoid exacerbation of bipolar symptoms or seizures in epileptic patients. Despite a poor correlation between plasma concentration and clinical response, CBZ plasma concentrations are generally maintained in the range of 6–12 mcg/mL. Due to autoinduction, plasma concentrations of CBZ may decrease during the first month of therapy and an increase in dose may be necessary. Autoinduction can continue for up to 30 days. Steady-state concentrations should be obtained twice a month during the first two months of treatment. Once steady-state concentrations are stabilized, plasma CBZ concentrations can be monitored every 2–3 months. For patients stabilized for over a year, less frequent monitoring may be indicated (e.g., two to three times per year). Baseline laboratory testing should include a complete blood count (CBC) with differential and platelet count (possibly a reticulocyte count and serum iron), liver enzymes, thyroid function, serum electrolytes, BUN, urine specific gravity, serum creatinine, neurologic assessment, and ECG if the patient is older than 40 years old or has pre-existing cardiac disease.¹⁰
Antipsychotics: Antipsychotic agents can be used for an acute manic episode and may be combined with a mood stabilizer for additive or synergistic effects.⁴³ Typical antipsychotics such as chlorpromazine and thioridazine are more sedating and cause more orthostatic hypotension, but cause fewer extrapyramidal side effects (EPS). Haloperidol, fluphenazine, and thiothixene cause less sedation and orthostasis but have a greater likelihood of causing EPS. Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone) cause less EPS and tardive dyskinesia. These newer agents have been used alone and in combination with mood stabilizers for bipolar disorder.^44-46 Clozapine appears to have efficacy in patients with refractory bipolar disorder, including rapid cyclers.⁴⁷ There is ongoing research on the role of the atypical antipsychotic agents. These agents appear to be effective for bipolar mania, mixed episodes, schizoaffective disorder, and psychosis associated with bipolar disorder without causing significant EPS or tardive dyskinesia.

Olanzapine is the first atypical agent approved by the FDA for the short-term treatment of acute manic episodes.²¹ It was evaluated in two double-blinded placebo-controlled trials in patients with manic or mixed-manic episodes associated with bipolar I disorder.^45-47 The FDA’s approval of olanzapine for the treatment of acute manic episodes associated with bipolar disorder was based on results from two placebo-controlled trials involving patients with a primary diagnosis of bipolar disorder: one three-week trial involving 67 patients and one four-week trial involving 115 patients.^45,46 The trials included patients with manic and mixed episodes, with or without psychotic features, and with or without a rapid-cycling course. Olanzapine led to a significant improvement in mania, as measured by the Young-Mania Rating Scale (YMRS), and was well tolerated.

One hundred and thirteen patients from the three-week trial entered an open-label extension phase (49 weeks) and received 5–20 mg/day of olanzapine for an average of 201 days. Patients showed statistically significant improvement in manic symptoms. There was no significant difference in antimanic response based on the presence or absence of psychotic features at the index episode. Cognitive functioning (PANSS Cognitive component) and PANSS Hostility factor was significantly improved. There were improvements in mean change from baseline to endpoint on the Simpson-Angus and Barnes Akathisia, and no statistically significant worsening on the AIMS total. No patient experienced tardive dyskinesia during the study. Significant improvement was noted in the HAMD-21. These results suggest that olanzapine is safe and effective in the long-term treatment of mania, with or without psychotic features, and appears to exert a beneficial effect on cognitive functioning as measured by the PANSS Cognitive component. Olanzapine was well tolerated, with very few EPS and no clinically significant changes in labs, vitals, or ECG parameters.⁴⁸

Olanzapine has also been compared to lithium in mania and shown to be at least as effective in the treatment of acute mania and to be free of significant EPS.⁴⁹ Doses ranged from 5–20 mg/day. The recommended starting dose for olanzapine is 15 mg/day. A study was recently completed evaluating the efficacy of olanzapine as an add-on mood-stabilizer to existing valproate or lithium therapy in the acute treatment of bipolar I disorder. If olanzapine is found to be safe and effective, with an improved safety profile compared to typical antipsychotics, atypical antipsychotics may become the preferred add-on therapy, replacing typical antipsychotics.

Antipsychotic agents are often prescribed for acute mania, as they work more rapidly than lithium to control psychotic symptoms and psychomotor agitation.^11,50 Doses should be individualized; relatively low doses may be effective in some patients while psychotic or agitated patients may require higher doses.¹¹ The antipsychotic agent should be slowly tapered and discontinued once the acute manic episode is controlled (usually in 7–14 days). Whenever possible, patients should be maintained only on a mood stabilizer to minimize the risks associated with the intermittent administration of antipsychotic medications (i.e., tardive dyskinesia).^10,49 Although patients may require long-term use of an antipsychotic along with a mood stabilizer, there are little data to support the use of antispychotic agents as monotherapy for long-term treatment of bipolar disorder.¹⁶ Since atypical antipsychotics have a superior safety profile compared to traditional antipsychotics, their role in acute mania is being redefined.

Cases of neurotoxicity (e.g., confusion, hyperthermia, severe rigidity, mutism, urinary incontinence, tremor, and irreversible tardive dyskinesia) have been reported with the combined use of lithium and antipsychotics.¹⁰ Neurotoxicity is more common with higher lithium and antipsychotic doses if there is preexisting encephalopathy, or in elderly patients. Symptoms usually disappear if both drugs are discontinued and if lithium is reinstituted at lower doses. Lithium and antipsychotics may be safely given together if lower doses are used and if lithium plasma concentrations are maintained below 1.0 mEq/L.¹⁰ Patients receiving both lithium and phenothiazines may have a higher RBC/plasma lithium ratio, and haloperidol can increase plasma lithium concentrations.
Benzodiazepines: Benzodiazepines can serve as alternatives to antipsychotic therapy in acutely manic patients and have been used in conjunction with mood stabilizers during the acute mania phase.⁸ They are generally well tolerated and, at higher doses, can rapidly treat patients with agitation.¹¹ Benzodiazepines have their best efficacy in managing acute mania or breakthrough symptoms, but are less effective for maintenance therapy.¹⁰ Lorazepam is initiated at a dose of 0.05 mg/kg TID and can then be titrated upwards. When combined with antipsychotic agents, lower doses of benzodiazepines should be used.¹¹ When patients are stabilized, doses of benzodiazepines should be tapered down to the lowest effective dose. Upon discontinuation, the benzodiazepine dose should be slowly reduced over several weeks to avoid withdrawal symptoms. A potential drug interaction can occur between lithium and clonazepam, resulting in lithium toxicity. This may be either a pharmacokinetic interaction that results in increased lithium concentrations or a synergistic neurotoxic effect.⁵¹

Drugs that reduce the availability of NE have been suggested for use in bipolar disorder. Both clonidine and propranolol have been utilized in a few patients, with some success.^8,10 GABA-mimetic agents such as clonazepam may be effective in high doses for controlling acute mania, but this may be secondary to sedation instead of a specific antimanic effect.
Calcium Channel Blockers: If the calcium hypothesis of bipolar disorder is correct, then calcium channel blockers such as verapamil should be effective.^10,52 Some data suggest that verapamil is effective in mania, but studies show conflicting results.¹¹ Verapamil and diltiazem may increase plasma concentrations of CBZ, lower plasma lithium concentrations, and the lithium–verapamil combination may increase cardiotoxicity due to additive calcium antagonist effects. Little information is available about the efficacy of other calcium antagonists but a few case reports suggest they also have antimanic effects.⁸ Verapamil may be considered a fourth-line agent if patients cannot be treated with lithium, CBZ, or VPA. Patients who respond to lithium but cannot tolerate its adverse effects may be candidates for calcium channel blockers.
Other Agents: Growing interest in two new anticonvulsants (gabapentin, lamotrigine) has surfaced recently. Research into gabapentin’s mood stabilizing effects is being conducted and preliminary data show some positive effects.^53,54 Therapy is initiated at a dose of 300 mg TID, with titration to 3,600 mg/day, if needed. Gabapentin can cause Gl upset, somnolence and dizziness.⁴³ Interest in lamotrigine’s mood-stabilizing effects has resulted in its use in the treatment of bipolar disorder, and several multicenter studies are in process. Lamotrigine has been reported useful in treating refractory bipolar depression.⁴³ Its major adverse effects include Gl upset, dizziness, ataxia and rash. When used in combination with valproic acid, the incidence of rash appears to be greater. Lamotrigine is initiated at a dose of 25 mg/day for the first week, and increased to 50 mg/day during the second week. The usual dosage range is 50–250 mg daily, although some patients may require higher doses. A slow titration is necessary in order to reduce the incidence of rash appears to be greater. Lamotrigine is initiated at a dose of 25 mg/day for the first week, and increased to 50 mg/day during the second week. The usual dosage range is 50–250 mg daily, although some patients may require higher doses. A slow titration is necessary in order to reduce the incidence of rash. For patients maintained on valproate, the initial dose of lamotrigine should be 25 mg every other day for the first two weeks. Multicenter clinical trials with lamotrigine in doses of 50 mg, 200 mg and 400 mg versus lithium and placebo are underway. Until more data are available, lamotrigine should be used as a late option.

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