KatCarney

Side Effects in the Treatment of Bipolar Affective Disorder


Henry A. Nasrallah, MD, Irving Kuo, MD
Medscape Psychiatry & Mental Health 8(2), 2003. © 2003 Medscape

Posted 08/29/2003
Introduction
Bipolar affective disorder can be a difficult and complex disorder to treat. The clinician needs to be aware that there are multiple facets of this disorder that require different treatment strategies, especially in light of the various mood states that can exist within a bipolar patient, including manic, depressive, and mixed states. Within the manic phase of the illness, the clinician also needs to be cognizant of whether this is a classic euphoric manic phase or possible irritable or dysphoric state. Patients with rapid cycling bipolar disorder or with psychotic features present additional challenges to the treating psychiatrist. Comorbid conditions such as substance abuse and anxiety disorders are common in bipolar patients and often complicate the treatment course. Many, if not most, bipolar patients require multiple medications in order to effectively control their symptoms. The treating clinician needs to be thoroughly familiar with the various side effect profiles of the array of pharmacotherapeutic options available for treatment, especially when utilizing multiple medications in the same patient. The safety and tolerability of any pharmacologic interventions are of paramount importance when treating bipolar patients due to the special vulnerability of this population to poor or erratic adherence with treatment.

Side Effects With Mood Stabilizers
Mood stabilizers are the first-line treatment of choice for bipolar affective disorder. Currently, the approved mood stabilizers for bipolar disorder are lithium, divalproex, and lamotrigine. They are commonly used either as monotherapy or in combination with an atypical antipsychotic. Lithium was the first mood stabilizer utilized for bipolar disorder, and side effects of this medication are well known. Lithium has a very narrow therapeutic window and must be dosed and followed carefully in order to maintain patients in the effective, nontoxic range. Up to 75% of patients will suffer from some type of side effects from lithium.[1] Common side effects include tremor, polyuria, polydipsia, weight gain, gastrointestinal symptoms (nausea, vomiting, diarrhea), dyscoordination, acne, and edema. Most of these side effects are dose related. Lithium also can cause some benign ECG changes and occasionally can be associated with cardiac conduction abnormalities. Lithium also has been associated with the exacerbation of pre-existing cardiac arrhythmias. Approximately 5% to 35% of patients will develop hypothyroidism while on lithium.[1,2] Longer-term usage of lithium also has been associated with renal changes, including interstitial fibrosis, tubular atrophy, and occasionally glomerular sclerosis. Lithium-induced renal insufficiency has been reported, especially for patients on the medication for 10 or more years. Toxic side effects (serum levels >/= 2.0 meq/L) include worsening of side effects seen with a therapeutic serum level including coarse tremor, increased nausea and diarrhea, confusion, and blurred vision. Higher levels can lead to profound neurologic effects (seizures, coma), cardiac dysrhythmias, and death.

Divalproex has been used extensively over the last decade in the treatment of bipolar affective disorder. It appears to be especially useful in the treatment of mixed and rapid cycling states. Unlike lithium, divalproex has a much wider therapeutic window, and purposeful overdose of this medication appears to be safer than with lithium. Common side effects of this medication include sedation, gastrointestinal symptoms, tremor, and a benign increase in hepatic transaminase levels. These side effects can usually be managed with dosage adjustments. Other side effects include weight gain and alopecia, both of which can be distressing to patients. Divalproex also has been associated with leukopenia and thrombocytopenia, both of which are usually benign in nature. Both of these hematologic effects are usually reversible with either dose reduction or discontinuation of the medication. Polycystic ovarian syndrome (PCOS) has been allegedly associated with divalproex treatment, but this relationship is not clear and there are indications that PCOS may be a comorbidity of bipolar and epilepsy patients before treatment with divalproex. Although rare, this medication also has been associated with acute pancreatitis.

Lamotrigine has recently been approved for the maintenance treatment of bipolar patients. It has been shown that lamotrigine treatment can reduce the risk of relapse of both depressive and manic phases of the illness. Side effects include headache, dizziness, ataxia, blurred or double vision, and rash. The incidence of rashes is approximately 10%, with the incidence of a serious rash (Stevens-Johnson variety) estimated to be 0.08% to 0.13%.[3] Rash is most commonly seen early in the course of treatment (within the first 8 weeks) and can be minimized by a slow titration schedule. Clinicians should also be aware of pharmacokinetic interactions when combining this medication with other mood stabilizers/anticonvulsants, such as carbamazepine, which induces oxidative enzymes and accelerates the metabolism of lamotrigine, thereby diminishing its serum concentrations. Divalproex can inhibit lamotrigine's metabolism and may significantly increase its blood levels.

Although not officially approved for usage in bipolar disorder, carbamazepine is often utilized in the treatment of bipolar mania. However, this medication is associated with multiple side effects, and up to 50% of patients receiving this medication complain of side effects.[4] Side effects include neurologic symptoms such as ataxia, diplopia, and fatigue. Leukopenia, thrombocytopenia, increased hepatic enzymes, and hyponatremia are also associated with carbamazepine treatment. Rarely, more serious and side effects such as aplastic anemia, hepatic failure, exfoliative dermatitis, and pancreatitis have also been associated with this medication. Carbamazepine is also associated with multiple drug-drug effects, and can be a powerful hepatic inducer of cytochrome enzymes that hasten the clearance of several medications. This may limit its utility in patients who are receiving other medications.


Side Effects of Atypical Antipsychotic Agents
The atypical antipsychotic medications have been utilized with increasing frequency in bipolar affective disorder, both to control mania as well as to treat associated psychotic symptoms. The incidence of extrapyramidal side effects (EPS) and the subsequent risk for tardive dyskinesia is much lower with atypicals than with conventional antipsychotics. This is especially relevant for bipolar patients, who appear to be at increased risk for acute movement disorders as well as tardive dyskinesia.

Olanzapine currently is the only approved atypical antipsychotic for the treatment of acute mania, either as a monotherapy or in conjunction with another mood stabilizer. Common side effects of olanzapine include somnolence, orthostatic hypotension, syncope, dry mouth, and increased appetite and weight gain. The latter symptoms of increased appetite and significant weight gain have been especially difficult for some patients, as the increase in weight can be significant (average of 27 pounds after one year according to study by the manufacturer[5]) and may lead to diabetes,[6] dyslipidemia, hypertension, and other components of the metabolic syndrome.[7]

Although the other atypical antipsychotics have not yet been approved for the treatment of bipolar affective disorder, they are commonly utilized for the treatment of mania. Placebo-controlled clinical trials have been completed and submitted to the US Food and Drug Administration for all the atypicals. Risperidone has recently been studied in the treatment of manic symptoms and has shown efficacy in this area.[8] Side effects of this medication include an increased incidence of EPS, mainly with higher dosages, increased prolactin levels, moderate weight gain, headache, and dizziness.

Quetiapine is another atypical agent whose several controlled trials have been completed for the treatment of bipolar disorder, either as monotherapy or as an add-on to a mood stabilizer such as lithium or divalproex.[9] The side effects of this medication include somnolence and occasional hypotension. Quetiapine has a placebo-level incidence of EPS and prolactin.

Both ziprasidone and aripiprazole have also been studied for the treatment of acute bipolar mania. Ziprasidone, in one study with inpatients with acute mania, was found to be superior to placebo.[10] Side effects of ziprasidone included sedation and some widening of the QTc interval. Aripiprazole, a partial dopamine and serotonin agonist recently approved for the treatment of schizophrenia, has also been shown in controlled studies to be effective in treating bipolar mania.[11] Side effects of this drug include gastrointestinal effects, insomnia, and somnolence. Both of these medications also have a very low incidence of EPS, weight changes, or prolactin elevation.


Side Effects of Antidepressants
Antidepressant medications have been utilized for the treatment of the depressive phase of bipolar disorder. The newer antidepressants have been widely used in this regard, displacing the older antidepressants such as the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). The newer antidepressant medications appear effective in treating bipolar depression and also have been associated with less medication-induced switching to a manic episode when compared with the TCA and MAOI agents.[12] In addition, because of the highly increased incidence of suicidal behavior in bipolar depressed patients, the newer antidepressants appear to be safer in terms of overdose lethality than the TCA or MAOI antidepressants. Selective serotonin reuptake inhibitor (SSRI) antidepressants in combination with a mood stabilizer have been the most common treatment strategy for bipolar depression. Common side effects of SSRIs include gastrointestinal effects, sexual dysfunction (mainly decreased libido and delayed ejaculation), insomnia, or sedation. Of the non-SSRI newer antidepressants, bupropion has been utilized because of its low rate of switching to mania. However, it can be anxiogenic, can cause insomnia, and is contraindicated in patients with a seizure or eating disorder. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, appears to have a slightly higher switch to mania rate, and has many of the side effects of the SSRIs plus hypertensive effects. Mirtazapine, an alpha 2A antagonist, is another widely utilized antidepressant. Its prominent side effects include sedation and weight gain.

Antidepressants should be avoided in bipolar patients (especially bipolar II) who are rapid cycling as they can precipitate or exacerbate this condition.[13] In addition, tapering and discontinuation of antidepressants are recommended in patients with a mixed or manic episode as they can precipitate or exacerbate such episodes.


Side Effects and Polypharmacy
As stated above, the use of multiple medications, a rational polypharmacy approach, has become commonplace in the treatment of bipolar disorder. The combination of two mood stabilizers, a mood stabilizer with an antipsychotic agent, or a mood stabilizer with an antidepressant has become accepted as standard clinical care. The clinician, however, should be aware of the potential for side effects to be additive. For example, both lithium and divalproex can cause weight gain, and the addition of an antipsychotic medication like olanzapine can make this situation even worse for the patient. The combination of two agents such as divalproex and olanzapine or quetiapine can cause undue sedation. The use of lithium and divalproex together can lead to a significant tremor. Also, the additive gastrointestinal side effects of a mood stabilizer such as lithium or divalproex with an SSRI may also distress the patient. Thus, the clinician needs to be aware of the side effects of each separate agent and the potential effects of combining these medications. Medication compliance has often been a challenging issue for clinicians when treating bipolar patients over the long-term, and the tolerability of these medications is one of the key factors in patient treatment compliance.


Conclusion
The multiple facets of bipolar affective disorder demand that psychiatrists be evidence-based and judicious in the medications they choose to prescribe for their bipolar patients. They need to be aware of both the therapeutic indications of these medications as well as the potential side effects of each. The different types of medications utilized in bipolar disorder all have their unique side effect profiles, and some of them overlap in nature. The clinician needs to be aware of not only the adverse effects of each single agent, but also aware of additive effects when combining medications. Careful consideration of these factors may be crucial in the area of patient compliance and ultimately successful treatment of this serious, life-long psychiatric disorder.


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Henry A. Nasrallah, MD, Associate Dean; Professor of Psychiatry, Neurology, & Neuroscience, University of Cincinnati Medical Center, Cincinnati, Ohio

Irving Kuo, MD, Assistant Professor of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, Arkansas

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