A Review of Medication Side Effects and Treatment Adherence in Bipolar Disorder

Tanya R. Anderson, MD, Joseph F. Goldberg, MD, and Martin Harrow, PhD

Dr. Anderson is assistant professor of psychiatry in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago.

Dr. Goldberg is research scientist in the Department of Psychiatry Research at the Zucker Hillside Hospital of the North Shore–Long Island Jewish Health System in Glen Oaks, New York.

Dr. Harrow is professor in the Department of Psychiatry at the University of Illinois College of Medicine.

Disclosure: Dr. Anderson is on the speaker’s bureau of AstraZeneca. Dr. Goldberg is a consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Novartis, Organon, Ortho-McNeil, Pfizer, and UCB Pharma; is on the speaker’s bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Novartis; and has received grant and/or research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Pfizer, The Robert Wood Johnson Foundation, Shire, and UCB Pharma.

Funding/support: This work was supported in part by grant nos. MH-26341 and MH-01936 from the National Institute of Mental Health awarded to Drs. Goldberg and Harrow, by a National Allegiance for Research on Schizophrenia and Depression Young Investigator Award to Dr. Goldberg, and by an unrestricted grant from GlaxoSmithKline.

Please direct all correspondence to: Joseph F. Goldberg, MD, The Zucker Hillside Hospital, 75-59 263rd St, Glen Oaks, NY 11004; Tel: 718-470-4134; Fax: 718-343-1659; E-mail: [email protected].

Abstract

How do the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits? The growing range of pharmacotherapy options across all phases of bipolar illness should, ideally, enhance the ability of clinicians to provide optimal treatments while considering differential adverse effects and drug tolerability. Such approaches help to increase medication adherence in patients who might otherwise discontinue treatment due to adverse effects. Clinically diverse, often significant adverse effects are evident with both older and newer drug therapies for bipolar illness. Most notably, problems related to gastrointestinal upset, weight gain, glucose dysregulation, sexual dysfunction, cognitive impairment, dermatologic reactions, and central nervous system effects are a potential liability with numerous compounds. Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic agents. These include slow-dose escalations, preferential use of delayed-release formulations, and adjunctive treatments with additional agents. Clinical decisions to switch primary medications due to adverse effects—rather than treat through adverse effects—must reflect careful balancing of drug efficacy (benefits) versus side-effect liability (costs).

Introduction

Rates of medication nonadherence among patients with bipolar disorder are unacceptably high, ranging from 10% to 60% (median 40%) of patients discontinuing treatment.¹ Evidence of this high rate was shown in a recent study of the bipolar medication lithium,² which found that health maintenance organization enrollees with bipolar disorder discontinued lithium a median of only 72 days after starting it. With such high rates of treatment nonadherence in bipolar patients, it is therefore critical for clinicians to understand how the tolerability and adverse-effect profiles of newer psychotropic drugs for bipolar disorder balance against their enhanced therapeutic benefits. As such, this article provides an overview of common adverse effects associated with current pharmacotherapies for bipolar disorder, and describes strategies for their management in order to optimize treatment outcomes.

Paradoxically, while psychotropic medications are prescribed in efforts to enhance patient functionality and quality of life, they may actually create new physical, cognitive, or other problems that can jeopardize treatment adherence and physical well-being (Table). In fact, patients may interpret the adverse effects of medications such as lithium as problems that mimic physical illness and may obscure diagnostic issues related to patients with bipolar disorder.³

Additionally, while current texts and guidelines caution against or limit the use of antidepressants in patients with bipolar disorder,^4,5 data from the National Disease and Therapeutic Index indicate that antidepressants are prescribed more frequently than mood stabilizers.⁶ Therefore, common side effects associated with antidepressant use are also enumerated in this article.

Adverse Effects and Treatment Adherence

Among bipolar patients, attitudes and expectations about adverse effects appear to contribute more to medication nonadherence than do actual adverse effects themselves.⁷ That aside, the balance between therapeutic efficacy and adverse effects is illustrated in clinical trials that compare benefits versus dropout rates due to adverse effects. For example, a recent 18-month comparison of bipolar relapse prevention⁸ compared lithium or divalproex plus placebo or olanzapine. Although one might expect more dropout due to adverse effects among those taking more medications, trial completion was three times more likely for those on combination therapy (31.4%) than monotherapy (10.4%), while adverse effects were more common for those on monotherapy (9.8%) than combination therapy (16.7%). Similarly, Keck and colleagues⁹ found significantly greater medication adherence during combined maintenance treatment with lithium plus divalproex compared to either one alone, again suggesting that if combinations produce better efficacy than monotherapies, better efficacy in turn may help to promote treatment adherence.

Adverse Effects Associated with Medications Used in Bipolar Disorder

Gastrointestinal Disturbances

Nausea, vomiting, and diarrhea are commonly seen with lithium, valproate, and selective serotonin reuptake inhibitors (SSRIs). Bowden and colleagues¹⁰ demonstrated that nearly 50% of patients treated with lithium experienced nausea and diarrhea. The onset of nausea tends to be related to peak serum levels and may reflect the rapidity with which plasma levels are increased.^4,11 Therefore, temporarily reducing the dose (as long as clinical efficacy is not compromised) or prescribing a slow-release formulation may alleviate nausea and other upper gastrointestinal (GI) effects. However, in some patients, diarrhea is reportedly increased by some slow-release formulations due to more distal absorption.^12,13 Nausea may also be alleviated by taking lithium with meals.⁴ Use of lithium citrate syrup is also reported to decrease GI side effects.¹⁴

Similarly, GI disturbances are the most frequent adverse events associated with valproate. Zarate and colleagues¹⁵ demonstrated that approximately 63% of patients discontinued generic valproate treatment due to GI side effects; subsequent treatment with the enteric-coated formulation of divalproex was better tolerated. The extended-release formulation of divalproex may be associated with less nausea than the delayed-release preparation.¹⁶

All SSRIs have been shown to produce some degree of nausea and GI disturbance. Such effects appear to be transient and typically resolve within the first month of treatment.¹⁷ Gradual dose titration may be helpful in avoiding onset of these symptoms.

Weight Gain

Although weight gain is not the most common side effect associated with bipolar medication use, it may be the most distressing.¹⁸ In addition, overweight and obesity are significant public health concerns in the United States: they affect >61% of all American adults¹⁹ and are associated with hypertension, type II diabetes, and cardiovascular disease, as well as many other medical conditions.²⁰ Independent of pharmacotherapy, rates of overweight and obesity are substantially elevated among individuals with bipolar disorder and may be directly related to recurrent depressive episodes as well as poorer functional outcome.²¹

The majority of agents currently used to treat bipolar disorder have been associated with some degree of weight gain, although variability may exist across compounds. Data from a 1-year monotherapy study¹⁰ of relapse prevention comparing lithium, divalproex, and placebo demonstrate that only patients treated with divalproex experienced significantly more weight gain than those taking placebo. However, weight gain has been associated with lithium use in other reports.²² In early reports, carbamazepine was associated with less weight gain than lithium,²³ although data from a more recent controlled maintenance trial²⁴ revealed appetite increases as occurring more often with carbamazepine (33%) than lithium (17%). Weight has been shown to remain stable or slightly decrease with the anticonvulsant lamotrigine.²⁵

In both short- and long-term comparative studies of olanzapine or divalproex monotherapy in bipolar disorder, patterns of weight gain have differed with each treatment. For example, more weight gain was evident with olanzapine than divalproex during a 12-week acute mania study,²⁶ and total weight was more extensive with olanzapine than divalproex monotherapy over a 1-year relapse prevention study.²⁷ When weight gain occurs with olanzapine it tends to arise rapidly during the first few weeks and months, plateauing by 9 months.²⁸ By contrast, weight gain with divalproex appears to occur more gradually (such that, for example, the magnitude of weight gain with divalproex matched that seen with olanzapine after 9 months in a trial by Tohen and colleagues²⁷).

An inherent problem in attributing weight increases to psychotropic drug therapy involves judging the extent to which it may alternatively reflect illness-specific phenomena, such as hyperphagia, lethargy, and other vegetative signs. Further complicating the picture is the observation that some patients may be genetically predisposed to gain more weight when taking an atypical antipsychotic, such as clozapine.²⁹ This indicates that not all patients may share the same adverse effect vulnerability.

Generalizations about weight changes associated with second-generation antipsychotics are limited by intermixed data involving patients with bipolar disorder, schizophrenia, and other diagnoses.^20,28 Across diagnoses, clozapine and olanzapine appear to be associated with the most weight gain (ranging from approximately 2.7–5.3 kg).²⁰ Ziprasidone produces nominal weight gain (approximately 0.5 kg), while risperidone and quetiapine have been associated with intermediate gain (approximately 1.6–2.4 kg).^20,30 Aripiprazole appears to be associated with minimal weight gain in the existing short-term studies for bipolar disorder³¹; longer-term (ie, 1-year) trials in schizophrenia patients reveal a >7% increase in body weight for 30% of patients with low (<23) body mass index (BMI), 19% for those with normal BMI (23–27), and 8% for those with BMI >27.³²

Adjunctive treatment with the anticonvulsant topiramate may be beneficial in reducing psychotropic drug-induced weight gain. Data show that patients treated with topiramate in combination with lithium, valproate, carbamazepine, or an antipsychotic lost an average of 9.4 pounds over 5 weeks.³³ However, topiramate itself is associated with a range of side effects, including paresthesias, renal calculi, increased intraocular pressure, secondary narrow-angle glaucoma, and cognitive dysfunction.³⁴ Preliminary findings with the anticonvulsant zonisamide, which is potentially useful in bipolar disorder,³⁵ suggest that it too may be associated with weight loss.³⁶

It is often difficult for clinicians to know when it is more advantageous to attempt remedial strategies aimed at overcoming an adverse effect, such as weight gain, and when it is preferable to substitute an alternative agent. The obvious limitation of this latter strategy is that therapeutic efficacy for a given patient cannot be assumed across diverse agents, even within a given class (as exemplified by the variable efficacy across antimicrobials, antiarrhythmics, antiepileptics, and other types of medication classes).

Nonpharmacologic interventions that have shown success for psychotropic-induced weight gain include dietary counselling prior to prescribing medications,³⁷ diet programs,³⁸ exercise programs,³⁹ and behavior modification programs, although the success of behavioral programs may not always be sustained long-term.^7,40

Dyslipidemias and Glucose Dysregulation

Awareness has grown regarding the potential for individuals with bipolar disorder to be at risk for cardiovascular disease,⁴¹ as well as adult-onset diabetes mellitus.⁴² Both conventional and atypical antipsychotics have been associated with an increased risk for new-onset type II diabetes,^43,44 and some second-generation antipsychotics may impose a heightened risk for elevated low-density lipoprotein cholesterol and triglyceride levels.^44,45 The mechanisms by which conventional or second-generation antipsychotics may be associated with glucose dysregulation are likely complex and not merely the byproduct of peripheral insulin resistance due to weight gain.³¹ Serious instances of diabetic ketoacidosis have been described within weeks of beginning some second-generation antipsychotics.^31,45 A nested case study⁴³ in the United Kingdom observed that antipsychotic exposure may increase risk for type II diabetes alongside a range of other baseline risk factors, including psychiatric diagnosis, hypertension, and alcoholism.

Recently, the Food and Drug Administration requested updated product labeling for all atypical antipsychotics; this labeling includes a warning regarding the risk of hyperglycemia and diabetes.⁴⁶ However, the FDA did not address the differing amounts of risk relevant to each agent. Rather, the label only states that patients who develop suggestive symptoms during treatment with an atypical antipsychotic should be tested for diabetes. Patients at risk for diabetes (eg, those with obesity or family history of diabetes) should undergo fasting glucose testing at baseline, and periodically throughout treatment, and patients with a history of diabetes who begin taking atypical antipsychotics should be monitored for a worsening of glucose control.⁴⁶

Sexual Dysfunction

Effects on sexual function ranging from diminished libido to orgasmic and erectile dysfunction are considered to be relatively prevalent with SSRIs (incidence rates reported have been as high as 34%)⁴⁷; however, they may also occur with other psychotropics. Depression and other severe psychiatric disorders can themselves obviously contribute to loss of sexual interest, requiring careful clinical evaluation to differentiate iatrogenic from illness-related symptoms.

A number of pharmacologic and nonpharmacologic strategies have been described, each with varying degrees of success. In the case of SSRIs, undesired pharmacologic agonism at the postsynaptic 5-HT_2A receptor has been implicated in the mechanism of sexual dysfunction,⁴⁸ suggesting that agents which block this receptor, such as nefazodone, mirtazapine, or second-generation antipsychotics, may entail fewer sexual side effects.

SSRI dosage reductions have been advocated by some authors as one possible strategy, although no controlled trials exist to examine this approach rigorously.⁴⁷ Drug holidays have been reported to have a modest degree of success with some SSRIs,⁴⁹ although periodic planned drug cessation interferes with spontaneity and may discourage overall patient compliance. Moreover, in the case of SSRIs with a longer half-life, such as fluoxetine, this approach may be of little value. Using medications that either modify or compensate for the increased genitourinary serotonergic tone, such as cyproheptadine,^50,51 represents another plausible strategy, particularly for patients who have shown good response and otherwise tolerate the SSRI well. Varying degrees of evidence, from controlled trials to clinical reports, exist to support the use of numerous adjunctive agents, including granisetron,⁵² sildenafil,⁵³ yohimbine,⁵⁴ ginkgo biloba,⁵⁵ methylphenidate,⁵⁶ amantadine,⁵⁷ or buspirone,⁵⁸ although most controlled trials with these agents have yielded only modest success. The antidepressant bupropion also has been suggested as a possible substitution strategy for an SSRI, based on its relatively lower incidence of sexual side effects,⁵⁹ although clinicians should not automatically assume that the substitution of any one antidepressant for another will show equal efficacy. Open trials augmenting serotonergic drugs with bupropion also suggest its value as an adjunctive strategy to help diminish SSRI-associated sexual dysfunction.⁶⁰ A recent placebo-controlled trial⁶¹ of bupropion augmentation of SSRIs found improved sexual desire and frequency but no global change in sexual functioning with bupropion compared to placebo.

Cognitive Impairment and Sedation

Cognitive dysfunction—particularly impaired attention and executive function—have increasingly become recognized as common features that are intrinsic to bipolar disorder across its illness phases.⁶² Thus, clinicians must discern the extent to which subjective complaints involving memory, attention, or concentration are reflections of a genuine neurocognitive deficit,⁶³ or likely the result of the illness or of medication.

Mental sluggishness is often described as an adverse effect associated with lithium, even among healthy individuals.⁶⁴ One uncontrolled study⁶⁵ reported improvement in the cognitive complaints associated with lithium after switching to divalproex. Among anticonvulsant agents, cognitive impairment appears to be less likely to occur with either lamotrigine or gabapentin among both epilepsy and bipolar patients.⁶⁶ Topiramate is associated with somnolence, impaired concentration or attention, word-finding difficulties, and subjective cognitive dulling.⁶⁶ In the authors’ experience, adverse effects such as these occur most often when dosages are escalated too rapidly above 50–100 mg/day. In the aftermath of several negative randomized controlled trials to assess the antimanic efficacy of topiramate for bipolar mania, increasing attention has focused on its potential value for ancillary problems related to bipolar illness, such as weight gain.

Cognitive dysfunction is well established with the use of first-generation antipsychotics, particularly low-potency neuroleptics that possess significant anticholinergic effects. Cognitive impairment has generally been described as less extensive with second-generation antipsychotics in schizophrenics⁶⁷ or in healthy volunteers,⁶⁸ although little information is available specifically for patients with bipolar disorder. In one of the few existing preliminary studies of neurocognitive function and pharmacotherapy for bipolar disorder, Reinares and colleagues⁶⁹ observed better attentional functioning in bipolar patients taking risperidone than conventional antipsychotics.

Dermatologic Effects

Many psychotropic drugs have been associated with cutaneous reactions. In the case of lamotrigine, skin rashes have been the most frequent adverse event leading to drug discontinuation in controlled trials in epilepsy.^70,71 However, in nearly all instances, such rashes have been benign and likely the result of rapid dose escalation strategies which were previously recommended in the first few years lamotrigine was available. Currently, rashes of any kind occur in approximately 10% of patients treated with lamotrigine; severe cases resulting in hospitalization occur in 0.3% of adults and 1% of children. Importantly, the revised slower-dose escalation schedule established in 1994 has led to a marked reduction in the incidence of skin rash. The incidence of rash is higher when given with concomitant valproate due to their pharmacokinetic interaction, although lamotrigine can be safely co-prescribed with valproate when doses are escalated twice as slowly as with monotherapy.³⁴ Rash and Stevens-Johnson syndrome have also been associated with use of divalproex⁷² and carbamazepine.³⁴

In the case of lithium, case reports have described exacerbations or first occurrences of psoriasis,⁷³ which may be improved with the use of appropriate dermatologic preparations or by lowering the lithium dose. Severe pustular acne that does not respond well to dermatologic treatment is also associated with lithium treatment and resolves only with lithium discontinuation.³

Tremor

Tremor, whether resting or exacerbated by activity, is a common problem for patients taking lithium. Incidence rates range from 4% to 65%. The wide variability is due to differences in definition and reporting and possibly also to differences in peak lithium levels.⁷⁴ Lithium-induced tremor is frequently treated successfully with b-blockers, such as propranolol, although patients should be monitored for bradycardia due to this combination.⁷⁴

Symptomatic tremor also occurs in approximately 10% of patients treated with valproate.⁷⁵ Valproate-induced tremor may be treated with amantadine or propranolol, both of which are associated with side effects of their own.⁷⁶

Mania Induction and Rapid Cycling

Antidepressants have been reported to induce mania in approximately one-third of patients overall with bipolar disorder,^77-80 although the likelihood that any given antidepressant trial might lead to a manic or hypomanic episode in a known bipolar patient is probably <15% to 20%.^79,81 Although practitioners frequently assume that SSRIs or other newer-generation antidepressants are substantially less likely than older antidepressants to induce mania, the database from which this impression has arisen is not extensive.^80-85 Growing evidence has begun to suggest that some patients with bipolar disorder may inherently be at higher risk for developing antidepressant-induced mania; such vulnerability factors may include a history of prior antidepressant-induced mania, a family history of bipolar disorder or other genetic factors, exposure to multiple antidepressant trials, and comorbid substance abuse.^79,80 Recent naturalistic studies^86-88 have begun to challenge a prior literature linking antidepressant overuse with mood destabilization or cycle acceleration. However, while these reports attest to the persistence of depression in bipolar disorder, it is difficult to conclude from such noncontrolled, nonrandomized studies which bipolar patients are or are not suitable candidates for receiving standard antidepressants to manage their depression.

Standard mood stabilizers, such as lithium or valproate, are thought to confer some protection against the possibility of antidepressant-induced mania, although this assumption is not robustly reported within the literature.^80,89,90 By contrast to standard antidepressants or standard mood stabilizers, the compound lamotrigine has demonstrated antidepressant efficacy both acutely⁹¹ and long term,^92,93 without a greater risk than placebo for inducing mania.

Depressive episodes in bipolar disorder are traditionally difficult to treat. The depressive episodes in bipolar patients often do not respond favorably to many of the mood stabilizers currently approved for use in bipolar disorder, and this may encourage antidepressant use. On the other hand, both lithium and valproate have some antidepressant properties.^3,96,97 The magnitude of lithium’s protective effect against recurrent depression appears substantially smaller than its efficacy to prevent manias,⁹⁸ although lithium and lamotrigine are nonetheless both considered appropriate first-line pharmacotherapies for bipolar depression according to the revised American Psychiatric Association’s “Practice Guidelines for the Treatment of Patients with Bipolar Disorder.”⁴

Special Considerations in Women

While epidemiologic studies indicate that bipolar disorder equally afflicts men and women,⁹⁹ a number of gender differences have been observed, including a higher incidence of rapid cycling and mixed states among women than men,¹⁰⁰ as well as a higher likelihood of comorbid alcohol abuse or dependence among bipolar women than bipolar men compared to proportional rates in the general population.¹⁰¹ Therapeutic outcomes with certain core treatments, such as lithium, appear comparable in both men and women,¹⁰² although gender differences become important when considering adverse-effect profiles across existing psychotropic agents.

First-generation (and some second-generation) antipsychotics, and to some extent SSRIs, may elevate serum levels of prolactin, leading to galactorrhea, sexual dysfunction, impaired fertility, and menstrual disorders.⁴ In addition, menstrual disturbances associated with valproate use are common among female epileptic populations.¹⁰³ It has been suggested that polycystic ovarian syndrome (PCOS) and/or hyperandrogenism occur at increased rates among females taking valproate for epilepsy.^103,104 Links between PCOS and valproate use remain controversial among nonepileptic women, such as those with migraine or bipolar disorder.^105-108

Carbamazepine, oxcarbazepine, and topiramate all increase the metabolism of oral contraceptives, reducing their effectiveness and necessitating the use of other forms of birth control.⁴ A case series of seven women with epilepsy who received oral contraceptives while being treated with lamotrigine demonstrated that the oral contraceptives reduced lamotrigine plasma levels by 41% to 64% (mean 49%), leading the authors to recommend serum level monitoring of lamotrigine when prescribed concomitantly with an oral contraceptive.¹⁰⁹

Laboratory Monitoring

Periodic laboratory testing has the potential to negatively impact patient compliance. In addition, there is no clear agreement even among experts as to the frequency with which laboratory monitoring should be conducted when prescribing lithium, divalproex, or other anticonvulsant drugs used for bipolar disorder.¹¹⁰ The revised APA practice guideline for bipolar disorder⁴ notes that most psychiatrists obtain hematologic and hepatic function tests at least every 6 months for stable patients taking divalproex, or more often based on clinical status. Among patients taking lithium, the APA practice guideline recommends monitoring renal function every 2–3 months during the first 6 months of treatment, and thyroid function once or twice during this time; these parameters may be checked every 6–12 months thereafter in stable patients, or more often if clinically indicated. In the case of carbamazepine, the APA practice guideline advises obtaining a complete blood count, platelet measures, and liver function tests every 2 weeks during the first 2 months of treatment, and every 3 months thereafter in stable patients.⁴

At present, atypical antipsychotic agents, as well as newer-generation anticonvulsants, such as topiramate and lamotrigine, do not require monitoring for these side effects, nor is regular monitoring of serum levels required.⁴ However, in September 2003, the FDA called for the manufacturers of all atypical antipsychotics to include a product warning label regarding the potential increased risk for diabetes and hyperglycemia, particularly among patients with intrinsic background factors for diabetes, such as obesity or a family history of Type II diabetes.⁴⁶

Clinicians should always give female patients a pregnancy test before initiation of any psychotropic medication, due to the risks of teratogenesis.

Conclusion

Aside from acquiring a sound knowledge of the efficacy of a drug, it is the responsibility of the clinician to closely consider the side-effect profile of a given medication, as well as the unique concerns of the individual patient.

While medications used in treating bipolar disorder have traditionally been associated with numerous adverse events, new information is emerging regarding ways to reduce the incidence and severity of side effects. In addition, new treatment options for treating bipolar disorder continue to emerge. Many of these offer safer side-effect profiles and do not require laboratory monitoring, although the risks and benefits of choosing any pharmacotherapy must be individually tailored to a patient based on their unique clinical circumstances. Safe and appropriate pharmacotherapy for bipolar illness today involves the thoughtful integration of evidence-based efficacy with the anticipation and management of potential adverse effects.

Controversies persist about the potential for antidepressants to worsen the course of bipolar disorder by inducing mania or potentially accelerating cycle frequency in a subgroup of patients. Current practice guidelines advise against the use of antidepressants without mood stabilizers for bipolar I disorder, and caution is warranted when clinicians augment mood stabilizers with standard antidepressants in order to minimize the risk for destabilizing mood both short-term and long-term. PP

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