Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications
Dr. Camacho is a research fellow with the International Mood Center in the Department of Psychiatry at the University of California in San Diego, and is attending psychiatrist at Imperial County Behavioral Health in El Centro, California.
Disclosure: The author reports no financial, academic, or other support of this work.
Please direct all correspondence to: Alvaro Camacho, MD, University of California, San Diego, International Mood Center, Department of Psychiatry, 9500 Gilman Dr, Mail Code 0603, La Jolla, CA 92037-0603; Tel: 619-252-0428; Fax: 619-497-6686; E-mail: email@example.com.
• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
The use of addictive substances is prevalent among individuals with bipolar disorder (the so-called “dual diagnosis” phenomenon). New studies have led to the proposal that the two groups of disorders exist on a continuum. The Akiskal-Pinto bipolar spectrum schema describes this continuum as bipolar type III 1/2. This review explores the possibility that some forms of substance abuse, especially stimulant abuse, can belong to the bipolar spectrum. These forms of substance abuse respond to anticonvulsant medications used as mood stabilizers. The review is divided into the following sections: neurobiology of addictive disorders, epidemiology of bipolar illness and comorbid substance abuse (particularly stimulant abuse), and clinical correlation with proposed treatment options. The proposed spectrum, with emphasis on stimulant use and bipolar disorder, provides an alternative understanding to a phenomenon that otherwise remains a diagnostic dilemma and therapeutic quagmire. Anticonvulsant medications appear to be a viable joint option for a proportion of patients with this condition.
Patients with comorbid mental illness and substance abuse disorders (SUD) frequently present for treatment with a confusing array of psychiatric and physical findings. The importance of identifying the association between mental illness and SUD in these patients was recognized as early as 1979 by McLellan and colleagues.1 Assessment of comorbid mental illness and SUD can be difficult; it begins with an open mind to avoid premature closure of diagnostic possibilities, lest the patient be left without adequate treatment.2 Given the high frequency of substance abuse among patients with mental disorders, clinicians should use a probing diagnostic approach.2-4 In order to clarify the relationship between SUD and mental illness it is recommended that they assess: when the initial mental symptoms began, and, in the case of an exacerbation, under which circumstances the symptoms began again; when the SUD started and whether the symptoms preceded the development of substance abuse; which subjective effects the substance has on the psychiatric symptoms (relief, exacerbation or cessation); and whether or not patterns of substance use alleviate the underlying psychiatric phenomena.
Of all Axis I mental disorders, mood disturbances—especially bipolar disorder—are most likely to co-occur with SUD. Studies5,6 have described that an earlier onset of bipolar disorder is seen in patients who develop SUD compared to those who do not, suggesting that an earlier age at onset of mood symptoms may put individuals at risk for developing an addiction disorder.
This review attempts to inform the clinician about the increasing evidence of comorbidity between bipolar disorder and substance use, with a particular emphasis on stimulant use disorders. The article will review the neurobiology of addiction and then the epidemiology of bipolar disorder and addictions, both of which should aid in building clinical correlations, especially with regard to emerging treatments. Stimulant abuse will again be the main focus of the model of bipolar disorder proposed in this article.
Neurobiology of Addiction
Addiction can be viewed as a form of drug-induced neuronal plasticity. Many studies identifying possible transcription factors that could contribute to the developing of tolerance and eventual dependence on addictive substances are currently underway. Two of the most studied transcription factors are the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the ΔFosB. These transcription factors are responsible for the autoregulation of intracellular transmission, which promotes the biosynthesis of certain neurotransmitters, such as norepinephrine, dopamine, glutamate, and γ-aminobutyric acid, among others, that are responsible for stable adaptations of neuronal function and the reward effects of addictive substances.7
Research has shown that the upregulation of the cAMP pathway and the eventual activation of CREB occurs in response to the administration of several drugs of abuse, including opiates, stimulants, and ethanol. The same has been described for the ΔFosB transcription factor.8-10 Thus, these transcription factors play a role in the acute and chronic administration of addictive substances. The activation of CREB is the result of the upregulation of the second messenger pathway of cAMP, which has been described as an adaption to chronic exposure to drugs of abuse, leading to tolerance and dependence. On the other hand, ΔFosB has been implicated in the acute adaptations of addictive substances or sensitization, which refers to the enhanced response to the substance use.7-11
CREB and ΔFosB seem to balance each other. CREB has been implicated in drug inhibition and states of withdrawal, depression, and dysphoria, whereas the Fos family of transcription factors has been associated with euphoria, increased locomotor responses to drugs, and rewarding responses to drugs, especially morphine and cocaine.7,8,12 These features bear some resemblance to the biphasic cyclothymic phenomenology of the bipolar spectrum.13 However, whether these underlying mechanisms are similar is speculative at this point.
Data from the Epidemiological Catchment Area study14 reported that the lifetime prevalence of any substance abuse or dependence among individuals with bipolar disorder types I and II is 56.1%, and is 60.7% in patients with only bipolar I disorder.2,14 Patients with more complicated forms of bipolar disorder (eg, mixed or rapid-cycling) are also more likely to have SUD.5,15 Antisocial personality disorder is the only psychiatric condition with a reported higher rate of comorbid SUD.2,16,17
A recent study done by Copeland and Sorensen18 found that mood disorders accounted for 71% of the diagnoses among individuals with methamphetamine use disorders. A previous study by Winokur and colleagues19 found that individuals with bipolar disorder not only have a higher incidence of alcoholism but also a considerable tendency toward stimulant abuse and dependence. Additionally, these investigators postulated the hypothesis between a common familial-genetic diathesis for a subtype of bipolar disorder and stimulant abuse. This was corroborated in another study,20 which reported that 72% of individuals with a history of alcohol use disorder had a lifetime prevalence of stimulant use (26% with powder cocaine and 46% with crack cocaine). McElroy and colleagues21 described a cohort of 288 bipolar patients in which 33% had lifetime prevalence of alcohol use disorder, followed by an 18% lifetime prevalence of stimulant (including cocaine) use disorder. Moreover, there was no significant difference between patients with bipolar I and bipolar II disorder and their comorbid substance use.
Dalton and colleagues22 reported a lifetime rate of 40% of suicide attempts in a cohort of 336 subjects with bipolar I disorder, bipolar II disorder, schizoaffective disorder, and comorbid substance abuse. The authors described that the use of drugs among this cohort was a significant predictor for suicide attempts (P=.037); they described cannabis as the most frequently used substance (74%), followed by hallucinogens (18%), sedatives (18%), and cocaine (18%).
The question that many clinicians face on a daily basis is which disorder accounts for the symptomatology that the patient is experiencing. Based on the literature reviewed, and building on the Akiskal-Pinto formulation,23 Camacho and Akiskal24 hypothesized the existence of a bipolar-stimulant spectrum. Just as in some depressives with familial-genetic permission for bipolarity who manifest hypomania upon antidepressant challenge,25,26 they suggested that in another group of potential bipolar depressives, stimulant use can bring about the first overt hypomanic or manic episode. They also suggested that anticonvulsants can stabilize the underlying bipolar dysregulation, treat the withdrawal phenomena from substances of abuse, and reduce the craving for the substance.
Emerging Treatment Approaches
Treatment with Mood Stabilizers
The use of divalproex sodium has provided promising results not only in the treatment of patients with comorbid bipolar and SUD, but also as an aid for preventing further relapse. It can be used as an adjunctive agent for detoxification, as well. Starting doses can be 500 mg at night, increased up to 2,000 mg in divided doses. It is important to monitor liver function, pancreatic function, and serum levels when using divalproex.27-29 More longitudinal studies are needed to assess the length of abstinence in these patients.
A preclinical study using carbamazepine posed interesting questions about the utility of this mood stabilizer in treating methamphetamine-related bipolar symptoms and in reducing associated methamphetamine cravings.30 Brady and colleagues31 postulated the utility of this mood stabilizer in patients with cocaine dependence and comorbid affective disorders, and found a trend toward fewer positive urine drug tests. Another study32 demonstrated improvement on self-ratings of depression and irritability. Doses of carbamazepine start at 300 mg BID, and can be increased up to 1,600 mg/day. Patients on carbamazepine should be monitored for hyponatremia and thrombocytopenia.
Lithium has shown some efficacy in reducing amphetamine-related locomotor activation.33 Larger epidemiological trials are needed to validate this finding. Lithium has also been used safely in the treatment of bipolar adolescents with secondary substance dependence.34,35 A recent study36 demonstrated that bipolar patients treated with lithium have a lower risk for suicide than those treated with divalproex (after controlling for comorbid medical and psychiatric conditions). Usual starting doses of lithium are 300 mg twice daily, with doses up to 1,200 mg/day or higher. It is important to monitor lithium levels (usually between 0.6–1.2 mEq/L), and thyroid and renal function. Future studies need to address this medication specifically in those patients with comorbid bipolarity and some types of substance abuse.
Gabapentin has been extremely useful for treatment of comorbid bipolar, anxiety, and substance abuse disorders.37 A recent study reported that gabapentin appeared to be safe and efficacious in reducing the use of cocaine in a group of psychiatric patients.38
Since oxcarbazepine may be considered a prodrug,39 it may be less likely to cause drug-drug interactions. Treatment with oxcarbazepine is started at 600 mg BID, with doses up to 2,400 mg/day. Current consensus states that the dose of oxcarbazepine should be 50% higher than that of carbamazepine. Oxcarbazepine does not have the same well-established record as carbamazepine in the treatment of comorbid substance abuse with bipolar disorder, although the literature has reported its promising use.40,41
Dosing for topiramate ranges from 300–800 mg. It has been reported that this medication has minimal drug interactions, and may cause weight loss (a potential “virtue”); however, it can cause cognitive dulling.42 This agent can potentially be used for the augmentation treatment bipolar disorder.43 Additionally, it has been reported that topiramate might help as an adjunct treatment in diminishing the impulsive cravings in patients with alcohol use disorders.44,45
Brown and colleagues46 described the potential benefit of lamotrogine in the treatment of patients with bipolar disorder and comorbid cocaine use. This finding is important, since lamotrigine appears to possess antidepressant properties that may be beneficial for patients who are experiencing protracted dysphoria from stimulant withdrawal and who have a comorbid bipolar diathesis.46,47
This newer anticonvulsant differs mainly from the others because of its beneficial side-effect profile and reduced risk of drug-drug interactions.41 Studies have reported some benefit of zonisamide in the treatment of bipolar disorder and other psychiatric conditions.48,49 However, as reported by McElroy and Keck,50 it is necessary to guide clinical practice on evidence-based medicine, leaving enough flexibility to tailor the appropriate treatment to each individual patient. Although the medications described above, including zonisamide and the other mood stabilizers, are helpful in treating patients that fall into the substance abuse bipolar spectrum, there is a need for more studies that will further validate the importance of adequately treating this complicated disorder.
Other Potential Treatments
Several short-term trials using antidepressants demonstrated some reduction in the consumption of stimulants, and showed potential in achieving abstinence.51 These trials have been performed using imipramine, desipramine, fluoxetine, and pramipexole.52-55
However, it is generally best to avoid antidepressants in stimulant abuse patients, since these patients could be switched to a mixed or manic state. Treatment of these patients with an anticonvulsant first to control their increased irritability, dysphoria, racing thoughts, insomnia, and agitation beyond the expected phase of a withdrawal episode is therefore recommended.
New-generation antipsychotics have also been also used for the treatment of the proposed spectrum of bipolar and addictive disorders. Brown and colleagues56 reported that quetiapine could be used to stabilize patients with bipolar disorder and to reduce their cocaine use. Recently, a pilot trial showed that olanzapine was not effective in the treatment of primary cocaine dependence without baseline mood disorder.57 Future clinical trials need to elucidate the use of these medications in patients with comorbid bipolar disorder and substance abuse, especially stimulant use.
This review has presented information about two conditions, bipolar disorder and SUD, which could be considered as a continuum of a bipolar spectrum. This model of a continuum of bipolar and substance abuse disorders was exemplified using stimulant abuse as a case in point.24
A similar hypothesis involving the heroin-bipolar connection has been proposed by Maremmani and colleagues.58 Additionally, the proposed hypothesis by Khantzian and colleagues59 on “self-medication” in individuals with stimulant use disorders has raised several questions regarding possible associations between temperament and stimulant addiction. Aharonovich and colleagues60 recently tested a similar hypothesis: the investigators used the State-Trait Anger Expression Inventory in 60 individuals with SUD, including cocaine, heroin, and marijuana use disorders, and found that individuals with cocaine use disorders reported a trend toward more angry temperament compared with individuals with opioid addiction. Studies done by Helfrich and colleagues61 and Craig62 found that patients with cocaine abuse problems had increased problems with impulsive behavior, acting out, and authority figures, according to patients’ scores on the Minnesota Multiphasic Personality Inventory.61,62
When prescribing for such conditions, the clinician should keep in mind the possibility of increased side effects associated with the concomitant use of medications and addictive substances, especially stimulants,63,64 although it is also important to provide the care necessary to avoid devastating behavioral consequences of substance-related mood and psychotic disorders, particularly if there are stimulants involved. It is also important to treat comorbid bipolar disorder and substance abuse as a continuum and not as isolated disorders.24,65
Furthermore, experts in the field of addiction have emphasized the importance of a detailed lifetime evaluation for independent psychiatric problems and SUD. In this process, careful attention should be placed on patients with bipolar disorder, as they may not provide a reliable information about their comorbid substance abuse.66-68
Increasing training in the early identification of individuals with a bipolar-addiction diathesis could avoid problems, such as overprescribing stimulants or antidepressants in susceptible individuals whose initial presentation is depression.69 Despite reported stabilization of bipolar-related electroencephalographic changes with methylphenidate, the clinician should be cautious in prescribing stimulants to bipolar patients.70 With documented attention-deficit/hyperactivity disorder history preceding and/or co-existing with bipolar and substance abuse, mood-stabilizing anticonvulsants should be the mainstay of a treatment regimen; the difficult clinical judgment to add a stimulant to this regimen should be deferred to experts with a great deal of experience in this area.
Prospective studies on this subject should assess the risks and benefits of long-term use of stimulants for conditions such as attention-deficit disorder, which could be the initial presentation of a bipolar diathesis.71-74 Adequate follow-up and constant review of the working diagnosis is important to prevent the possible development of a complicated bipolar-stimulant use diathesis.75-78 The use of standardized questionnaires to estimate levels of cravings for substances and early identification of a bipolar spectrum could also possibly prevent devastating outcomes in these individuals.79,80
To summarize, this article presents co-occurring SUD and bipolar disorder as part of the bipolar spectrum, although it recognizes that knowledge on this subject is still limited. Understanding and identifying the different faces of the bipolar spectrum is necessary in order to offer prompt treatment, avoid suicide episodes, and educate patients about the detrimental effect of addictive substances.81,82 This clinically heuristic model to reconceptualize the relationship between bipolar spectrum and substance abuse disorders opens therapeutic opportunities to co-occurring bipolar and substance abuse disorders in both psychiatric and general medical settings. PP
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• The tolerability and adverse-effect profiles of the newer psychotropic drugs for bipolar disorder affect the therapeutic benefits of these agents.
• The ability of clinicians to provide optimal treatments after considering differential adverse effects and tolerability increases medication compliance in patients who might otherwise discontinue treatment due to adverse effects.
• Strategies exist for either minimizing or counteracting the adverse effects of most psychotropic 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).
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).
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
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.
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
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-HT2A 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.
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, 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 β-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 studies86-88 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
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.
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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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: Jgoldber1@lij.edu.