Articles

Print Friendly 

Are Some Forms of Substance Abuse Related to the Bipolar Spectrum? Hypothetical Considerations and Therapeutic Implications

Alvaro Camacho, MD

Return

Primary Psychiatry. 2004;11(9):42-46
 

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: acamacho@ucsd.edu.
 

Focus Points

• Substance abuse is the most common comorbid condition in individuals diagnosed with bipolar disorder.
• Alcohol and stimulants are the most commonly abused substances in patients with bipolar disorder.
• Patients with bipolar disorder and substance abuse should be started sooner rather than later on a mood stabilizer, despite the risks and side effects associated with the particular medication.
• Clinicians should pay close attention to premorbid dysphoria and irritability associated with states of withdrawal from substances, which could be the prodromal phase of a bipolar depressive episode; if left untreated, further relapse and exacerbation of mood symptoms is possible.
• Bipolar and substance abuse conditions may share a common diathesis, which may in part explain the overlap in therapeutic modalities.

 

Abstract

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.

 

Introduction

 

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.

 

Epidemiology

 

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%).

 

Clinical Correlation

 

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

 

Divalproex Sodium

 

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.

 

Carbamazepine

 

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

 

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

 

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

 

Oxcarbazepine

 

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

 

Topiramate

 

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

 

Lamotrigine

 

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

 

Zonisamide

 

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.

 

Discussion

 

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

 

Conclusion

 

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

 

References

 

1.  McLellan AT, Woody GE, O’Brien CP. Development of psychiatric illness in drug abusers. Possible role of drug preference. N Engl J Med. 1979;301(24):1310-1314.
2.   Rosethal RN, Westriech L. Treatment of persons with dual diagnosis of SUD and other psychological problems. In: McCrady BS, Epstein EE, eds. Addictions: A Comprehensive Textbook. New York, NY: Oxford University Press; 1999:439-476.
3.     Schuckit MA, Hesselbrock V. Alcohol dependence and anxiety disorders: what is the relationship? Am J Psychiatry. 1994;151(12):1723-1734.
4.   Schuckit MA, Irwin M, Brown SA. The history of anxiety symptoms among 171 primary alcoholics. J Stud Alcohol. 1990;51(1):34-41.
5. Dunner DL, Feinman J. The effect of substance abuse on the course of bipolar disorder. Biol Psychiatry. 1996;39:617.
6.   Brady KT, Sonne SC. The relationship between substance abuse and bipolar disorder. J Clin Psychiatry. 1995;56(suppl 3):19-24.
7.     Chao J, Nestler EJ. Molecular neurobiology of drug addiction. Annu Rev Med. 2004;55:113-132.
8.   Nestler EJ. Molecular neurobiology of addiction. Am J Addict. 2001;10(3):201-217.
9.   Terwilliger RZ, Beitner-Johnson D, Sevarino KA, Crain SM, Nestler EJ. A general role for adaptations in G-proteins and the cyclic AMP system in mediating the chronic actions of morphine and cocaine on neuronal function. Brain Res. 1991;548(1-2):100-110.
10. Unterwald EM, Cox BM, Kreek MJ, Cote TE, Izenwasser S. Chronic repeated cocaine administration alters basal and opioid-regulated adenylyl cyclase activity. Synapse. 1993;15(1):33-38.
11. Guitart X, Thompson MA, Mirante CK, Greenberg ME, Nestler EJ. Regulation of cyclic AMP response element-binding protein (CREB) phosphorylation by acute and chronic morphine in the rat locus coeruleus. J Neurochem. 1992;58(3):1168-1171.
12. Kelz MB, Nestler EJ. deltaFosB: a molecular switch underlying long-term neural plasticity. Curr Opin Neurol. 2000;13(6):715-720.
13. Akiskal HS, Khani MK, Scott-Strauss A. Cyclothymic temperamental disorders. Psychiatr Clin North Am. 1979;2:527-554.
14. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264(19):2511-2518.
15. Calabrese JR, Delucchi GA. Spectrum of efficacy of valproate in 55 patients with rapid-cycling bipolar disorder. Am J Psychiatry. 1990;147(4):431-434.
16. Rounsaville BJ, Anton SF, Carroll K, Budde D, Prusoff BA, Gawin F. Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry. 1991;48(1):43-51.
17. Weiss RD, Mirin SM, Michael JL, Sollogub AC. Psychopathology in chronic cocaine abusers. Am J Drug Alcohol Abuse. 1986;12(1-2):17-29.
18. Copeland AL, Sorensen JL. Differences between methamphetamine users and cocaine users in treatment. Drug Alcohol Depend. 2001;62(1):91-95.
19. Winokur G, Turvey C, Akiskal H, et al. Alcoholism and drug abuse in three groups—bipolar I, unipolars and their acquaintances. J Affect Disord. 1998;50(2-3):81-89.
20. Staines GL, Magura S, Foote J, Deluca A, Kosanke N. Polysubstance use among alcoholics. J Addict Dis. 2001;20(4):53-69.
21. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry. 2001;158(3):420-426.
22. Dalton EJ, Cate-Carter TD, Mundo E, Parikh SV, Kennedy JL. Suicide risk in bipolar patients: the role of co-morbid substance use disorders. Bipolar Disord. 2003;5(1):58-61.
23. Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am. 1999;22(3):517-534.
24. Camacho A, Akiskal HS. Proposal for a bipolar-stimulant spectrum: temperament, diagnostic validation and therapeutic outcomes with mood stabilizers. J Affect Disord. In press.
25. Akiskal HS, Hantouche EG, Allilaire JF, et al. Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II). J Affect Disord. 2003;73(1-2):65-74.
26. Akiskal HS, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J Affect Disord. 1983;5(2):115-128.
27. Brady K, Casto S, Lydiard RB, Malcolm R, Arana G. Substance abuse in an inpatient psychiatric sample. Am J Drug Alcohol Abuse. 1991;17(4):389-397.
28. Hertzman M. Divalproex sodium to treat concomitant substance abuse and mood disorders. J Subst Abuse Treat. 2000;18(4):371-372.
29. Brady KT, Sonne SC, Anton R, Ballenger JC. Valproate in the treatment of acute bipolar affective episodes complicated by substance abuse: a pilot study. J Clin Psychiatry. 1995;56(3):118-121.
30.  Miki M, Hamamura T, Ujike H, et al. Effects of subchronic lithium chloride treatment on G-protein subunits (Golf, Ggamma7) and adenylyl cyclase expressed specifically in the rat striatum. Eur J Pharmacol. 2001;428(3):303-309.
31.  Brady KT, Sonne SC, Malcolm RJ, et al. Carbamazepine in the treatment of cocaine dependence: subtyping by affective disorder. Exp Clin Psychopharmacol. 2002;10(3):276-285.
32. Cambell J, Nickels EJ, Penick EC, et al. Comparison of desipramine or carbamazepine to placebo for crack-cocaine dependent patients. Am J Addict. 2003;12(2):122-136.
33.  Gould TJ, Keith Ra, Bhat RV. Differential sensitivity to lithium’s reversal of amphetamine-induced open-field activity in two inbred strains of mice. Behav Brain Res. 2001;118:95-105.
34.  Kosten TR. Pharmacotherapeutic interventions for cocaine abuse. Matching patients to treatments. J Nerv Ment Dis. 1989;177(7):379-389.
35. Joshi P, Capozzoli JA, Coyle JT. Effective management with lithium of a persistent, post-traumatic hypomania in a 10-year-old child. J Dev Behav Pediatr. 1985;6(6):352-354.
36. Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J, Revicki D. Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003;290(11):1467-1473.
37. Perugi G, Toni C, Frare F, et al. Effectiveness of adjunctive gabapentin in resistant bipolar disorder: is it due to anxious-alcohol abuse comorbidity? J Clin Psychopharmacol. 2002;22(6):584-591.
38. Raby WN, Coomaraswamy S. Gabapentin reduces cocaine use among addicts from a community clinic sample. J Clin Psychiatry. 2004;65(1):84-86.
39. Grunze H, Walden J. Relevance of new and newly rediscovered anticonvulsants for atypical forms of bipolar disorder. J Affect Disord. 2002;72(suppl 1):S15-S21.
40. Nasr S. Oxcarbazepine for mood disorders. Am J Psychiatry. 2002;159(10):1793.
41. LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. JAMA. 2004;291(5):605-614.
42. Nemeroff CB. Safety of available agents used to treat bipolar disorder: focus on weight gain. J Clin Psychiatry. 2003;64(5):532-539.
43. Vieta E, Sanchez-Moreno J, Goikolea JM, et al. Adjunctive topiramate in bipolar II disorder. World J Biol Psychiatry. 2003;4(4):172-176.
44. Komanduri R. Two cases of alcohol craving curbed by topiramate. J Clin Psychiatry. 2003;64(5):612.
45. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for the treatment of alcohol dependence: a randomized controlled trial. Lancet. 2003;361(9370):1677-1685.
46. Brown ES, Nejtek VA, Perantie DC, Orsulak PJ, Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. J Clin Psychiatry. 2003;64(2):197-201.
47. Southam E, Kirkby D, Higgins GA, Hagan RM. Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats. Eur J Pharmacol. 1998;358(1):19-24.
48. McElroy SL, Kotwal R, Hudson JI, Nelson EB, Keck PE. Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial. J Clin Psychiatry. 2004;65(1):50-56.
49. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.
50. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry. 2000;48(6):539-557.
51. Gawin F, Kleber H. Pharmacologic treatments of cocaine abuse. Psychiatr Clin North Am. 1986;9(3):573-583.
52. Rosenbaum JF, Fredman SJ. Pramipexole treatment for cocaine cravings. Am J Psychiatry. 1999;156(11):1834.
53. Rosenblum A, Fallon B, Magura S, Handelsman L, Foote J, Bernstein D. The autonomy of mood disorders among cocaine-using methadone patients. Am J Drug Alcohol Abuse. 1999;25(1):67-80.
54. Gawin FH, Kleber HD. Cocaine abuse treatment. Open pilot trial with desipramine and lithium carbonate. Arch Gen Psychiatry. 1984;41(9):903-909.
55. Batki SL, Moon J, Delucchi K, et al. Methamphetamine quantitative urine concentrations during a controlled trial of fluoxetine treatment. Preliminary analysis. Ann N Y Acad Sci. 2000;909:260-263.
56.  Brown ES, Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord. 2002;4(6):406-411.
57.  Kampman KM, Pettinati H, Lynch KG, Sparkman T, O’Brian CP. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend. 2003;70(3):265-273.
58. Maremmani I, Pacini M, Lubrano S, Lovrecic M, Perugi G. Dual diagnosis heroin addicts. The clinical and therapeutic aspects. Heroin Addict Relat Clin Probl. 2003;5(2):7-98.
59. Khantzian EJ. The self-medication hypothesis of substance use disorders: a reconsideration and recent applications. Harv Rev Psychiatry. 1997;4(5):231-244.
60. Aharonovich E, Nguyen HT, Nunes EV. Anger and depressive states among treatment-seeking drug abusers: testing the psychopharmacological specificity hypothesis. Am J Addict. 2001;10(4):327-334.
61. Helfrich AA, Crowley TJ, Atkinson CA, Post RD. A clinical profile of 136 cocaine abusers. NIDA Res Monogr. 1983;43:343-350.
62. Craig RJ. Psychological functioning of cocaine free-basers derived from objective psychological tests. J Clin Psychol. 1988;44(4):599-606.
63. van Harten PN, van Trier JC, Horwitz EH, Matroos GE, Hoek HW. Cocaine as a risk factor for neuroleptic-induced acute dystonia. J Clin Psychiatry. 1998;59(3):128-130.
64. Bannet J, Ebstein RP, Belmaker RH. Clinical aspects of the interaction of lithium and stimulants. Br J Psychiatry. 1980;136:204.
65. Rohde LA, Szobot C. Lithium in bipolar adolescents with secondary substance dependency. J Am Acad Child Adolesc Psychiatry. 1999;38(1):4.
66. Marken PA, Stanislav SW, Lacombe S, Pierce C, Hornstra R, Sommi RW. Profile of a sample of subjects admitted to an acute care psychiatric facility with manic symptoms. Psychopharmacol Bull. 1992;28(2):201-205.
67.  Schuckit MA, Tipp JE, Bucholz KK, et al. The life-time rates of three major mood disorders and four major anxiety disorders in alcoholics and controls. Addiction. 1997;92(10):1289-1304.
68. Weiss RD. Relapse to cocaine abuse after initiating desipramine treatment. JAMA. 1988;260(17):2545-2546.
69. Beck C, Silverstone P, Glor K, Dunn J. Psychostimulant prescriptions by psychiatrists higher than expected: a self-report survey. Can J Psychiatry. 1999;44(7):680-684.
70. Bschor T, Muller-Oerlinghausen B, Ulrich G. Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: a case study. Clin Electroencephalogr. 2001;32(1):36-39.
71. Giedd JN. Bipolar disorder and attention-deficit/hyperactivity disorder in children and adolescents. J Clin Psychiatry. 2000;61(suppl 9):31-34.
72. Weller E, Weller RA, Dogin JW. A rose is a rose is a rose. J Affect Disord. 1998;51(2):189-193.
73. Biederman J, Mick E, Bostic JQ, et al. The naturalistic course of pharmacologic treatment of children with maniclike symptoms: a systematic chart review. J Clin Psychiatry. 1998;59(11):628-637.
74. Cocores JA, Patel MD, Gold MS, Pottash AC. Cocaine abuse, attention deficit disorder, and bipolar disorder. J Nerv Ment Dis. 1987;175(7):431-432.
75. DelBello MP, Soutullo CA, Hendricks W, Niemeier RT, McElroy SL, Strakowski SM. Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset. Bipolar Disord. 2001;3(2):53-57.
76. Carlson GA, Loney J, Salisbury H, Kramer JR, Arthur C. Stimulant treatment in young boys with symptoms suggesting childhood mania: a report from a longitudinal study. J Child Adolesc Psychopharmacol. 2000;10(3):175-184.
77. Carlson GA, Kelly KL. Manic symptoms in psychiatrically hospitalized children—what do they mean? J Affect Disord. 1998;51(2):123-135.
78. Lombardo GT. BPD and ADHD. J Am Acad Child Adolesc Psychiatry. 1997;36(6):719-720.
79. Mezinskis JP, Honos-Webb L, Kropp F, Somoza E. The measurement of craving. J Addict Dis. 2001;20(3):67-85.
80. Salloum IM, Thase ME. Impact of substance abuse on the course and treatment of bipolar disorder. Bipolar Disord. 2000;2(3 pt 2):269-280.
81. Lopez P, Mosquera F, de Leon J, et al. Suicide attempts in bipolar patients. J Clin Psychiatry. 2001;62(12):963-966.
82. Kilzieh N, Akiskal HS. Rapid-cycling bipolar disorder. An overview of research and clinical experience. Psychiatr Clin North Am. 1999;22(3):585-607.

Return

Focus Points

• 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).

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-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.

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 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

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

References

1. Lingam R, Scott J. Treatment non-adherence in affective disorders. Acta Psychiatr Scand. 2002;105(3):164-172.

2. Johnson RE, McFarland BH. Lithium use and discontinuation in a health maintenance organization. Am J Psychiatry. 1996;153(8):993-1000.

3. Brady KT. Difficulties in diagnosis and management of bipolar disorder: three case presentations. J Clin Psychiatry. 2000;61(supp 13):32-37.

4. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(suppl 4):1-50.

5. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press, Inc; 1990.

6. IMS America. National Disease and Therapeutic Index. Fairfield, CT: IMS Health; 1998.

7. Scott J, Pope M. Nonadherence with mood stabilizers: prevalence and predictors. J Clin Psychiatry. 2002;63(5):384-390.

8. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004;184:337-345.

9. Keck PE Jr, McElroy SL, Strakowski SM, Bourne ML, West SA. Compliance with maintenance treatment in bipolar disorder. Psychopharmacol Bull. 1997;33(1):87-91.

10. Bowden CL, Calabrese JR, McElroy SL, et al, for the Divalproex Maintenance Study Group. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57(5):481-489.

11. Persson G. Lithium side effects in relation to dose and to levels and gradients of lithium in plasma. Acta Psychiatr Scand. 1977;55(3):208-213.

12. Baldessarini RJ. Lithium salts and antimanic agents. In: Baldessarini RJ. Chemotherapy in Psychiatry: Principles and Practice. Cambridge, MA: Harvard University Press; 1985:93-127.

13. Lenox RH, Manji HK. Lithium. In: Schatzberg AF, Nemeroff CB, eds. The American Psychiatric Press Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press; 1995:303-349.

14. Arana GW, Rosenbaum JF. Mood stabilizers. In: Arana GW, Hyman SE, Rosenbaum JF, eds. Handbook of Psychiatric Drug Therapy. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:114-143.

15. Zarate CA Jr, Tohen M, Narendran R, et al. The adverse effect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study. J Clin Psychiatry. 1999;60(4):232-236.

16. Thompson NM, Yu KT, Mills SM, et al. Safety and efficacy of divalproex sodium extended-release (Depakote ER) in the pediatric neurology. Presented at: 55th Annual Meeting of the American Epilepsy Society; November 30–December 5, 2001; Philadelphia, PA.

17. Zajecka J, Amsterdam JD, Quitkin FM, et al. Changes in adverse events reported by patients during 6 months of fluoxetine therapy. J Clin Psychiatry. 1999;60(6):389-394.

18. Fakhoury WK, Wright D, Wallace M. Prevalence and extent of distress of adverse effects of antipsychotics among callers to a United Kingdom National Mental Health Helpline. Int Clin Psychopharmacol. 2001;16(3):153-162.

19. National Center for Health Statistics. Prevalence of Overweight and Obesity Among Adults: United States. Baltimore, MD: National Center for Health Statistics; 1999.

20. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696.

21. Fagiolini A, Kupfer DJ, Houck PR, Novick DM, Frank E. Obesity as a correlate of outcome in patients with bipolar I disorder. Am J Psychiatry. 2003;160(1):112-117.

22. Garland EJ, Remick RA, Zis AP. Weight gain with antidepressants and lithium. J Clin Psychopharmacol. 1988;8(5):323-330.

23. Coxhead N, Silverstone T, Cookson J. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Acta Psychiatr Scand. 1992;85(2):114-118.

24. Hartong EG, Moleman P, Hoogduin CA, Broekman TG, Nolen WA, for the LitCar Group. Prophylactic efficacy of lithium versus carbamazepine in treatment-naive bipolar patients. J Clin Psychiatry. 2003;64(2):144-151.

25. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;20(6):607-614.

26. Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 2002;63(12):1148-1155.

27. Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003;160(7):1263-1271.

28. Kinon BJ, Basson BR, Gilmore JA, Tollefson GD. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry. 2001;62(2):92-100.

29. Reynolds GP, Zhang Z, Zhang X. Polymorphism of the promoter region of the serotonin 5-HT(2C) receptor gene and clozapine-induced weight gain. Am J Psychiatry. 2003;160(4):677-679.

30. Taylor DM, McAskill R. Atypical antipsychotics and weight gain—a systematic review. Acta Psychiatr Scand. 2000;101(6):416-432.

31. Keck PE Jr, Buse JB, Dagogo-Jack JS, et al. Managing metabolic concerns in patients with severe mental illness. Postgrad Med. 2003;(spec report):1-92.

32. Keck PE Jr, Marcus R, Tourkodimitris S, et al, for the Aripiprazole Study Group. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651-1658.

33. Chengappa KNR, Levine J, Rathore D, Parepally H, Atzert R. Long-term effects of topiramate on bipolar mood instability, weight change and glycemic control: a case-series. Eur Psychiatry. 2001;16(3):186-190.

34. Physicians’ Desk Reference Electronic Library. Montvale, NJ: Medical Economics Company, Inc; 2002.

35. Kanba S, Yagi G, Kamijima K, et al. The first open study of zonisamide, a novel anticonvulsant, shows efficacy in mania. Prog Neuropsychopharmacol Biol Psychiatry. 1994;18(4):707-715.

36. Gadde KM, Franciscy DM, Wagner HR 2nd, Krishnan KR. Zonisamide for weight loss in obese adults: a randomized controlled trial. JAMA. 2003;289(14):1820-1825.

37. Holt RA, Maunder EM. Is lithium-induced weight gain prevented by providing health eating advice at commencement of lithium therapy? J Hum Nutr Diet. 1996;9:127-133.

38. Ball MP, Coons VB, Buchanan RW. A program for treating olanzapine-related weight gain. Psychiatr Serv. 2001;52(7):967-969.

39. Littrell KH, Petty RG, Hilligoss NM, et al. Educational interventions for the management of antipsychotic-related weight gain. Presented at: 154th Annual Meeting of the American Psychiatric Association; May 5–10, 2001; New Orleans, LA.

40. Peri MG. Maintenance effects in the long-term management of obesity. Clin Psychol Sci Pract. 1998;5:526-543.

41. Horrobin DF, Bennett CN. Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes. Prostaglandins Leukot Essent Fatty Acids. 1999;60(4):217-234.

42. Cassidy F, Ahearn E, Carroll BJ. Elevated frequency of diabetes mellitus in hospitalized manic-depressive patients. Am J Psychiatry. 1999;156(9):1417-1420.

43. Kornegay CJ, Vasilakis-Scaramozza C, Jick H. Incident diabetes associated with antipsychotic use in the United Kingdom general practice research database. J Clin Psychiatry. 2002;63(9):758-762.

44. Wirshing DA, Boyd JA, Meng LR, Ballon JS, Marder SR, Wirshing WC. The effects of novel antipsychotics on glucose and lipid levels. J Clin Psychiatry. 2002;63(10):856-865.

45. Jin H, Meyer JM, Jeste DV. Phenomenology of and risk factors for new-onset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry. 2002;14(1):59-64.

46. Center for Drug Evaluation and Research home page. Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/approval/index.htm. Accessed August 18, 2004.

47. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. 1999;19(1):67-85.

48. Murphy DL. Neuropsychiatric disorders and the multiple human brain serotonin receptor subtypes and subsystems. Neuropsychopharmacology. 1990;3(5-6):457-471.

49. Rothschild AJ. Selective serotonin reuptake inhibitor-induced sexual dysfunction: efficacy of a drug holiday. Am J Psychiatry. 1995;152(10):1514-1516.

50. Aizenberg D, Zemishlany Z, Weizman A. Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin Neuropharmacol. 1995;18(4):320-324.

51. McCormick S, Olin J, Brotman AW. Reversal of fluoxetine-induced anorgasmia by cyproheptadine in two patients. J Clin Psychiatry. 1990;51(9):383-384.

52. Nelson EB, Keck PE Jr, McElroy SL. Resolution of fluoxetine-induced sexual dysfunction with the 5-HT3 antagonist granisetron. J Clin Psychiatry. 1997;58(11):496-497.

53. Boyce EG, Umland EM. Sildenafil citrate: a therapeutic update. Clin Ther. 2001;23(1):2-23.

54. Hollander E, McCarley A. Yohimbine treatment of sexual side effects induced by serotonin reuptake blockers. J Clin Psychiatry. 1992;53(6):207-209.

55. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24(2):139-143.

56. Bartlik BD, Kaplan P, Kaplan HS. Psychostimulants apparently reverse sexual dysfunction secondary to selective serotonin re-uptake inhibitors. J Sex Marital Ther. 1995;21(4):264-271.

57. Michelson D, Bancroft J, Targum S, Kim Y, Tepner R. Female sexual dysfunction associated with antidepressant administration: a randomized, placebo-controlled study of pharmacologic intervention. Am J Psychiatry. 2000;157(2):239-243.

58. Landen M, Eriksson E, Agren H, Fahlen T. Effect of buspirone on sexual dysfunction in depressed patients treated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1999;19(3):268-271.

59. Masand PS, Ashton AK, Gupta S, Frank B. Sustained-release bupropion for selective serotonin reuptake inhibitor-induced sexual dysfunction: a randomized, double-blind, placebo-controlled, parallel-group study. Am J Psychiatry. 2001;158(5):805-807.

60. Kennedy SH, McCann SM, Masellis M, et al. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry. 2002;63(3):181-186.

61. Clayton AH, Warnock JK, Kornstein SG, Pinkerton R, Sheldon-Keller A, McGarvey EL. A placebo-controlled trial of bupropion SR as an antidote for selective serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 2004;65(1):62-67.

62. Martinez-Aran A, Vieta E, Reinares M, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry. 2004;161(2):262-270.

63. Burdick KE, Endick CJ, Goldberg JF. Assessing cognitive deficits in mood disorders: are self-reports valid? Poster presented at: 154th Annual Meeting of the American Psychiatric Association; May 5–10, 2001; New Orleans, LA.

64. Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI. The effect of lithium carbonate on the cognitive functions of normal subjects. Arch Gen Psychiatry. 1977;34(3):355-7.

65. Stoll AL, Locke CA, Vuckovic A, Mayer PV. Lithium-associated cognitive and functional deficits reduced by a switch to divalproex sodium: a case series. J Clin Psychiatry. 1996;57(8):356-359.

66. Goldberg JF, Burdick KE. Cognitive side effects of anticonvulsants. J Clin Psychiatry. 2001;62(suppl 14):27-33.

67. Weiser M, Shneider-Beeri M, Nakash N, et al. Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS? Schizophr Res. 2000;46(2-3):81-89.

68. Beuzen JN, Taylor N, Wesnes K, Wood A. A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers. J Psychopharmacol. 1999;13(2):152-158.

69. Reinares M, Martinez-Aran A, Colom F, Benabarre A, Salamero M, Vieta E. Long-term effects of the treatment with risperidone versus conventional neuroleptics on the neuropsychological performance of euthymic bipolar patients [in Spanish]. Actas Esp Psiquiatr. 2000;28(4):231-238.

70. Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40(7):985-991.

71. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother. 1999;33(10):1037-1042.

72. Calabrese JR, Sullivan JR, Bowden CL, et al. Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management. J Clin Psychiatry. 2002;63(11):1012-1019.

73. Straussberg R, Harel L, Ben-Amitai D, Cohen D, Amir J. Carbamazepine-induced Stevens-Johnson syndrome treated with IV steroids and IVIG. Pediatr Neurol. 2000;22(3):231-233.

74. Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry. 1995;56(7):283-287.

75. Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Treatment of valproate tremors. Neurology. 1983;33(10):1380-1382.

76. Karas BJ, Wilder BJ, Hammond EJ, Bauman AW. Valproate tremors. Neurology. 1982;32(4):428-432.

77. Wehr TA, Goodwin FK. Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry. 1987;144(11):1403-1411.

78. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152(8):1130-1138.

79. Goldberg JF, Whiteside JE. The association between substance abuse and antidepressant-induced mania in bipolar disorder: a preliminary study. J Clin Psychiatry. 2002;63(9):791-795.

80. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5(6):407-420.

81. Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord. 2001;3(5):259-265.

82. Post RM, Leverich GS, Nolen WA, et al, for the Stanley Foundation Bipolar Network. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord. 2003;5(6):396-406.

83. Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry. 1991;148(7):910-916.

84. Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry. 1994;55(9):391-393.

85. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry. 1994;164(4):549-550.

86. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chart review. J Clin Psychiatry. 2001;62(8):612-616.

87. Altshuler L, Suppes T, Black D, et al. Impact of antidepressant discontinuation after acute bipolar depression remission on rates of depressive relapse at 1-year follow-up. Am J Psychiatry. 2003;160(7):1252-1262.

88. Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914-920.

89. Bottlender R, Rudolf D, Strauss A, Moller HJ. Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord. 2001;63(1-3):79-83.

90. Henry C, Sorbara F, Lacoste J, Gindre C, Leboyer M. Antidepressant-induced mania in bipolar patients: identification of risk factors. J Clin Psychiatry. 2001;62(4):249-255.

91. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD, for the Lamictal 602 Study Group. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60(2):79-88.

92. Bowden CL, Calabrese JR, Sachs G, et al, for the Lamictal 606 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400. Erratum in: Arch Gen Psychiatry. 2004;61(7):680.

93. Calabrese JR, Bowden CL, Sachs G, et al, for the Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013-1024.

94. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079-1088. Erratum in: Arch Gen Psychiatry. 2004;61(2):176.

95. Ketter T, Tohen M, Vieta E, et al. Open-label maintenance treatment for bipolar depression using olanzapine for olanzapine/fluoxetine combination. Poster presented at: 6th International Society for Bipolar Disorders Conference; February 9–13, 2004; Sydney, Australia.

96. Strakowski SM, McElroy SL, Keck PE. Clinical efficacy of valproate in bipolar illness: comparisons and contrasts with lithium. In: Halbreich U, Montgomery SA, eds. Pharmacotherapy for Mood, Anxiety, and Cognitive Disorders. Washington, DC: American Psychiatric Press; 2000:143-157.

97. Winsberg ME, DeGolia SG, Strong CM, Ketter TA. Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression. J Affect Disord. 2001;67(1-3):207-212.

98. Geddes JR, Burgess S, Hawton K, Jamison K, Goodwin GM. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161(2):217-222.

99. Leibenluft E. Women with bipolar illness: clinical and research issues. Am J Psychiatry. 1996;153(2):163-173.

100. Arnold LM. Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003;26(3):595-620.

101. Frye MA, Altshuler LL, McElroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160(5):883-889.

102. Viguera AC, Tondo L, Baldessarini RJ. Sex differences in response to lithium treatment. Am J Psychiatry. 2000;157(9):1509-1511.

103. Isojarvi JI, Tauboll E, Pakarinen AJ, et al. Altered ovarian function and cardiovascular risk factors in valproate-treated women. Am J Med. 2001;111(4):290-296.

104. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med. 1993;329(19):1383-1388.

105. Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry. 2002;63(suppl 4):42-55.

106. Rasgon NL, Altshuler LL, Gudeman D, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry. 2000;61(3):173-178.

107. O’Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry. 2002;63(4):322-330.

108. McIntyre RS, Mancini DA, McCann S, Srinivasan J, Kennedy SH. Valproate, bipolar disorder and polycystic ovarian syndrome. Bipolar Disord. 2003;5(1):28-35.

109. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47(1-2):151-154.

110. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The expert consensus guideline series: medication treatment of bipolar disorder 2000. Postgrad Med. 2000;(spec)


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.


Return