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David J. Hellerstein, MD, and Gregory B. Biedermann, MD

Primary Psychiatry. 2003;10(2):47-52

 

Dr. Hellerstein is clinical director at the New York State Psychiatric Institute in New York City.

Dr. Biedermann is a resident in the Department of Internal Medicine at Boston Medical Center in Massachusetts.

Acknowledgment: Dr. Biedermann would like to thank Project House, Inc.

Disclosure: This work was supported by an unrestricted educational grant from Cephalon, Inc. Dr. Hellerstein is on the speakers bureau for Forest Laboratories, Pfizer, and Bristol-Myers Squibb. Dr. Hellerstein receives grant funding from Forest, Pfizer, Eli Lilly, GlaxoSmithKline, Bristol-Myers Squibb, Wyeth, Merck &?Co, the National Institute of Mental Health, and the National Insititute of Drug Abuse, and he is a consultant for Bristol-Myers Squibb

Please direct all correspondence to: David J. Hellerstein, MD, New York State Psychiatric Institute, 1051 Riverside Dr, Box 101, New York, NY 10032; Tel: 212-543-5790; Fax: 212-543-5674; E-mail: hellers@pi.cpmc.columbia.edu.

 


 

Abstract

Do scheduling restrictions influence the prescribing practices of physicians treating patients who require psychostimulants? Central nervous system (CNS) stimulants are beneficial for a variety of conditions, including attention-deficit/hyperactivity disorder (ADHD), narcolepsy, residual daytime sleepiness in sleep apnea, and fatigue. However, they are also associated with the potential for drug abuse, increased risk of addiction, a short half-life, possible toxicity, and prescription concerns associated with United States Drug Enforcement Agency (DEA) scheduling laws. This article presents results from a survey of family practice physicians conducted at the 1998 American Academy of Family Physicians meeting regarding scheduled CNS stimulants. The survey queried physicians about the conditions for which they prescribe CNS stimulants, the frequency with which they prescribe them, their concerns when prescribing them, and how those concerns affect their choice of prescribing a schedule IV drug over a schedule II drug. Of the 342 United States physicians surveyed, 266 currently prescribe CNS stimulants. The disorders for which the highest percentage of physicians reported prescribing CNS stimulants were ADHD (93%) and narcolepsy (49%). The drug prescribed most frequently by physicians was methylphenidate (95%). Dextroamphetamine (32%) and pemoline (24%) were prescribed less often than methylphenidate. Two concerns that were expressed more frequently for methylphenidate, a schedule II drug, than for pemoline, a schedule IV drug, were the logistical problems for patients and no allowance of refills. A large majority of the physicians (71%) expressed a preference for prescribing a less strictly controlled drug (schedule IV) before a more strictly controlled drug (schedule II). This survey suggests that concerns about the use of schedule II drugs and DEA scheduling in particular may influence prescribing behavior.

Introduction

Central nervous system (CNS) stimulants may be beneficial for the pharmacologic treatment of neurobiological disorders affecting attention and sleep, such as attention-deficit/hyperactivity disorder (ADHD), narcolepsy, and fatigue. Drugs for the treatment of these disorders include methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline. Although the exact modes of action are not known for these stimulants, all of the compounds most likely exert their psychostimulant effects via interaction with dopaminergic systems.1 Methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline are approved by the United States Food and Drug Administration for the treatment of ADHD.2-5 For the treatment of narcolepsy, methylphenidate, dextroamphetamine, and dextroamphetamine/amphetamine have been approved.2,4,5 More recently, modafinil, a nonamphetamine wake-promoting agent, was approved for treatment of the excessive daytime sleepiness associated with narcolepsy.6

The potential benefits of CNS stimulants are compromised by a number of drawbacks. These drawbacks include potential for drug abuse, increased addiction risk, tolerance, short half-life, toxicity, and logistic difficulties in accessing the drug. The stimulatory and arousal effects that are mediated in the brain by these psychoactive agents increase their likelihood for physical and psychological dependence.7,8 Amphetamines have been extensively abused; patients tend to become tolerant to the drug and increase their dosage without the knowledge of their physicians.4 Methylphenidate has been shown to have an abuse pattern similar to that of cocaine, and the morbidity and mortality rates associated with methylphenidate abuse are greater than those usually observed for a group of patients involved in intravenous drug abuse.9

Despite numerous anecdotal reports of amphetamine abuse, CNS stimulants are widely prescribed. Nevertheless, the incidence of abuse of psychostimulants, such as methylphenidate, appears to be relatively low when appropriately prescribed by a physician.10-12 A recent study13 reviewed the available literature and found no hard data documenting abuse or diversion of prescribed methylphenidate. Admittedly, illegal use is, by its very nature, hard to document. Nonetheless, in efforts to prevent medication abuse and inappropriate dispensing of CNS stimulants, federal and state regulatory laws are in place to control drug prescription practices. At the federal level, the United States Drug Enforcement Agency (DEA) enforces the scheduling of drugs according to the Controlled Substances Act of 1970. Controlled drugs are divided into five schedules based on their potential for abuse, with schedule I drugs having the highest abuse potential and schedule V drugs the least (Table 1).

Some state regulatory policies impose stricter requirements than the federal government, such as the special triplicate prescription forms required in New York for all schedule II drugs and for benzodiazepines, which may be schedule IV drugs because of their potential to induce dependence.14 Following the addition of benzodiazepines to the New York State Department of Health Triplicate Prescription Program in January 1989, a statewide decrease in benzodiazepine prescribing was seen.14,15 Although the abuse of benzodiazepines appears to have been curtailed under these stricter regulations, many patients may have been denied access to needed medications for legitimate indications and may have received less appropriate drugs as substitutes due to the regulations.14,16

The restrictions imposed by federal and state policies, such as the Triplicate Prescription Program, may help explain why the nonbenzodiazepine schedule IV drug zolpidem tartrate is the most commonly prescribed hypnotic in the US.17 The question is whether negative perceptions and regulatory initiatives actually influence a physician’s prescribing behavior in any way.

We administered a survey in order to examine physicians’ attitudes that may influence their CNS stimulants prescribing practices. The survey determined the use of methylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, and pemoline for the treatment of ADHD, narcolepsy, sleep disorders (including sleep apnea), and fatigue. Physician concerns and difficulties regarding the prescription and dispensing of scheduled CNS stimulants (schedule II versus schedule IV) were analyzed.

Methods

A survey of current stimulant prescribing practices among physicians was administered at the American Academy of Family Physicians Scientific Assembly, September 17–19, 1998 in San Francisco, California. The survey was administered from a booth at the meeting by Project House, Inc. and 382 surveys were collected. Only surveys from US physicians (N=342) were used in data analysis. All non-US surveys (n=21) and surveys that did not specify the state in which the physician practiced (n=19) were excluded. Data analysis of two items (types of CNS stimulants currently prescribed and disorders for which CNS stimulants are currently prescribed) was based on 266 surveys of physicians who were current prescribers of CNS stimulants. A description of drug schedules according to the Controlled Substances Act of 1970 was provided for participating physicians. Survey information was entered and analyzed using Statistical Program for the Social Sciences 6.1 for Windows.

Results

The survey queried US physicians about the conditions for which they prescribed CNS stimulants, the CNS stimulants they prescribed most often, and their concerns about prescribing the schedule II stimulant methylphenidate and the schedule IV stimulant pemoline (Table 2). Of the 342 physicians surveyed, 332 (97%) were family practitioners. The remaining 10 specified general practice, internal medicine, pediatrics, neurology, sports medicine, or public health as their specialty.

Among all physicians currently prescribing CNS stimulants, 93% reported that they prescribe CNS stimulants at least sometimes for the treatment of ADHD. They used a 5-point scale ranging from 1–5 (“never” to “always”). Nearly half (49%) reported that they at least sometimes prescribe stimulants for narcolepsy, 23% prescribe for sleep disorders, including sleep apnea, and 13% prescribe for fatigue. Eighteen percent reported that they prescribed stimulants at least sometimes for other conditions, including depression, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, and migraine (Figure 1). Methylphenidate was prescribed at least sometimes by nearly all of the prescribing physicians (95%), while dextroamphetamine (32%), pemoline (24%), and dextroamphetamine/amphetamine (20%) were less often prescribed (Figure 2).



The survey examined concerns with prescribing the schedule II stimulant methylphenidate (Figure 3) and the schedule IV stimulant pemoline (Figure 4). Physicians were most concerned about side effects, efficacy, and abuse potential for both drugs. With regard to prescribing practices involving methylphenidate, physicians were also primarily concerned with the prohibition on refills and logistical problems for patients, such as requiring additional visits to obtain prescriptions. The exclusion of refills was even more of a concern than efficacy of the drug. However, these factors were not concerns associated with pemoline. Physicians reported liver toxicity as the primary concern when prescribing pemoline (Figure 4) with the exception of concerns about side effects and toxicity.


Figure 5 indicates a likely influence of scheduling restrictions on prescribing practices. Among all the physicians surveyed, a majority (71%) reported that they would prefer to prescribe a schedule IV agent rather than a schedule II agent. The investigators who administered the survey noted, however, that many physicians had to refer to the chart of scheduling definitions because they did not immediately recall the various scheduling assignments.

Discussion

CNS stimulants are appropriately prescribed for conditions such as ADHD, narcolepsy, and fatigue. Yet, with the psychoactive nature of these agents comes the potential for abuse and addiction, and this has led to stringent control of these drugs under federally mandated scheduling regulations.

Although this strict regulatory control of scheduled medications has had positive effects in preventing drug abuse and discouraging improper prescription practices, unintended and unwanted effects have also ensued.14,18 Such unwanted results include prescribing scheduled medications in an overly cautious manner that may cause needless suffering; increased prescribing and use of less satisfactory alternative drugs; physician apprehension about potential legal consequences; and physician dissatisfaction with intrusive government regulations.14,18-20

The survey results presented here lend insight into the practices, attitudes, and concerns of physicians regarding the dispensing of scheduled CNS stimulant medications. Physicians cited logistical difficulties (ie, prohibition on refills, logistical problems for patients) as notable concerns specific only for the more strictly scheduled drug (schedule II but not schedule IV). Perhaps most importantly, physicians reported that they would prefer to prescribe a less strictly scheduled drug (schedule IV) before a more strictly scheduled one (schedule II).

Why then is methylphenidate, a schedule II drug, so much more widely prescribed than the less strictly controlled stimulant pemoline, a schedule IV drug?

The answer most likely lies in the efficacy and adverse effect profiles of the respective drugs. Pemoline is believed to be less effective than methylphenidate in the treatment of ADHD,21 and liver toxicity has been commonly reported with pemoline use, relegating it to second-line treatment.22-24 In the treatment of narcolepsy, compliance with pemoline has been shown to be better than that seen with methylphenidate and dextroamphetamine, two schedule II drugs.25 These observations thus suggest that a less strictly scheduled CNS stimulant with efficacy and toxicity equivalent to that of a more strictly scheduled agent may be of considerable usefulness for the physician treating ADHD, narcolepsy, or fatigue.

When reviewing the data from the survey, it must be kept in mind that state-to-state differences in physicians’ responses is likely a factor. Drug regulation policies can vary widely at the state level. This survey was conducted in California, and although the largest proportion of respondents (18%) was from California, responses covered 48 of the 50 United States. This coverage of almost the entire US may lend support to inferences that can be made from the data regarding regulatory practices at the federal level. State drug policies are also changing because some states are implementing, or planning to implement, computer-based electronic data transfer systems for tracking and regulating prescriptions.25,26 Such electronic data transfer databases can reduce the paperwork burden and misprescribing practices associated with current regulatory operations.25

The survey revealed a great deal of out-of-label prescribing of stimulants (eg, for fatigue, depression, cognitive disorders, and other nonapproved conditions). Notwithstanding their status as controlled substances, CNS stimulants may be prescribed in this manner because of patient pressure, lack of approved drugs for these indications, and general physician appreciation of the wake-promoting effects of such drugs, despite the lack of large, controlled trials confirming such clinical impressions. Several small studies in patients with refractory depression, cancer, and fatigue associated with human immunodeficiency virus infection have shown that treatment with CNS stimulants can safely ameliorate fatigue and depressive symptoms in these patient populations.27-29 Together with clinical observations in actual practice, these trials underscore the need for well-controlled formal studies that assess the safety and efficacy of this type of agent in fatigue and depression, thereby providing data to facilitate evaluations of risk-to-benefit ratios.

Continued education about CNS-related disorders and appropriate therapy options is important for the physician. Such education may reduce the underprescription of effective treatments because of drug-abuse concerns or as a result of inconvenient prescribing restrictions. Furthermore, insofar as FDA approval may not provide the optimal criterion for the use of psychotropic medications in certain patient populations, recommendations for off-label uses of such agents may require additional guidelines. In the case of scheduled drugs such as CNS stimulants, such guidelines may require the cooperation of several professional organizations, including patient advocacy groups and local authorities.

Conclusion

CNS stimulants are an important part of the pharmaceutical arsenal for the treatment of attention and sleep disorders. The strict regulation of these controlled substances can impose logistical obstacles for the physician and the patient, hindering access to medications in cases of legitimate need. Physicians can improve their prescribing practice by improving their understanding of which drugs are appropriate for each diagnosis, including an awareness of risk/benefit issues ensuing from choosing a schedule II over a schedule IV medication. Given the educational effort required to handle these substances appropriately in the treatment of CNS disorders, both physicians and patients would benefit from the advent of newer, less rigidly controlled psychoactive agents with lower abuse potential and improved efficacy and safety. Better data are needed on the efficacy and safety of these substances in indications that are currently not approved so that physicians can better assess the likely benefits to their patients relative to possible risks. PP

References

1. Koob GF. Stimulants: basic mechanisms and pharmacology. In: Kryger MH, Roth R, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders Co; 2000:419-428.

2. Ritalin [package insert]. Novartis:?East Hanover, NJ; 1999.

3. Cylert. [package insert]. Medical Economics Company, Inc.; 1999.

4. Dexedrine. [package insert]. Medical Economics Company, Inc.; 1999.

5. Adderall. [package insert].Shire Richwood, Inc.; 1998.

6. Provigil. [package insert].Cephalon, Inc; 2000.

7. Dackis CA, Gold MS. Addictiveness of central stimulants. Adv Alcohol Subst Abuse. 1990;9:9-26.

8. Wise RA, Bozarth MA. Brain mechanisms of drug reward and euphoria. Psychiatr Med. 1985;3:445-460.

9. Parran TV Jr, Jasinski DR. Intravenous methylphenidate abuse. Prototype for prescription drug abuse. Arch Intern Med. 1991;151:781-783.

10. Spier SA. Toxicity and abuse of prescribed stimulants. Int J Psychiatry Med. 1995;25:69-79.

11. Fernandez F, Adams F, Holmes VF, Levy JK, Neidhart M. Methylphenidate for depressive disorders in cancer patients. An alternative to standard antidepressants. Psychosomatics. 1987;28:455-461.

12. Woods SW, Tesar GE, Murray GB, Cassem NH. Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry. 1986;47:12-15.

13. Llana ME, Crismon ML. Methylphenidate: increased abuse or appropriate use? J Am Pharm Assoc (Wash). 1999;39:526-530.

14. Weintraub M, Singh S, Byrne L, Maharaj K, Guttmacher L. Consequences of the 1989 New York state triplicate benzodiazepine prescription regulations. JAMA. 1991;266:2392-2397.

15. Benzodiazepines: additional effects of the triplicate program. N Y State J Med. 1990;90:273-275.

16. Schwartz HI. Negative clinical consequences of triplicate prescription regulation of benzodiazepines. N Y State J Med. 1991;91:9S-12S.

17. List of top 200 drugs includes a few surprises. Drug Topics. 1999;143:30-33.

18. Jaffe JH. Impact of scheduling on the practice of medicine and biomedical research. Drug Alcohol Depend. 1985;14:403-418.

19. Clark HW. Legal implications of prescribing opioid controlled substances. Am J Orthop. 1998;27:29-32.

20. Glass RM. Benzodiazepine prescription regulation. Autonomy and outcome [editorial]. JAMA. 1991;266:2431-2433.

21. Gittelman R, Kanner A. Psychopharmacotherapy. In: Quay H, Werry J, eds. Psychopathological Disorders of Childhood. 3rd ed. New York, NY: John Wiley & Sons; 1986:455-494.

22. Berkovitch M, Pope E, Phillips J, Koren G. Pemoline-associated fulminant liver failure: testing the evidence for causation. Clin Pharmacol Ther. 1995;57:696-698.

23. Adcock KG, MacElroy DE, Wolford ET, Farrington EA. Pemoline therapy resulting in liver transplantation. Ann Pharmacother. 1998;32:422-425.

24. Stevenson RD, Wolraich ML. Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder. Pediatr Clin North Am. 1989;36:1183-1197.

25. Clark HW. Policy and medical-legal issues in the prescribing of controlled substances. J Psychoactive Drugs. 1991;23:321-328.

26. Schiff GD, Rucker TD. Computerized prescribing. Building the electronic infrastructure for better medication usage. JAMA. 1998;279:1024-1029.

27. Masand PS, Anand VS, Tanquary JF. Psychostimulant augmentation of second generation antidepressants: a case series. Depress Anxiety. 1998;7:89-91.

28. Breitbart W, Rosenfeld B, Kaim M, Funesti-Esch J. A randomized, double-blind, placebo-controlled trial of psychostimulants for the treatment of fatigue in ambulatory patients with human immunodeficiency virus disease. Arch Intern Med. 2001;161:411-420.

29. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics. 1996;37:57-62.

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Michael J. Robinson, MD, FRCPC
Primary Psychiatry. 2003;10(1):43-49

 

Dr. Robinson is assistant professor of psychiatry in the Department of Psychiatry, Division of Consultation-Liaison Psychiatry, at Queens University in Ontario, Canada.

Disclosure: Dr. Robinson in on the Speakers Bureau of Organon Canada and Lundbeck Canada, and receives financial support from AstraZeneca and Eli Lilly.

Please direct all correspondence to: Michael J. Robinson, MD, Division of Consultation Liaison Psychiatry, Kingston General Hospital, Connell 4, Room 2-486, 76 Stuart Street, Kingston, Ontario K7L 2V7, Canada; Tel: 613-548-7839; Fax: 613-548-6030; E-mail: mjr4@post.queensu.ca


 

Abstract

What are the potential benefits of next-generation antidepressants? Currently available antidepressants have a number of limitations. Some of these include low response and remission rates, delayed onset of action, poor tolerability, persistent adverse effects, and the potential for clinically significant pharmacokinetic drug interactions. While the advantages of future antidepressants remain to be elucidated, we can speculate that future antidepressant development will address current limitations. New developments in antidepressant psychopharmacology are vast. The development of enantiomeric antidepressants is a good example of potential improvements of some of the current shortcomings including efficacy, tolerability, and the pharmacokinetic and pharmacodynamic properties of antidepressants. Additionally, investigations of new potential mechanisms of action beyond current monoamine-based models of action are being actively pursued.

Introduction

Lifetime risk of major depressive disorder (MDD) varies from 10% to 25% in women and 5% to 12% for men in community samples.1 People who are depressed have increased risks for other medical illnesses, consume higher health care costs, and have higher mortality rates.2-4 The burdens of mental illnesses, such as depression, have been seriously underestimated by traditional approaches that take into account deaths but not disability. While psychiatric conditions are responsible for little more than 1% of deaths, they account for almost 11% of disease burden worldwide. It is estimated that depression will be the second leading cause of disability in the world by the year 2020 and the leading cause of disability in females and developing countries.5

The number of antidepressants available for somatic treatment of mood disorders has expanded appreciably in the last decade. The tricylic antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs) have traditionally served as the benchmarks for measuring efficacy and tolerability. Although TCAs are effective treatment, they have numerous side effects, a narrow therapeutic index, and are potentially life threatening in overdose.

Since the introduction of fluoxetine in 1988, the selective serotonin reuptake inhibitors (SSRIs) have shown efficacy comparable to the TCAs, with improved safety. Since the development of SSRIs, newer antidepressants that have been available in North America include serotonin norepinephrine reuptake inhibitors (eg, venlafaxine), serotonin antagonist reuptake inhibitors (eg, nefazodone and trazodone), noradrenergic specific serotonergic antidepressants (eg, mirtazapine) and norepinephrine reuptake inhibitors (eg, reboxetine). These antidepressants continue to work on monoamine models of antidepressant action.

Currently available treatments have a number of limitations. It is hoped that future development of antidepressants will address these shortcomings. This article briefly reviews some of the current limitations with available antidepressants and outlines new developments and future directions in antidepressant discovery.

Current Limitations of Antidepressants

Low Remission Rates

In short-term clinical trials, response is operationally defined as a 50% reduction from baseline scores on the Hamilton Rating Scale for Depression (HAM-D) or the Montgomery-Åsberg Depression Rating Scale (MADRS). Partial response is defined as a reduction in score of 25% to 49%. The operational definition of remission in clinical trials includes a final score of ≤7 on the 17-item HAM-D scale, of <10 on the 21-item HAM-D scale, and a score of ≤8–12 on the MADRS. While response to therapy is a useful endpoint in short-term clinical trials, the endpoint in long-term trials and the goal of treatment in clinical practice should be remission.6 Response rates of all antidepressants are reportedly 60% to 70%, leaving a sizable minority, 30% to 40%, who do not respond to the drug treatment or will have only a partial response. Unfortunately, even fewer patients achieve full remission of their mood disorder. Approximately 30% to 40% of patients taking antidepressants achieve full remission, leaving 60% to 70% of patients without full remission.7,8 Potential consequences of failing to achieve remission include increased likelihood of relapse, poor outcome, future treatment nonresponsiveness, residual disability, and even suicide.9

All antidepressants reportedly produce similar response rates, and therefore are reported to be equally efficacious in the treatment of mood disorders. But are all antidepressants equal in terms of remission rates?

Currently available antidepressants work on the monoamine-based mechanism of action and enhance either singly, or in combination, serotonergic, noradrenergic, and, to a lesser extent, dopaminergic neurotransmission. TCAs have heterogeneous effects on neurotransmitter systems. Some TCAs, such as imipramine, clomipramine, and amitriptyline, have a dual mechanism of action, with roughly equivalent selectivity for norepinephrine and serotonin. Conversely, TCAs, including maprotiline, desipramine, and nortriptyline, are substantially more selective for norepinephrine then they are for serotonin.

SSRIs principally inhibit serotonin while newer agents, such as venlafaxine, mirtazapine, duloxetine, and milnacipran, enhance both serotonergic and noradrenergic neurotransmission. Traditionally, drugs that had multiple mechanisms were synonymous with “dirty drugs” because it implied unwanted side effects. We typically think of TCAs in this regard. Later, there was a trend to develop more selective drugs, such as the SSRIs, which attempted to remove unwanted side effects. More recently, there has again been a trend to add multiple mechanisms together to improve both tolerability and efficacy.10 Evidence for enhanced efficacy among antidepressants with dual action versus single action has been examined in a number of studies and meta-analyses.11,12

A small, preliminary, open study of the combination of fluoxetine and desipramine suggested that treatment that engages both noradrenergic and serotonergic systems may enhance remission rates.13 Additional studies and meta-analyses of TCAs over SSRIs conclude that TCAs with a dual mechanism of action are significantly more efficacious than SSRIs.11,12 Furthermore, a recent report by Thase and colleagues14 presented the results of a pooled analysis of remission rates comparing venlafaxine and the SSRIs fluoxetine, paroxetine, and fluvoxamine. Data from eight comparable randomized, double-blind studies of MDD were pooled to compare remission rates during treatment with venlafaxine, SSRIs, or placebo. It included original data from a total of 2,045 patients. Remission rates were reported to be 45% for venlafaxine, 35% for SSRIs, and 25% for placebo. The difference reported between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. In light of these findings, current evidence suggests that a dual mechanism of antidepressant action provides superior efficacy especially in terms of remission rates.

Delayed Onset of Action

Although the synaptic effects of antidepressants occur within hours of ingestion, the therapeutic or clinical effects are not seen for several weeks. In controlled trials, statistically significant differences between active treatment and placebo often require 4 weeks or more to emerge. The usually expected delay of efficacy for any antidepressant is between 10 days and 3 weeks at therapeutic doses. There are a number of potential consequences of delayed onset of antidepressant action. These may include increased vulnerability for suicide, longer hospital stays, prolonged physical, psychological, and social impairment, as well as the increasing economic burden of depression.15

Clinical trials to date have not been designed to adequately assess the timing of antidepressant action onset. Primarily, this results from no set standard for measuring rapid onset of action.16 A consensus meeting of the European College of Neuropsychopharmacology in 1994 considered that relative responses in the first 2 weeks should form the basis of the claim for rapid-response antidepressant.17

How one should measure rapid-response on the HAM-D, for example, has not been operationalized as it has for response and remission. In addition, clinical trials assessing rapid onset of action should have frequent early clinical assessments. While no trial has been adequately designed to prospectively assess early onset of action, a few clinical studies have been conducted that suggest some of the newer antidepressant agents may have an earlier onset of action.15 These include trials of citalopram, venlafaxine, and mirtazapine.

In two studies comparing citalopram with placebo, patients from both studies showed greater reductions in HAM-D scores than placebo-treated patients starting at week 1, which continued throughout the trial endpoint.18,19 In comparison trials with other antidepressants, citalopram has exhibited evidence suggesting a faster time to onset compared with fluoxetine, sertraline, imipramine, and mianserin.15,20-22 In each of the studies, citalopram-treated patients were significantly more improved at week 2 than comparison patients.

In comparison studies of venlafaxine with placebo, venlafaxine-treated patients also seems to exhibit statistically significant improvements in scores of depression relative to placebo-treated patients after 1–2 weeks.15,23,24 Venlafaxine has been dosed aggressively in comparison studies with placebo. In a prospective head-to-head comparison of venlafaxine to fluoxetine, in which both venlafaxine and fluoxetine were dosed aggressively, several outcome measures suggested an earlier response to venlafaxine than to fluoxetine.25

In a comparison study with placebo, mirtazapine was found to be significantly superior to placebo beginning at week 1 and continuing throughout the 6-week trial.26 In comparison with other antidepressants, mirtazapine appeared to have a faster onset of action than citalopram, but with comparable improvements in study measures at the endpoint.27 In a retrospective analysis comparing mirtazapine with fluoxetine, paroxetine, and citalopram, mirtazapine appeared to have a faster onset of action compared to fluoxetine and paroxetine, but not citalopram.15 While there are several methodologic shortcomings of the studies, there is some evidence to suggest that the onset of effect for some antidepressants may be earlier than for others.

Side Effects

Newer antidepressants appear to have side effects that are more tolerable than those of MAOIs or TCAs. Side-effect profiles of antidepressants may largely be understood by knowledge of their respective neuroreceptor actions and by the clinical effects produced by these actions (Tables 1 and 2). Among serotonergic agents, side effects resulting from 5-HT2A may include insomnia, anxiety/agitation, and sexual dysfunction, 5-HT2C may cause irritability and decreased appetite, and 5-HT3 may cause nausea, vomiting, and headache. Side effects such as tachycardia, blood pressure effects, dry mouth, and sweating, which are associated with newer agents, may also result from noradrenergic receptor stimulation. Side effects of dry mouth, sedation, postural hypotension, may result from interactions at other receptors including muscarinic, cholinergic, histaminergic, and postsynaptic α1-adrenergic.

There are multiple reasons why patients stop taking their antidepressants. Maddox and colleagues28 studied common reasons for noncompliance in general practice. In their study, approximately 52% of patients stopped taking their medication during a 12-week period and two thirds did not inform their general practitioner. In addition, 30% of patients stopped taking their medication because of side effects experienced within the first 4 weeks of treatment. Despite recent advances and improvements in antidepressant tolerability with minimal overdose toxicity, tolerability continues to be one of the leading causes of nonadherence to treatment, thereby limiting treatment success.

Drug-Drug Interactions

Depression requires months or even years of maintenance pharmacotherapy. Some surveys have shown that up to 30% of patients may be co-prescribed an antidepressant that interacts with cytochrome P450 (CYP) enzymes and other prescribed medications. It is quite likely that most patients receiving antidepressant medications will take at least one other drug at some point during treatment. In addition, polypharmacy is common in patients with chronic medical conditions. Hence, the physician must constantly be aware and keep up-to-date with potentially clinically significant drug interactions that may occur with the use of antidepressants.

Drug interactions are commonly classified as pharmacodynamic or pharmacokinetic. A pharmacodynamic drug interaction occurs when the pharmacologic response to one drug is modified by another drug without the effects being the result of the change in drug concentration. The pharmacokinetic interactions include alternate distortion, distribution, metabolism, or excretion and can result in changing the drug concentration in tissues. However, the majority of drug interactions of concern involve alterations of drug metabolism. The liver is a primary agent of elimination of psychoactive drugs including antidepressants. The most important enzymes in terms of understanding pharmacokinetic drug interactions are those of the CYP system. A complete discussion of drug interactions is beyond the scope of this article; an extensive guide to psychotropic drug interactions is presented by DeVane and colleagues.29 Briefly, the substrate is an agent or a drug to which metabolism is catalyzed by CYP isozymes. An inducer is an agent or drug that increases the catalytic activity of the enzyme, allowing for increased rate of metabolism, whereas an inhibitor decreases the catalytic activity of an enzyme, resulting in the opposite effect on the enzyme. Prediction of metabolic drug interactions for the practicing clinician is aided by knowing the metabolic pathways of the drug and whether the drug to be combined in therapy has inhibitory effects on that enzyme. It should be remembered however, that concentration changes do not necessarily translate into clinically meaningful interactions. Table 3 lists the inhibitory potentials of currently available antidepressants. Antidepressants presently may cause significant drug-drug interactions based on their inhibitory potential and the co-prescribed medications. Some of these potential interactions may be serious.

Next-Generation Antidepressants

With remission as the target treatment for depression, it is apparent that our current antidepressant treatments do not adequately meet this treatment goal. Future antidepressants will demonstrate greater efficacy than previous antidepressants with increased remission rates (Table 4). The next-generation antidepressants will have a rapid onset of efficacy. This will help to decrease patient suffering, risk of suicide, and economic burden of depression. By improving the tolerability of next-generation antidepressants, we hope to positively impact treatment adherence. To reduce the clinical impact of potential drug interactions, future antidepressant development will include medications devoid or with only minimal effects on inducing or inhibiting CYP enzymes and will be substrates for metabolism on a variety of enzymes. This will minimize concerns for potential pharmacokinetic drug interactions.

New Developments

As we develop increasing knowledge of the neurophysiologic mechanisms of mood disorders, more treatments will become available. There are numerous agents currently being developed in the area of mood disorders treatment, including those with novel mechanisms of action. Thus far, monoamine models of antidepressant action have been the focus of research. Currently, all antidepressants available are hypothesized to work by directly or indirectly enhancing one or a combination of the monoamines, including serotonin, norepinephrine, and dopamine. However, monoamine-based hypotheses of antidepressant action are ultimately incomplete as they do not fully explain several important clinical limitations of current treatment including incomplete efficacy, low remission rates, and delayed response.30

Although the majority of current agents in development largely center on manipulating the monoamine model of antidepressant action, there is a number of new models of antidepressant action for which agents are being developed and studied. The following section will briefly review some new agents in the later stages of clinical development and will comment on some potential novel mechanisms of antidepressant action.

Enantiomers

Many drugs, including antidepressants, are chiral compounds. A chiral compound is a mixture of two mirror-image stereoisomers of each other, each called an enantiomer; the mixture is called the racemate. It is now well established that a stereospecific biotransformation of a chiral drug can affect its clinical properties. The potential benefits of developing enantiomeric drugs include improvements in clinical efficacy, enhanced tolerability, refined pharmacokinetic and pharmacodynamic properties, decreased risk for drug interactions, reduced toxicity, improved dosing schedules, and hopefully cost effectiveness.31 Chiral antidepressants that exist as racemic mixtures are increasingly being relaunched with the inactive isomer removed. For example, citalopram is a racemic antidepressant of R- and S-enantiomers. Escitalopram (S-citalopram) is the first enantiomeric refinement of a racemic antidepressant to be available in clinical practice. Current information suggests that it has advantages of dose reduction, some side effects lessened, and some drug interactions reduced. There is also a suggestion in animal models that it may have the rapid onset of action.32 As our understanding of stereochemistry improves in relation to psychopharmacology, it is possible that some of the shortcomings of currently available antidepressants may be improved upon through the development of enantiomeric antidepressants.

Novel Mechanisms

A full inclusive discussion of the numerous novel mechanisms under investigation is well beyond the scope of this article. There are several mechanisms for which agents are currently being developed that will hopefully add new strategies to the pharmacologic treatment of depression (Table 5).30,33 Some of these novel mechanisms involve modulation of the monoamines and can be thought of as an extension or enhancement to the current monoamine-based therapies. This includes drugs with selective affinity for the serotonin 5-HT1A receptor with evidence suggesting that 5-HT1A ligands are safe and effective in major depression.34 In addition to ligands with selective affinity for only one serotonin receptor there are other drugs under development with mixed affinity for various serotonergic receptors. Clinical data on the safety and efficacy of these agents are not yet available.

Neurokinin antagonists might be novel antidepressants. Unexpected observations of improved mood in some studies of substance P antagonists being tested in pain and inflammation led to a serendipitous finding that has precipitated the investigation and development of neurokinin receptor antagonists. It has also led to the development of the hypothesis of neurokinin function in emotional dysfunction. The neurokinin neurotransmitter system is a family of three related peptides known as neurokinins (substance P, neurokinin A, and neurokinin B). There are specific receptor subtypes that correspond to these three neurokinins (neurokinin 1, neurokinin 2, and neurokinin 3, respectively). Selective antagonists for all three neurokinin receptors are in development and testing.35-37

Finally, other areas being investigated include the N-methyl-D-aspartate (NMDA) model of antidepressant activity with the development of selective NMDA antagonists which have been demonstrated to be effective in animal models of depression and in models predictive of antidepressant action.38 Abnormalities of the hypothalamic-pituitary-adrenal axis function in depressed subjects is well characterized.39 This has led to the investigation of the role of corticotropin-releasing hormone in the mechanism of action of antidepressants with the development of the corticotropin-releasing factor antagonists. Looking beyond the receptor, antidepressant action may involve important effects on postsynaptic intracellular signal processing. There are agents being studied that address modulation of postreceptor mechanisms to exert antidepressant action.

Conclusion

Major depression is a common condition that contributes globally to significant disease burden and disability. Despite our major advances in antidepressant psychopharmacology over the past decade, there still remain many limitations to our currently available treatments. Antidepressant treatment is plagued with low remission rates that add to the number of patients living with disability attributable to depression. We continue to struggle to find antidepressants that will have a faster onset of action. Even though newer antidepressants have improved on safety and tolerability over the older TCAs and MAOIs, adverse effects continue to negatively impact treatment adherence and success. Complicating current treatments is the issue of potentially clinically significant drug interactions, which requires that the prescribing physician remain updated in their pharmacologic knowledge of these medications and their potential to cause or contribute to drug interactions. The future next-generation antidepressant will hopefully address some of these shortcomings.

New developments, such as enantiomeric antidepressants, may help us to address a few of these limitations as well. Finally, future antidepressants may involve several of the many new mechanisms of action that are being investigated. PP

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed rev. Washington, DC: American Psychiatric Association; 2000.

2. Johnson J, Weissman MM, Klerman GL. Service utilization and social morbidity associated with depressive symptoms in the community. JAMA. 1992;267:1478-1483.

3. Lesperance F, Frasure-Smith N. Depression in patients with cardiac disease: a practical review. J Psychosom Res. 2000;48:379-391.

4. Wulsin LR, Vaillant GE, Wells VE. A systematic review of the mortality of depression. Psychosom Med. 1999;61:6-17.

5. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349:1498-1504.

6. Bakish D. New standard of depression treatment: remission and full recovery. J Clin Psychiatry. 2001;62(suppl 26):5-9.

7. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200.

8. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry 2001;62(suppl 16):26-31.

9. Stahl SM. Why settle for silver, when you can go for gold? Response vs. recovery as the goal of antidepressant therapy. J Clin Psychiatry. 1999;60:213-214.

10. Stahl SM. Selecting an antidepressant by using mechanism of action to enhance efficacy and avoid side effects. J Clin Psychiatry. 1998;59(suppl 18):23-29.

11. Anderson IM. SSRIs versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress Anxiety. 1998;7(suppl 1):11-17.

12. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord. 2000;58:19-36.

 

Drs. Garcia and Lynn are Psychosomatic Medicine/Psycho-Oncology fellows and Dr. Breitbart is Chief of Psychiatry Service, all in the Department of Psychiatry and Behavioral Sciences at Memorial Sloan-Kettering Cancer Center in New York City.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.
Off-label disclosure: This article includes discussion of unapproved/investigational treatments for delirium, depression, fatigue, nausea, pain, and palliative sedation in the cancer population.

Please direct all correspondence to: William Breitbart, MD, FAPM, FAPA, Chief, Psychiatry Service, Vice Chairman, Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, 641 Lexington Ave, 7th floor, New York, NY 10022; Tel: 646-888-0020; E-mail: Breitbaw@mskcc.org.


 

Focus Points

• Antipsychotics play an adjuvant role in the management of pain, nausea, and terminal sedation, but are primary agents in the management of delirium in the palliative care setting.
• Benzodiazepines play an adjuvant role in the management of pain, nausea, and delirium, but are primary agents in the management of palliative sedation.
• Psychostimulants are useful as primary antidepressants in the palliative care setting and are also helpful as adjuvant agents in the management of pain, opioid-induced sedation, and fatigue.
• Antidepressants are effective in the treatment of depression in patients with life-threatening illness, even in the palliative care setting; however, their use near the end of life is limited by the time required for the onset of beneficial effects.
 

Abstract

Psychotropic medications have had significant roles in the management of a variety of symptoms in patients living with chronic medical illness and in patients at the end of life. Intuitively, this may make sense given the considerable overlap of psychological and somatic symptoms in this population. Several reviews of the use of specific agents exist in the literature. However, a brief overview of the most commonly used psychotropic drug classes in palliative care can be helpful for a primary care provider to have as a guide to their usefulness in this population. This article reviews the use of antipsychotics, benzodiazepines, antidepressants, and psychostimulants/wakefulness agents for symptoms such as depressed mood, pain, nausea, palliative sedation, and delirium.

Introduction

Palliative care, as both a movement and a medical subspecialty, has grown over time from a small hospice movement focusing on the care of the actively dying to a clinical specialty focusing on symptom control and provision of support to those living with chronic, life-threatening illnesses in addition to those at the end of their lives.1 Given the burden of disease these patients face, it is perhaps not surprising that psychological symptoms such as depression, anxiety, and hopelessness are as frequent, if not more so, than other target symptoms such as pain.1 Inversely, perhaps in part due to their proximity to mental suffering and its treatment, practitioners of this discipline have long used psychotropic medications for a variety of symptoms, both in traditional and novel ways. However, the evidence upon which some of these practices rest are variable and at times appear more historic than supported by either accumulated clinical experience or empirical evidence. The following is a brief review of some of the ways that psychotropic medications are being used in palliative care and the evidence upon which their use rests.

Antipsychotics

Antipsychotics have played a variety of novel roles in the treatment of the medically ill, including in the palliative care population. These drugs are divided into typical and atypical agents. Typical antipsychotics, which include haloperidol and chlorpromazine, are primarily dopamine (D)2 receptor antagonists, blocking these receptors nonspecifically throughout the brain. This results in both their efficacy against the positive symptoms of psychotic disorders like schizophrenia, but also contributes to the associated negative sequelae such as cognitive and extrapyramidal side effects (EPS). In contrast, atypical antipsychotics are serotonin-dopamine antagonists and specifically block various serotonin and dopamine receptors simultaneously in specific regions of the brain. Through a series of complex interactions between the serotonin and dopamine regulation systems in the various dopamine pathways, atypical antipsychotics help solve the “paradox” initially posed by typical antipsychotics, allowing the treatment of both positive and negative symptoms of schizophrenia while also reducing side effects of generalized dopamine blockade, such as EPS.2

The result is a heterogenous group of drugs with a wide variety of potential actions that have been exploited in novel ways. Their use in the palliative care setting is an example of the flexibility with which these medications are now used, though the evidence for these uses remains variable.

Antipsychotics in Delirium

Delirium is the most common neuropsychiatric disorder reported in the terminally ill.3-10 Various studies report prevalence rates between 20% to 88%,3,5,6,11 with rates rising sharply as the time of death approaches.4,9,10 Although there initially was some concern regarding the reversibility of delirium in the terminally ill, it has been increasingly clear that this is not the case and ~50% of delirium in the terminally ill cancer patients are reversible with appropriate treatment.10 Breitbart and colleagues3 provide a thorough review of the management of delirium in the terminally ill.

Although the mainstay of treatment for delirium still remains identifying and reversing the underlying medical cause, antipsychotics continue to play a role in the symptomatic management of delirium, particularly in the terminally ill where aggressive investigation and intervention must be weighed against comfort and quality of life.5,12-17 A summary of routes of administration and dosages is provided in Table 1.

 

Typical Antipsychotics
Haloperidol has been the traditional drug of choice for the symptomatic treatment of delirium,5 and this remains the case in the palliative care setting.11-14,18 Typically, low doses of 0.5–2.0 mg are administered every 1–8 hours and titrated to effect,5,6,12,14,19 with a maximum daily dose of 20 mg in most patients.3 Lower doses are associated with better tolerability.14 The United States Food and Drug Adminstration has issued a warning about the risk of QTc prolongation with the intravenous (IV) route, requiring routine electrocardiograms in non-terminal patients. Advantages of haloperidol include tolerability (at lower doses), flexibility of route (PO [by mouth], IV, SC [without food], intramuscular [IM]), and relative safety and efficacy.3,5,11,14

Chlorpromazine has been found to be as useful as haloperidol,20 but is considerably more sedating, anticholinergic, and hypotensive.3,14,21 This may make it a reasonable second-line agent for agitation that does not respond to haloperidol. Dosages for chlorpromazine range from 12.5–50.0 mg IV or SC every 4–8 hours, to a maximum of 300 mg per 24 hours for most patients.20,22

Methotrimeprazine is similar to chlorpromazine, and has also been found to be useful in the palliative care setting both as a neuroleptic for delirium and as an anxiolytic and analgesic that is equipotent to morphine.22 Unfortunately, this agent is not available in the US, though it is widely used elsewhere. Dosages for methotrimeprazine range from 10–20 mg IV, IM, or SC every 4–8 hours.20,22,23

There is one case report24 of zuclopenthixol acetate, an injectible typical antipsychotic with a 2–3 day efficacy window, being used successfully in delirium at the end of life. Again, this medication is not available in the US.

Atypical Antipsychotics
Of the atypical antipsychotics, risperidone, olanzapine, and quetiapine have some evidence beyond case reports of efficacy in the management of delirium.3,12,14,25,26 Risperidone has been found to be efficacious at doses of 0.5–2.0 mg PO BID in delirious patients14,27,28; one small double-blind study29 confirmed its efficacy as similar to haloperidol in delirious patients. Further evidence supports that there is reduced risk of EPS with risperidone as compared to haloperidol.30,31

Olanzapine has been found to be efficacious in the treatment of delirium in patients with advanced cancer without the complication of EPS,32 and appears comparable in effect to haloperidol.33,34 However, it may be less useful in those with hypoactive delirium, those with central nervous system (CNS) spread of cancer as the etiology of their delirium, or older patients (>70 years of age).32 Dosing for olanzapine in delirium in the terminally ill appears to be ~2.5–20.0 mg/day PO.14

Quetiapine has a few open-label studies and case reports suggesting efficacy in the treatment of delirium, but sedation was a limiting factor.35,36 Some case reports suggest that ziprasidone and aripiprazole may also be efficacious in delirium,37-39 but the former is limited by its potential cardiac side effects38 and the latter is still very limited in its evidence.39,40

Antipsychotics in Pain

Pain is a common symptom in terminally ill patients, with some suggestion that up to 50% of the terminally ill are in moderate to severe pain,41,42 and that an estimated 25% of cancer patients die in severe pain.41

Although the mainstay of pain management remains opiates, antipsychotics have played an adjunct role, though the evidence for this may be limited.43 Methotrimeprazine, as mentioned previously, is a unique typical antipsychotic that is equianalgesic to morphine, has none of the opiod effects on gastrointestinal motility, and likely also has anti-emetic and anxiolytic effects.41 Fluphenazine has been used successfully in combination with tricyclic antidepressants for neuropathic pain.44

Data for the usefulness of atypical antipsychotics is scanty, but one small prospective study45 showed improvement of pain scale scores, reduced need to increase opiates daily, and some mild sedative effects with the adjunct use of olanzapine with opiates in cancer pain.

Antipsychotics in Nausea and Emesis

Nausea is a very common experience in both the active and palliative phases of treatment of cancer.46-48 Although the bulk of the literature reflects treatment of nausea and emesis in patients outside of the palliative setting, a few studies do suggest that the same antipsychotics found to be useful during chemotherapy may be useful in the hospice setting.46-50

Phenothiazines, including chlorpromazine, methotrimeprazine, and perphenazine, have been found to be useful as anti-emetics via D2 blockade.49 Prochlorperazine belongs to this family of antipsychotics, though its primary role has always been as an anti-emetic.49 Haloperidol and droperidol have also been found to be useful for emesis via case reports and small trials,51-53 including in the palliative population.46,47

Aside from prochloperazine, olanzapine has perhaps the most robust evidence for its anti-emetic effect in cancer patients both in the acute and palliative treatment phase.48,49 It is useful both for the acute and delayed emesis of chemotherapy54,55 as well as for intractable nausea in palliative care patients.48,50 A proposed mechanism of action is its strong antagonism of serotonin (5-HT)6 and 5-HT3, which along with its selective D2 receptor antagonism may work at several places in the central regulation of emesis.56

Antipsychotics in Palliative Sedation

Palliative sedation, or terminal sedation, is a controversial practice with many definitions. Perhaps the most inclusive and general is “the use of pharmacological agents to induce unconsciousness for treatment of truly distressing and refractory symptoms in the terminally ill.”57

Although there are no official clinical guidelines in the US, practitioners are guided by those of other nations58 as well as some limited data.59 There is little role for antipsychotics in palliative sedation except in the context of treating delirium. However, chlorpromazine has been used based on clinical experience, in part due to its sedating effects and relatively easy titration.57 Its dosing and titration appears to be very similar to its use in delirium.

Benzodiazepines

Benzodiazepines represent a class of anxiolytics that bind selectively to gamma-aminobutyric acid receptors, resulting in several therapeutic effects (sedation, anxiolysis, muscle relaxant, anticonvulsant) and side effects (amnestic agents, ataxia, tolerance, and withdrawal).2 Like antipsychotics, these agents have played a wide variety of roles in palliative care throughout the decades, sometimes despite limited evidence.60,61

Benzodiazepines in Delirium

Although historically benzodiazepines played a significant role in the treatment of delirium, there has been sufficient accumulated evidence to clarify that they are not useful as single agents in this disorder, both in non-palliative and palliative populations, and likely worsen clinical outcomes when used alone.5,14,17,19 This appears to be largely due to their cognitive and disinhibitory effects.14 In contrast, there is some evidence that lorazepam may have a role as adjunct therapy for hyperactive deliriums that do not respond to haloperidol alone.14 This relatively rapid-acting and short-lived agent may be more effective in rapidly sedating agitated patients than haloperidol alone, and may also help minimize the EPS associated with haloperidol.62 A typical dosing for this would be 1–2 mg PO/IV/IM Q1–4 hours, to be given in conjunction with regularly scheduled haloperidol.14

Benzodiazepines in Pain

As in delirium, benzodiazepines have had a historic role in the treatment of both acute and chronic pain, but accumulating evidence suggests that their role is likely to be adjunct at best, perhaps more related to their anxiolytic effect.63 There is some suggestion in the literature that their anti-convulsant properties may provide some efficacy in neuropathic pain.64 One study65 in particular noted that alprazolam appeared to be useful as adjunct treatment for phantom limb pain in cancer patients. Similarly, clonazepam may be useful in the management of certain types of neuropathic pain in cancer patients.66,67 Interestingly, an earlier study63 examining the possible role of alprazolam in increasing the potency of morphine found little improvement of analgesic effect but a significant improvement in opiate-related nausea.

Benzodiazepines in Nausea and Emesis

Benzodiazepines appear to have valuable adjunct roles in nausea and emesis, largely in the treatment of anxiety and anticipatory nausea and emesis associated with chemotherapy, particularly in children.49,68-70 One study71 found the adjunct efficacy of lorazepam added to metoclopromide or dexamethasone regimens for chemotherapy-induced nausea to be equivalent to the adjunct efficacy of diphenhydramine added to these same regimens, but with better control of anticipatory anxiety symptoms and superior patient satisfaction in the lorazepam arm of treatment. Another study72—a randomized, double-blind, crossover design—showed improved efficacy of lorazepam over placebo when added as an adjunct to prochlorperazine for chemotherapy-induced nausea. However, there was no evidence found in the literature in this review to support the role of benzodiazepines as single or primary anti-emetics.49 No clear guidelines for dosing of benzodiazepines for the treatment of emesis were found.

Benzodiazepines in Palliative Sedation

Palliative sedation is one of the few areas of palliative care where benzodiazepines are considered a mainstay of treatment.57-59,73 Although historically, opiates and occasionally antipsychotics were utilized for this purpose, existing palliative sedation guidelines recommend midazolam as the preferred agent for this intervention.57 The reasoning for this, supported by primarily accumulated clinical experience, is that deliberate overdose of opiates to the point of sedation often result in other unpleasant side effects, such as delirium, restlessness, sweating, myoclonus, and nausea.57-59 Suggested dosing for midazolam in palliative sedation is 0.4 mg/hour, with dose escalation to 4.5–10.0 mg/hour.57

Antidepressants

Similar to other psychotropic medications, antidepressants as a class can be used for the treatment of several different symptom profiles in the terminally ill. All antidepressants act through the monoamine transmitter system—impacting the release, breakdown, or reuptake of serotonin, norepinephrine or both—ultimately in delayed effect, impacting gene expression in the neurons targeted by those monoamines.2 (Table 2 lists medications by class and clinical doses.74)

 

 

 

As a class, through these similar mechanisms, these drugs can all cause to different extents neuropsychiatric side effects. Serotonin syndrome is an uncommon but potentially life-threatening toxicity from excessive serotonergic activity which clinically presents as rapid onset tremor, hyperreflexia, mental status changes, and autonomic instability. Definitive treatment is the removal of the serotonergic agent. Due to the potential serotonergic reuptake inhibition of some opiate analgesics (including fentanyl), care should be taken.75 These agents are also associated with akathisia—the subjective feeling of restlessness and objective motor agitation—usually in the lower limbs, bilaterally, and symmetrically.75 This is similarly treated by removal of the causative agent.

Depression

Estimates of depression in the palliative care setting vary widely, depending on the diagnostic methods used.76,77 Some have cited rates from 13% to 26% in the terminally ill.78 Depression is thought to reduce quality of life and be associated with a desire for hastened death.78-82 Yet, treatment of depression is complicated by the fact that most traditional antidepressants take several weeks to have therapeutic effect; the goal of intervention in this setting is rapid onset of action. Thus, considerations for antidepressants are often based largely on side effect profiles, potential drug-drug interactions, and treatment goals in the setting of life expectancy.78

Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are generally considered the first line for the treatment of depressive disorders in the medically ill due to the high efficacy and low side effect profile of this class. However, these medications take several weeks to show therapeutic effect. In patients with a life expectancy of several months, these medications have been shown to be helpful and effective.83,84 Older SSRIs, fluoxetine and paroxetine, are potential inhibitors of cytochrome P450 enzymes, increasing the potential for drug-drug interactions.64 Sertraline, citalopram, or escitalopram carry a lower risk of inhibition and thus potential drug interactions.64

Tricyclic Antidepressants
While tricyclic antidepressants (TCAs) have been shown to be effective, with sufficient time to therapeutic benefit,84 they are less frequently used for depression alone given their anticholinergic, anti-andrenergic, and antihistaminic side effects. TCAs are more likely to be chosen for combined treatment of depression and neuropathic pain.

Serotonin Norepinephrine Reuptake Inhibitors
Serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine are generally found to be well tolerated and with side effect profiles similar to SSRIs. Venlafaxine acts as an SSRI at lower doses, usually only inhibiting norepinephrine at doses >150–225 mg. Both are noted to contribute to hypertension.

Other Antidepressants
Buproprion, acting through reuptake inhibition of dopamine and some norepinephrine, is a well-tolerated antidepressant, noted to have some mild stimulating effects providing benefit to the depressed patient with prominent fatigue. It is noted to lower seizure threshold and thus is to be used with caution in patients with CNS tumors, pathology, or underlying seizure disorders. Mirtazepine, a noradrenergic and specific serotonin antidepressant, has delayed antidepressant effects through its actions at 5-HT2 and 5-HT3, but also causes rapid weight gain and sedation through its high affinity for H1; these side effects can be beneficial for patients with insomnia and weight loss.85

Pain

One of the most difficult problems in palliative care is achievement of appropriate and sufficient palliation from pain. Many antidepressants have been shown to have analgesic effects both directly and through augmentation of opioid analgesics, independent of depressive symptoms.86 Most studies investigate the impact of these medications in addition to opioid compounds rather than as an alternative.

Tricyclic Antidepressants
TCAs have the most robust evidence for efficacy in the treatment of pain, likely three routes: antidepressant activity, potentiation of analgesic activity,87,88 and direct analgesic effects.89 Amitriptyline is the most widely studied in many different types of pain, yet efficacy has been shown for imipramine, desipramine, nortriptyline, clomipramine, and doxepin.64,87,89-91 Evidence suggests that dosing for pain control should be targeted to serum levels similar to those sought for antidepressant effect.91

Selective Serotonin Reuptake Inhibitors
Some trials have demonstrated efficacy of the SSRIs in the treatment of neuropathic and cancer-related pain intensity, usually equal to or approaching that of the TCAs. Fluoxetine has been demonstrated to decrease cancer-related pain intensity84 and to act as a potentiator of morphine.92 Similarly, paroxetine and citalopram have demonstrated efficacy in the treatment of neuropathic pain, in some cases equal to that of imipramine.93,94 Similar evidence has yet to be specifically demonstrated for the newest of the SSRIs.

Fatigue

Fatigue is found to be a highly distressing and prevalent symptom which impacts patients’ quality of life.95 Fatigue is described as a sense of tiredness or exhaustion out of proportion to recent activity and is not responsive to rest.96 It can be found as a side effect of opiate treatment (sedation) or associated as a symptom of depression. However, it is increasingly acknowledged as an independent complaint.97

Buproprion
Bupropion is often considered to be a “stimulant-like” antidepressant. It has been shown in open-label trials of the sustained release formulation, at doses between 100–300 mg, to demonstrate significant improvement in the treatment of fatigue in both depressed and non-depressed cancer patients.98,99

Selective Serotonin Reuptake Inhibitors
Several clinical trials of SSRIs for the treatment of fatigue have failed to show any significant effect of this drug class on fatigue alone.100-102 Thus, SSRIs are thought only to have a role in the treatment of fatigue as a symptom of a greater depressive disorder.

Psychostimulants and Wakefulness-promoting Agents

Traditional psychostimulant medications, methylphenidate and dextroamphetamine, act predominately through release of dopamine from the presynaptic terminal, and additionally through blocking reuptake of that same dopamine.2 These medications are generally considered to be well tolerated but do have known side effects, including agitation, insomnia, tachycardia, hypertension, and—as a result of the increased dopamine levels—psychotic symptoms.2,103 In addition to tablet forms, methylphenidate is available in a transdermal patch.

Modafinil is a novel psychotrophic agent used to promote wakefulness in settings of excessive sleepiness; it is used for narcolepsy, obstructive sleep apnea, and shift work. While it may block some dopamine reuptake similar to the stimulants, it is thought to enhance the activity of the hypothalamic wakefulness center, promoting release of histamine, orexin, and hypocetin.2,95 It is has less potential for dependence and fewer side effects than traditional stimulants.

Depression

Methylphenidate and dextroamphetamine have been shown in the palliative care population to be a rapid and effective treatment of depressive symptoms.104-107 Response is anticipated within 48 hours of initiation of treatment with psychostimulants.108 While attention must be paid to possible side effects (agitation, insomnia, tachycardia, hypertension, or rarely psychotic symptoms), these medications are noted to be very well tolerated in this population.103

Pain

Psychostimulants have been shown to have clear and rapid onset effects on pain. In addition to treating the excessive sedation associated with opiate treatment, both methylphenidate and dextroamphetamine have been shown in small clinical trials to potentiate the therapeutic effects of opiates.109-112

Fatigue

Methylphenidate has been demonstrated in both clinical trial and open-label studies to show significant improvement in the treatment of fatigue.95,109-111 Dosing of methylphenidate has ranged from 5 mg/day–10 mg BID and as high as 30 mg total daily dose.95,109-111,113,114 While some studies have reported patients to be largely free of troublesome side effects, others noted patients experiencing problems with insomnia and cardiovascular toxicity.

Used at low doses (200–225 mg) in chronically ill and cancer patients, modafinil has been demonstrated in open-label trials to show significant reduction in fatigue following several weeks of treatment without significant side effects.95,115 Clinical experience suggests that this effect can be achieved quite rapidly and does not require weeks of treatment for improvement. However, randomized clinical trials are still needed to confirm these clinical observations.

Conclusion

Psychotropic medications have had significant roles in the management of a variety of symptoms in patients living with chronic medical illness and in patients at the end of life. This article provides a summary of the available evidence for the traditional and novel indications for antipsychotics, benzodiazepines, antidepressants, and psychostimulants. PP

References

1.    Chochinov H, Breitbart W, eds. Handbook of Psychiatry in Palliative Medicine. New York, NY: Oxford University Press; 2009
2.    Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. New York, NY: Cambridge University Press; 2008.
3.    Breitbart W, Alici Y. Agitation and delirium at the end of life: “we couldn’t manage him”. JAMA. 2008;300(24):2898-2910.
4.    Lawlor PG, Gagnon B, Mancini IL, et al. Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med. 2000;160(6):786-794.
5.    Michaud L, Burnand B, Stiefel F. Taking care of the terminally ill cancer patient: Delirium as a symptom of terminal disease. Ann Oncol. 2004;15 suppl 4:iv199-203.
6.    Massie MJ, Holland J, Glass E. Delirium in terminally ill cancer patients. Am J Psychiatry. 1983;140(8):1048-1050.
7.    Pereira J, Hanson J, Bruera E. The frequency and clinical course of cognitive impairment in patients with terminal cancer. Cancer. 1997;79(4):835-842.
8.    Bruera E, Miller L, McCallion J, Macmillan K, Krefting L, Hanson J. Cognitive failure in patients with terminal cancer: a prospective study. J Pain Symptom Manage. 1992;7(4):192-195.
9.    Spiller JA, Keen JC. Hypoactive delirium: assessing the extent of the problem for inpatient specialist palliative care. Palliat Med. 2006;20(1):17-23.
10.    Gagnon P, Allard P, Mâsse B, DeSerres M. Delirium in terminal cancer: a prospective study using daily screening, early diagnosis, and continuous monitoring. J Pain Symptom Manage. 2000;19(6):412-426.
11.    Fang C, Chen H, Liu S, Lin C, Tsai L, Lai Y. Prevalence, detection and treatment of delirium in terminal cancer inpatients: a prospective survey. Jpn J Clin Oncol. 2008;38(1):56-63.
12.    Gagnon PR. Treatment of delirium in supportive and palliative care. Curr Opin Support Palliat Care. 2008;2(1):60-66.
13.    Leonard M, Agar M, Mason C, Lawlor P. Delirium issues in palliative care settings. J Psychosom Res. 2008;65(3):289-298.
14.    Breitbart W, Freidlander M, Lawlor P. Delirium in the terminally ill. In: Chochinov H, Breitbart W, eds. Handbook of Psychiatry and Palliative Medicine. 2nd ed. New York, NY: Oxford University Press; In press.
15.    Tune L. The role of antipsychotics in treating delirium. Curr Psychiatry Rep. 2002;4(3):209-212.
16.    Breitbart W, Marotta R, Platt MM, et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry. 1996;153(2):231-237.
17.    Fernandez F, Levy JK, Mansell PW. Management of delirium in terminally ill AIDS patients. Int J Psychiatry Med. 1989;19(2):165-172.
18.    Jackson KC, Lipman AG. Drug therapy for delirium in terminally ill patients. Cochrane Database Syst Rev. 2004;(2):CD004770.
19.    Breitbart W. Psychiatric management of cancer pain. Cancer. 1989;63(11 suppl):2336-2342.
20.    Platt MM, Breitbart W, Smith M, Marotta R, Weisman H, Jacobsen PB. Efficacy of neuroleptics for hypoactive delirium. J Neuropsychiatry Clin Neurosci. 1994;6(1):66-67.
21.    Practice guideline for the treatment of patients with delirium. American Psychiatric Association. Am J Psychiatry. 1999;156(5 suppl):1-20.
22.    Oliver DJ. The use of methotrimeprazine in terminal care. Br J Clin Pract. 1985;39(9):339-340.
23.    Joshi N, Breibart WS. Psychopharmacologic management during cancer treatment. Semin Clin Neuropsychiatry. 2003;8(4):241-252.
24.    Tarumi Y, Watanabe S. The potential role of zuclopenthixol acetate in the management of refractory hyperactive delirium at the end of life. Pain Symptom Manage. 2008;35(4):336-339.
25.    Boettger S, Breitbart W. Atypical antipsychotics in the management of delirium: a review of the empirical literature. Palliat Support Care. 2005;3(3):227-237.
26.    Sipahimalani A, Masand PS. Use of risperidone in delirium: case reports. Ann Clin Psychiatry. 1997;9(2):105-107.
27.    Liu CY, Juang YY, Liang HY, Lin NC, Yeh EK. Efficacy of risperidone in treating the hyperactive symptoms of delirium. Int Clin Psychopharmacol. 2004;19(3):165-168.
28.    Parellada E, Baeza I, de Pablo J, Martínez G. Risperidone in the treatment of patients with delirium. J Clin Psychiatry. 2004;65(3):348-353.
29.    Han CS, Kim YK. A double-blind trial of risperidone and haloperidol for the treatment of delirium. Psychosomatics. 2004;45(4):297-301.
30.    Horikawa N, Yamazaki T, Miyamoto K, et al. Treatment for delirium with risperidone: Results of a prospective open trial with 10 patients. Gen Hosp Psychiatry. 2003;25(4):289-292.
31.    Mittal D, Jimerson NA, Neely EP, et al. Risperidone in the treatment of delirium: Results from a prospective open-label trial. J Clin Psychiatry. 2004;65(5):662-667.
32.    Breitbart W, Tremblay A, Gibson C. An open trial of olanzapine for the treatment of delirium in hospitalized cancer patients. Psychosomatics. 2002;43(3):175-182.
33.    Sipahimalani A, Masand PS. Olanzapine in the treatment of delirium. Psychosomatics. 1998;39(5):422-430.
34.    Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive Care Med. 2004;30(3):444-449.
35.    Pae CU, Lee SJ, Lee CU, Lee C, Paik IH. A pilot trial of quetiapine for the treatment of patients with delirium. Hum Psychopharmacol. 2004;19(2):125-127.
36.    Schwartz TL, Masand PS. Treatment of delirium with quetiapine. Prim Care Companion J Clin Psychiatry. 2000;2(1):10-12.
37.    Alao AO, Moskowitz L. Aripiprazole and delirium. Ann Clin Psychiatry. 2006;18(4):267-269.
38.    Leso L, Schwartz TL. Ziprasidone treatment of delirium. Psychosomatics. 2002;43(1):61-62.
39.    Young CC, Lujan E. Intravenous ziprasidone for treatment of delirium in the intensive care unit. Anesthesiology. 2004;101(3):794-795.
40.    Straker DA, Shapiro PA, Muskin PR. Aripiprazole in the treatment of delirium. Psychosomatics. 2006;47(5):385-391.
41.    Breitbart W, Passik SD, Casper D. Psychological and psychiatric interventions in pain control. In: Doyle D, Hanks G, Cherny NI, Calman K, eds. The Oxford Textbook of Palliative Medicine. 4th ed, New York, NY: Oxford University Press. In press.
42.    Weiss SC, Emanuel LL, Fairclough DL, Emanuel EJ. Understanding the experience of pain in terminally ill patients. Lancet. 2001;357(9265):1311-1315.
43.    Seidel S, Aigner M, Ossege M, Pernicka E, Wildner B, Sycha T. Antipsychotics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2008;(4):CD004844.
44.    Langohr HD, Stöhr M, Petruch F. An open and double-blind cross-over study on the efficacy of clomipramine (anafranil) in patients with painful mono- and polyneuropathies. Eur Neurol. 1982;21(5):309-317.
45.    Khojainova N, Santiago-Palma J, Kornick C, Breitbart W, Gonzales GR. Olanzapine in the management of cancer pain. J Pain Symptom Manage. 2002;23(4):346-350.
46.    Glare P, Pereira G, Kristjanson LJ, Stockler M, Tattersall M. Systematic review of the efficacy of antiemetics in the treatment of nausea in patients with far-advanced cancer. Support Care Cancer. 2004;12(6):432-440.
47.    Weschules DJ. Tolerability of the compound ABHR in hospice patients. J Palliat Med. 2005;8(6):1135-1143.
48.    Jackson WC, Tavernier L. Olanzapine for intractable nausea in palliative care patients. J Palliat Med. 2003;6(2):251-255.
49.    National Cancer Institute. Nausea and Vomiting PDQ. Health Professional Version. Available at: www.cancer.gov/cancertopics/pdq/supportivecare/nausea/HealthProfessional. Accessed March 23, 2009.
50.    Srivastava M, Brito-Dellan N, Davis MP, Leach M, Lagman R. Olanzapine as an antiemetic in refractory nausea and vomiting in advanced cancer. J Pain Symptom Manage. 2003;25(6):578-582.
51.    Plotkin DA, Plotkin D, Okun R. Haloperidol in the treatment of nausea and vomiting due to cytotoxic drug administration. Curr Ther Res Clin Exp. 1973;15(9):599-602.
52.    Kelley SL, Braun TJ, Meyer TJ, Rempel P, Pearlman NW. Trial of droperidol as an antiemetic in cisplatin chemotherapy. Cancer Treat Rep. 1986;70(4):469-472.
53.    Mason BA, Dambra J, Grossman B, Catalano RB. Effective control of cisplatin-induced nausea using high-dose steroids and droperidol. Cancer Treat Rep. 1982;66(2):243-245.
54.    Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer. 2005;13(7):529-534.
55.    Passik SD, Lundberg J, Kirsh KL, et al. A pilot exploration of the antiemetic activity of olanzapine for the relief of nausea in patients with advanced cancer and pain. J Pain Symptom Manage. 2002;23(6):526-532.
56.    Bymaster FP, Falcone JF, Bauzon D, et al. Potent antagonism of 5-HT(3) and 5-HT(6) receptors by olanzapine. Eur J Pharmacol. 2001;430(2-3):341-349.
57.    Cowan JD, Walsh D. Terminal sedation in palliative medicine–definition and review of the literature. Support Care Cancer. 2001;9(6):403-407.
58.    Reuzel RP, Hasselaar GJ, Vissers KC, van der Wilt GJ, Groenewoud JM, Crul BJ. Inappropriateness of using opioids for end-stage palliative sedation: a Dutch study. Palliat Med. 2008;22(5):641-646.
59.    Cowan JD, Palmer TW. Practical guide to palliative sedation. Curr Oncol Rep. 2002;4(3):242-249.
60.    Daud ML. Drug management of terminal symptoms in advanced cancer patients. Curr Opin Support Palliat Care. 2007;1(3):202-206.
61.    Lagman RL, Davis MP, LeGrand SB, Walsh D. Common symptoms in advanced cancer. Surg Clin North Am. 2005;85(2):237-255.
62.    Menza MA, Murray GB, Holmes VF, Rafuls WA. Controlled study of extrapyramidal reactions in the management of delirious, medically ill patients: intravenous haloperidol versus intravenous haloperidol plus benzodiazepines. Heart Lung. 1988;17(3):238-241.
63.    Coda BA, Mackie A, Hill HF. Influence of alprazolam on opioid analgesia and side effects during steady-state morphine infusions. Pain. 1992;50(3):309-316.
64.    Breitbart W, Gibson C. Psychiatric aspects of cancer pain management. Primary Psychiatry. 2007;14(9):81-91.
65.    Fernandez F, Adams F, Holmes VF. Analgesic effect of alprazolam in patients with chronic, organic pain of malignant origin. J Clin Psychopharmacol. 1987;7(3):167-169.
66.    Caccia MR. Clonazepam in facial neuralgia and cluster headache. Clinical and electrophysiological study. Eur Neurol. 1975;13(6):560-563.
67.    Swerdlow M, Cundill JG. Anticonvulsant drugs used in the treatment of lancinating pain. A comparison. Anaesthesia. 1981;36(12):1129-1132.
68.    Greenberg DB, Surman OS, Clarke J, Baer L. Alprazolam for phobic nausea and vomiting related to cancer chemotherapy. Cancer Treat Rep. 1987;71(5):549-550.
69.    Mori K, Saito Y, Tominaga K. Antiemetic efficacy of alprazolam in the combination of metoclopramide plus methylprednisolone. Double-blind randomized crossover study in patients with cisplatin-induced emesis. Am J Clin Oncol. 1993;16(4):338-341.
70.    Potanovich LM, Pisters KM, Kris MG, et al. Midazolam in patients receiving anticancer chemotherapy and antiemetics. J Pain Symptom Manage. 1993;8(8):519-524.
71.    Kris MG, Gralla RJ, Clark RA, et al. Consecutive dose-finding trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone. Cancer Treat Rep. 1985;69(11):1257-1262.
72.    Bishop JF, Olver IN, Wolf MM, et al. Lorazepam: a randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and prochlorperazine. J Clin Oncol. 1984;2(6):691-695.
73.    Hasselaar JG, Reuzel RP, Verhagen SC, de Graeff A, Vissers KC, Crul BJ. Improving prescription in palliative sedation: compliance with Dutch guidelines. Arch Intern Med. 2007;167(11):1166-1171.
74. Miller K, Massie MJ. Depression and anxiety. Cancer J. 2006;12(5):388-397.
75. Jackson N, Doherty J, Coulter S. Neuropsychiatric complications of commonly used palliative care drugs. Postgrad Med J. 2008;84(989):121-126.
76. Brugha TS. Depression in the terminally ill. Br J Hosp Med. 1993;50(4):175,177-181.
77. Wilson KG, Chochinov HM, Skirko MG, et al. Depression and anxiety disorders in palliative cancer care. J Pain Symptom Manage. 2007;33(2):118-129.
78. Breitbart W, Alici-Evcimen Y, Rueda-Lara M. Lederberg M. Psycho-oncology. In: Sadock BJ, Sadock VA, eds. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 8th ed. New York, NY: Lippincott, Wilkins and Williams. In press.
79. Block SD. Assessing and managing depression in the terminally ill patient. ACP-ASIM end-of-life care consensus panel. American College of Physicians – American Society of Internal Medicine. Ann Intern Med. 2000;132(3):209-218.
80. Reich M. Depression and cancer: recent data on clinical issues, research challenges and treatment approaches. Curr Opin Oncol. 2008;20(4):353-359.
81. Shimizu K, Akechi T, Shimamoto M, et al. Can psychiatric intervention improve major depression in very near end-of-life cancer patients? Palliat Support Care. 2007;5(1):3-9.
82. O’Mahony S, Goulet J, Kornblith A, et al. Desire for hastened death, cancer pain and depression: report of a longitudinal observational study. J Pain Symptom Manage. 2005;29(5):446-457.
83. Fisch MJ, Loehrer PJ, Kristeller J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol. 2003;21(10):1937-1943.
84. Holland JC, Romano SJ, Heiligenstein JH, Tepner RG, Wilson MG. A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. Psychooncology. 1998;7(4):291-300.
85. Kast RE. Mirtazapine may be useful in treating nausea and insomnia of cancer chemotherapy. Support Care Cancer. 2001;9(6):469-470.
86. Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37(4):589-596.
87. Malseed RT, Goldstein FJ. Enhancement of morphine analgesia by tricyclic antidepressants. Neuropharmacology. 1979;18(10):827-829.
88. McQuay HJ, Carroll D, Glynn CJ. Dose-response for analgesic effect of amitriptyline in chronic pain. Anaesthesia. 1993;48(4):281-285.
89. Spiegel K, Kalb R, Pasternak GW. Analgesic activity of tricyclic antidepressants. Ann Neurol. 1983;13(4):462-465.
90. Hameroff SR, Cork RC, Scherer K, et al. Doxepin effects on chronic pain, depression and plasma opioids. J Clin Psychiatry. 1982;43(8 Pt 2):22-27.
91. Pilowsky I, Hallett EC, Bassett DL, Thomas PG, Penhall RK. A controlled study of amitriptyline in the treatment of chronic pain. Pain. 1982;14(2):169-179.
92. Hynes MD, Lochner MA, Bemis KG, Hymson DL. Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors. Life Sci. 1985;36(24):2317-2323.
93. Sindrup SH, Gram LF, Brøsen K, Eshøj O, Mogensen EF. The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain. 1990;42(2):135-144.
94. Sindrup SH, Bjerre U, Dejgaard A, Brøsen K, Aaes-Jørgensen T, Gram LF. The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin Pharmacol Ther. 1992;52(5):547-552.
95. Breitbart W, Alici Y. Pharmacologic treatment options for cancer-related fatigue: current state of clinical research. Clin J Oncol Nurs. 2008;12(5 suppl):27-36.
96. Mock V. Evidence-based treatment for cancer-related fatigue. J Natl Cancer Inst Monogr. 2004;(32):112-118.
97. Cella D, Davis K, Breitbart W, Curt G. Cancer-related fatigue: Prevalence of proposed diagnostic criteria in a united states sample of cancer survivors. Journal of clinical oncology 2001;19:3385.
98. Moss EL, Simpson JS, Pelletier G, Forsyth P. An open-label study of the effects of bupropion SR on fatigue, depression and quality of life of mixed-site cancer patients and their partners. Psychooncology. 2006;15(3):259-267.
99. Cullum JL, Wojciechowski AE, Pelletier G, Simpson JS. Bupropion sustained release treatment reduces fatigue in cancer patients. Can J Psychiatry. 2004;49(2):139-144.
100. Morrow GR, Hickok JT, Roscoe JA, et al. Differential effects of paroxetine on fatigue and depression: A randomized, double-blind trial from the university of rochester cancer center community clinical oncology program. J Clin Oncol. 2003;21(24):4635-4641.
101. Roscoe JA, Morrow GR, Hickok JT, et al. Effect of paroxetine hydrochloride (paxil) on fatigue and depression in breast cancer patients receiving chemotherapy. Breast Cancer Res Treat. 2005;89(3):243-9.
102. Capuron L, Gumnick JF, Musselman DL, et al. Neurobehavioral effects of interferon-alpha in cancer patients: Phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology. 2002;26(5):643-652.
103. Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: a review. J Clin Oncol. 2002;20(1):335-339.
104. Fisch M. Use of antidepressants for depression in patients with advanced cancer. Lancet Oncol. 2007;8(7):567-568.
105. Sood A, Barton DL, Loprinzi CL. Use of methylphenidate in patients with cancer. Am J Hosp Palliat Care. 2006;23(1):35-40.
106. Lawrie I, Lloyd-Williams M, Taylor F. How do palliative medicine physicians assess and manage depression? Palliat Med. 2004;18(3):234-238.
107. Lloyd-Williams M, Friedman T, Rudd N. A survey of antidepressant prescribing in the terminally ill. Palliat Med. 1999;13(3):243-248.
108. Macleod AD. Methylphenidate in terminal depression. J Pain Symptom Manage. 1998;16(3):193-198.
109. Bruera E, Brenneis C, Paterson AH, MacDonald RN. Use of methylphenidate as an adjuvant to narcotic analgesics in patients with advanced cancer. J Pain Symptom Manage. 1989;4(1):3-6.
110. Bruera E, Chadwick S, Brenneis C, Hanson J, MacDonald RN. Methylphenidate associated with narcotics for the treatment of cancer pain. Cancer Treat Rep. 1987;71(1):67-70.
111. Bruera E, Fainsinger R, MacEachern T, Hanson J. The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report. Pain. 1992;50(1):75-77.
112. Forrest WH, Brown BW, Brown CR, et al. Dextroamphetamine with morphine for the treatment of postoperative pain. N Engl J Med. 1977;296(13):712-715.
113. Sarhill N, Walsh D, Nelson KA, Homsi J, LeGrand S, Davis MP. Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study. Am J Hosp Palliat Care. 2001;18(3):187-192.
114. Sugawara Y, Akechi T, Shima Y, et al. Efficacy of methylphenidate for fatigue in advanced cancer patients: a preliminary study. Palliat Med. 2002;16(3):261-263.
115. MacAllister WS, Krupp LB. Multiple sclerosis-related fatigue. Phys Med Rehabil Clin N Am. 2005;16(2):483-502.

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Antidepressant-Associated Sexual Dysfunction: A Potentially Avoidable Therapeutic Challenge

Anita H. Clayton, MD

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Primary Psychiatry. 2003;10(1):55-61

 

Dr. Clayton is professor and vice chairin theDepartment of Psychiatric Medicine at the University of Virginia Health Systems in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer. No financial, academic, or other support was received for this work.

Please direct all correspondence to: Anita H. Clayton, MD, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22908-0623; Tel: 434-924-2241; Fax:?434-924-5149; E-mail: ahc8v@virginia.edu


 

Abstract

How can the occurrence of antidepressant-associated sexual dysfunction be minimized? In prospective studies, sexual dysfunction has been reported by up to 70% of patients using serotonergic antidepressants, which are associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or minimally affect serotonergic neurotransmission. Three approaches to managing antidepressant-associated sexual dysfunction include reduction or elimination of antidepressant doses suspected of causing sexual dysfunction, use of a second medication to reverse sexual dysfunction, or substitution of a second antidepressant not associated with sexual side effects. The introduction of new antidepressants augments the options for controlling or avoiding sexual dysfunction. For symptoms of depression, the norepinephrine and dopamine reuptake inhibitor bupropion sustained-release and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective as serotonergic antidepressants, but with a much lower incidence of sexual dyfunction.

Introduction

Clinically depressed individuals often suffer from sexual dysfunction, which can arise from numerous causes, including the depression itself, comorbid psychiatric or medical disorders, antidepressant therapy, and concomitant medications.1 A primary role of antidepressant therapy in the etiology of sexual dysfunction has become increasingly recognized since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.2 While SSRIs and other medications that enhance serotonergic function are most strongly associated with orgasm dysfunction,3-6 they may also be associated with disorders of other phases of the sexual response cycle, including desire and arousal.7-9 As data from well-controlled studies on the sexual side effects of SSRIs and other serotonergic antidepressants have accumulated over the last decade and a half, health care providers’ concern about these side effects and interest in exploring treatment strategies that minimize or eliminate sexual side effects have grown. This review, based on MEDLINE searches and systematic review of congress abstracts, considers clinical aspects, prevalence, and possible mechanisms of antidepressant-associated sexual dysfunction with a discussion of strategies to minimize the occurrence of this side effect.

Antidepressant-Associated Sexual Dysfunction

Clinical Consequences

Sexual dysfunction can adversely affect quality of life, self-esteem, and interpersonal relationships. These effects are of particular concern among patients with depression, in whom these issues may already be compromised. Moreover, antidepressant-associated sexual dysfunction may lead to medication noncompliance and premature discontinuation and thereby may increase the risk of relapse or recurrence of depression.10,11

In an open-label study of 1,022 patients with a mean 40 years of age, 59.1% reported antidepressant-associated sexual dysfunction.10 The study analyzed the following antidepressants: citalopram, paroxetine, venlafaxine, sertraline, fluvoxamine, fluoxetine, mirtazapine, nefazodone, amineptine, moclobemide, clomipramine, imipramine, maprotiline, phenelzine, and trazodone. Of those with sexual dysfunction attributed to antidepressants, 38.3% rated themselves as being concerned enough about sexual dysfunction to discontinue antidepressant therapy (Figure 1). Another 34.5% indicated that, although they did not intend to discontinue antidepressant therapy because of it, they and/or their partner were concerned or distressed about sexual dysfunction. That nearly 4 of 10 patients in this study were concerned enough about their sexual dysfunction to discontinue their antidepressant is worrisome in view of the fact that noncompliance with the therapeutic regimen may result in relapse or recurrence of depression.

In a patient survey (N=350) reported in 2001, 60% of patients indicated that they had stopped taking their prescribed antidepressant at one time or another, and 22% of patients indicated that they did not always take their antidepressant medication exactly as prescribed.11 Sexual dysfunction was one of the top five reasons for stopping medication or failing to use medication as prescribed. When asked to rate the impact of specific side effects, one fourth of the patients indicated that it would be extremely difficult to live with the side effects of orgasm dysfunction or erectile dysfunction.

Assessment

Across studies in which sexual dysfunction is a prospectively defined endpoint, the condition has been reported in up to 70% of patients using antidepressants such as SSRIs.9,12 Lower frequencies of sexual dysfunction are reported in studies in which sexual function was not objectively assessed or patients were not specifically queried.3,9 Variance in estimates of the prevalence of sexual dysfunction arises primarily from the fact that some studies specifically queried patients regarding sexual dysfunction whereas other studies relied on patients’ spontaneous reports. Because patients are usually reticent to initiate discussion about sexual dysfunction with their health care provider, reliance on spontaneous report of sexual dysfunction underestimates the commonality of the condition. This fact is illustrated by the results of a study (N=344) that assessed sexual dysfunction both via patients’ spontaneous reports and with a questionnaire. Whereas only 14% (28 of 200) of patients spontaneously reported sexual dysfunction, 58% (200 of 344 patients) subsequently reported sexual dysfunction when specifically asked.13

From a practical perspective, these results emphasize the importance of having health care providers discuss sexual function with their patients both before antidepressant therapy is initiated (to obtain a baseline measure) and during antidepressant therapy. Normalizing the issue by opening with an explanation of the frequency of sexual disorders in the general population and among depressed patients, as well as the frequency of sexual disorders associated with specific treatments for depression, can help remove the barriers to discussing sexual functioning with patients.1

Using the medical model to evaluate each stage of the sexual response cycle (desire, arousal, orgasm, resolution) or employing an assessment tool such as the Arizona Sexual Experiences (ASEX) Scale14 or the Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C)15 is also important in identifying and assessing sexual dysfunction. Once the presence of sexual dysfunction is confirmed, further evaluation is necessary to differentiate antidepressant-associated sexual dysfunction from sexual dysfunction that may be attributed to other causes.1 This evaluation should compare a sexual history with the current level of sexual functioning and should eliminate other contributing factors including comorbid medical or psychiatric conditions, medications, or substances of abuse. Because both erectile dysfunction and decreased libido commonly occur as symptoms of depression, it is important to determine the patient’s level of sexual functioning prior to the onset of depression to determine the relative contributions of depression and antidepressant therapy.1

Besides reliance on spontaneous reports, other factors that explain variability in estimates of the prevalence of sexual dysfunction include misattribution of depression-associated sexual dysfunction to antidepressant use, failure to account for other established correlates of decreased sexual function such as advancing age and physical illness, and variation among studies in the definition and measurement of sexual dysfunction. Moreover, many studies reporting on sexual dysfunction did not prospectively define it as an endpoint and were often not sufficiently powered to assess the influence of specific variables or interventions.

Several recent studies that have controlled for these methodological problems provide useful data on the prevalence of antidepressant-associated sexual dysfunction.4-6,16-18 The data from these recent studies are consistent in showing that the prevalence of sexual dysfunction differs by physiologic mechanism of the antidepressant: antidepressants affecting serotonergic neurotransmission are reliably associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or only minimally affect serotonergic neurotransmission. For example, in the first study to employ a validated rating scale to assess the effects of the 10 new-generation antidepressants on sexual dysfunction in a large population of patients, 37% of 6,297 patients consulting 1,100 primary care physicians in the United States, reported sexual problems associated with antidepressant use.18 The lowest rates of sexual dysfunction across all antidepressant groups were in patients treated with bupropion (22% and 25%, for the immediate-release and sustained-release [SR] forms, respectively) and nefazodone (28%). Patients treated with bupropion SR or nefazodone had a statistically significantly lower prevalence rate of sexual dysfunction than patients taking SSRIs (citalopram, fluoxetine, paroxetine, sertraline), or venlafaxine extended-release. The mean prevalence rate of presumed antidepressant-associated sexual dysfunction was 24.4% among a prospectively defined subpopulation of patients free from other probable causes of sexual dysfunction (ie, patients were 18–40 years of age, had no history of sexual side effects on previous antidepressants, had used their current antidepressant for at least 3 months, were not taking concomitant medications affecting sexual functioning, had no comorbid illness that would affect sexual functioning, and had a history of at least some sexual enjoyment). Patients treated with bupropion SR had the lowest prevalence (6.7%) of sexual dysfunction (Table 1).

Manifestations

The four phases of the sexual response cycle are desire, arousal (erection in men, engorgement and lubrication in women), orgasm, and resolution. The aspect of sexual functioning most often affected by serotonergic antidepressants is the ability to achieve orgasm, which is either delayed or does not occur in many patients treated with antidepressants.7 Because orgasm dysfunction, unlike other sexual problems such as decreased libido, rarely occurs as a manifestation of depression per se, it is more easily attributed to pharmacotherapy than are sexual symptoms that frequently occur as manifestations of depression.3 In addition to orgasm dysfunction, the serotonergic antidepressants have been linked to erectile dysfunction and decreased libido, although the data associating these sexual side effects with antidepressant therapy are less consistent.7

Mechanisms of Action

The mechanism of antidepressant-associated sexual dysfunction has not been determined. The range of possible mechanisms includes (1) nonspecific neurologic effects (eg, sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.8 It is probable that antidepressants impact several of these physiologic substrates of sexual function.

The association of some antidepressants and of depression itself with sexual dysfunction is not surprising in view of the fact that many of the neurotransmitter systems implicated in depression, including the serotonin, dopamine, and norepinephrine systems, are also implicated in control of sexual function. Animal research and data from studies in human subjects suggest that sexual behavior and function are enhanced by increases in brain dopaminergic function and inhibited by increases in brain serotonergic function.2,8,19,20 The latter observation is consistent with the association of serotonergic antidepressants with sexual dysfunction.

Management Strategies for Antidepressant-Associated Sexual Dysfunction

Four general approaches to managing antidepressant-associated sexual dysfunction have been adopted (Table 2). The first approach is deciding not to intervene for antidepressant-associated sexual dysfunction in the hope that spontaneous remission will occur. The second approach is to reduce or eliminate doses of the antidepressant suspected of causing sexual dysfunction. The third approach involves use of a second medication as an antidote to reverse sexual dysfunction. Finally, the fourth approach involves substitution of a second antidepressant unlikely to cause sexual side effects. Each of these strategies for managing antidepressant-associated sexual dysfunction is reviewed below.

No Intervention

Some health care providers decide not to intervene in the case of antidepressant-associated sexual dysfunction in the hope that sexual side effects may spontaneously remit over time.4 Spontaneous remission of antidepressant-associated sexual dysfunction has been reported in case studies.21,22 However, recent research suggests that it infrequently occurs within the first 6 months of initiation of therapy. In a prospective, open-label study of 1,022 outpatients taking antidepressants, 59% reported antidepressant-associated sexual dysfunction.10

Of the patients reporting sexual dysfunction, only 9.7% of them reported total improvement or spontaneous remission at the end of 6 months of antidepressant therapy; 79% of them reported no improvement. These data, suggesting that antidepressant-associated sexual dysfunction does not promptly remit, are consistent with data from the 16-week controlled comparison of sertraline and bupropion SR.16 In that study, sertraline-associated sexual dysfunction was observed at the end of the first treatment week (the initial assessment following the start of treatment) and was maintained throughout the 16-week treatment period. If spontaneous remission does not occur, failure to intervene may increase the likelihood of noncompliance with the antidepressant regimen—particularly among patients to whom sexual dysfunction is a significant concern.

Reducing or Eliminating Antidepressant Doses

Reducing the dose of antidepressant medication has been tried in attempts to ameliorate antidepressant-associated sexual dysfunction.8 This strategy has not been systematically assessed in controlled clinical studies but has been reported effective with an SSRI and a monoamine oxidase inhibitor.23,24 Depressive symptoms may reemerge with dose reduction.

Antidepressant drug holidays have also been employed as a strategy for reducing antidepressant-associated sexual dysfunction. Like the dose-reduction strategy, the efficacy of drug holidays in reducing antidepressant-associated sexual dysfunction has not been systematically studied. Positive results were obtained in one open-label, 30-patient study in which patients discontinued sertraline or paroxetine, but not fluoxetine, for the weekend. Discontinuation was associated with significant improvement in sexual functioning without a worsening of depressive symptoms.25

As drug holidays may result in antidepressant discontinuation syndrome and may provide a risk for relapse of depression, they are not an ideal strategy for most patients. Drug holidays may also limit patients’ spontaneity with respect to the timing of sexual activity. Furthermore, advising drug holidays for improvement of sexual dysfunction may encourage patients to be noncompliant with the treatment regimen during times when drug holidays are not advised or appropriate. Finally, in cases in which a drug holiday is effective in reducing sexual side effects, reinstatement of antidepressant therapy is likely to result in the reemergence of sexual dysfunction.

Reemergence of sexual dysfunction due to antidepressants was evaluated in a double-blind rechallenge study enrolling depressed patients who reported impairment in sexual function upon initiation of therapy with sertraline 100 mg OD.26 Patients discontinued sertraline for a 2-week period, and if their sexual functioning normalized during the 2-week period, were assigned to 8 weeks of double-blind treatment with sertraline 50 mg OD or the mixed serotonin antagonist/reuptake inhibitor nefazodone 100 mg BID. Beginning with the first week of reinstatement of sertraline therapy, sexual dysfunction reemerged. Whereas approximately 15% of patients were dissatisfied with sexual function before reinstatement of sertraline therapy, 50% were dissatisfied at week 1 of sertraline reinstatement. When doses were increased to 100 mg/day sertraline and 150 mg nefazodone BID during the second week of therapy, the proportion of sertraline-treated patients dissatisfied with sexual function increased to approximately 80%, which was consistently maintained through the remainder of the 8-week treatment period. These data suggest that drug holidays are not a viable long-term strategy for controlling antidepressant-associated sexual side effects, particularly for a chronic disease such as depression, which often requires life-long pharmacotherapy.

Adding an Antidote

Daily administration of pharmacotherapies that reverse sexual dysfunction and administration of antidotes acutely before sexual activity have also been tried. Agents used for this application are listed in Table 3.27-52 Although addition of an antidote can be successful in reducing the incidence of sexual side effects, it entails polytherapy, which relative to monotherapy increases the overall risk of side effects and drug interactions.

Of all of the agents administered as antidotes, only bupropion SR and buspirone have been demonstrated effective in placebo-controlled trials as well as open-label studies involving both sexes.27,32-37,51 Unlike some of the other augmentation therapies that have been tried, both bupropion SR and buspirone added to SSRI regimens appear to be well-tolerated. None of the other possible antidotes to antidepressant-associated sexual dysfunction have been evaluated in placebo-controlled studies. Evidence for their use is derived primarily from case reports and small, open-label investigations as follows:

• Several authors have reported that amantadine used for at least 2 days before sexual activity or on a regular basis reverses SSRI-associated sexual dysfunction.28-31 In a retrospective chart-review study involving records from 594 patients, amantadine was less effective than yohimbine at reversing SSRI-associated sexual dysfunction.52

• Sildenafil, which is currently approved only for management of erectile dysfunction in men, was reported in an open-label investigation to work as an antidote to antidepressant-induced sexual dysfunction in both men and women.38 Sildenafil is one of the only antidotes that can be taken on an as-needed basis shortly prior to sexual activity.

• Psychostimulants used intermittently or on a daily basis have been reported to be effective at reversing SSRI-associated sexual dysfunction.27,49 Possible drawbacks
of the use of psychostimulants include impairment of sexual function with increasing dose, the potential for abuse, and cardiovascular side effects.

• Ginkgo biloba has been reported in case reports and one uncontrolled study to counter SSRI-induced sexual dysfunction.27,46 As it is an over-the-counter herbal extract, its safety profile has not been assessed with the rigor that is applied to prescription medicines.

• Serotonin (5-HT)2 antagonists such as nefazodone and mirtazapine, as well as the 5-HT2 antagonist and antihistamine cyproheptadine, have been reported to be effective antidotes to antidepressant-associated sexual dysfunction.42-45,47,48 Cyproheptadine administered as daily therapy can interfere with the antidepressant efficacy of SSRIs.42,53 Administered acutely or chronically, it may also cause sedation, which can interfere with sexual function.

Substitution With an Antidepressant Unlikely to Cause Sexual Dysfunction

The development of new antidepressants with little or no adverse effects on sexual function has provided new opportunities for managing antidepressant-associated sexual dysfunction. Health care providers increasingly manage antidepressant-associated sexual dysfunction by starting new patients on an antidepressant shown to cause less sexual dysfunction than the SSRIs and venlafaxine. Similarly, in patients with antidepressant-associated sexual dysfunction, the sexually impairing antidepressant may be replaced with an antidepressant not associated with negative sexual side effects. These strategies have been shown to be effective with the nonserotonergic antidepressant bupropion SR as well as with the mixed serotonin antagonist/reuptake inhibitor nefazodone.7

Feiger and colleagues17 conducted a randomized, double-blind, parallel-group study to compare 6 weeks of treatment with nefazodone (n=71; mean modal end-of-treatment dose of 456 mg/day) and sertraline (n=72; mean modal end-of-treatment dose of 148 mg/day) with respect to efficacy, tolerability, and effects on sexual function. Sexual function was evaluated weekly via questionnaire. The results show that sertraline, but not nefazodone, significantly impaired sexual function, particularly among men. The following was noted among men during the last treatment week:

(1) 100% of those receiving nefazodone reported that they “fully enjoyed” or “sometimes enjoyed” sex compared with 57% of those receiving sertraline;

(2) 89% of those receiving nefazodone were at least moderately satisfied with sex compared with 50% of men receiving sertraline (Figure 2);

(3) 19% of those receiving nefazodone compared with 67% of those receiving sertraline reported difficulty with ejaculation; and

(4) 18% of those receiving nefazodone compared with 67% of those receiving sertraline indicated that they frequently, usually, or always took a long time to ejaculate.

Among women, 74% of those receiving nefazodone compared with 59% of those receiving sertraline were at least moderately satisfied with sex (Figure 2). Nefazodone-treated women achieved orgasm more easily and were more satisfied with the ability to achieve orgasm than were sertraline-treated women.

The effects on sexual function of bupropion SR have also been assessed in double-blind, head-to-head comparisons with SSRIs in patients with depression.4-6,16 In the first study, patients with moderate or severe depression received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks.16 To be included in the study, patients had to have normal sexual function (defined as absence of sexual arousal disorder, orgasm dysfunction, premature ejaculation, dyspareunia, or vaginismus) at baseline prior to the initiation of treatment, although sexual desire disorder associated with the depression could be present. The results demonstrate that the cumulative incidence of orgasm delay or failure was significantly (P<.001) greater among sertraline-treated patients (52%) than among bupropion SR-treated patients (8%), as was the overall incidence of sexual desire disorder (34% of sertraline-treated patients, 21% of bupropion-treated patients; P<.05) and the cumulative incidence of sexual arousal disorder (16% of sertraline-treated patients, 4% of bupropion SR-treated patients; P<.05). Consistent with these data, the percentage of patients satisfied with their sexual function at the end of the study increased substantially for bupropion SR (57% to 79%) but did not change for sertraline (57% to 58%). While bupropion SR had a better sexual tolerability profile than did sertraline, it conferred comparable efficacy for depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Severity, and the Clinical Global Impressions Scale for Improvement.54

These data were substantiated by two double-blind, placebo-controlled, 8-week studies that replicated the findings of the first study.4,5 The placebo-controlled studies also extended the earlier findings by demonstrating that the effects of bupropion SR on the incidence of orgasm dysfunction, sexual desire disorder, and sexual arousal disorder did not differ from those of placebo (with the exception of sexual arousal disorder on day 56 of treatment in one study4) in patients with major depression. In both of these studies as in the first one, differences between bupropion SR and sertraline were most marked for orgasm delay or failure, which of the sexual problems assessed was the most common one reported with sertraline therapy (Figure 3).

In a similar placebo-controlled study prospectively designed to compare the effects of bupropion SR (100–400 mg/day) with those of fluoxetine (10–60 mg/day) on sexual dysfunction, significantly more fluoxetine-treated patients experienced orgasm dysfunction beginning by the second treatment week and continuing throughout the study compared with bupropion SR- or placebo-treated patients (P<.001, Figure 4).6 This effect was observed both in patients defined as clinical responders (ie, those with a 50% decrease in total HAM-D scores during treatment) and in patients experiencing remission (ie, those with total HAM-D scores improved to less than 8). Worsened sexual functioning, decreased sexual desire, sexual arousal disorder, and dissatisfaction with sexual functioning were more often associated with fluoxetine than with bupropion SR or placebo.

Similar differences between treatments were reported in two prospective clinical trials in which patients with antidepressant-associated sexual dysfunction were switched from an SSRI to bupropion.55,56 Sexual side effects resolved while antidepressant efficacy was maintained in both studies. In one study, bupropion SR was initiated prior to discontinuation of paroxetine, sertraline, fluoxetine, or venlafaxine while in the other, bupropion was initiated 2 weeks after discontinuation of fluoxetine. Both of these methods of switching from an SSRI to bupropion were generally well tolerated.

Conclusion

Health care providers increasingly recognize antidepressant-associated sexual dysfunction as a significant problem among some patients. Sound sexual function is important in maintaining the patient’s quality of life and self-esteem, preserving interpersonal relationships, and ensuring compliance with the antidepressant regimen. The introduction of new antidepressants augments the range of options for controlling or avoiding sexual dysfunction. In particular, the norepinephrine and dopamine reuptake inhibitor bupropion SR and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective at controlling depressive symptoms as are antidepressants associated with sexual dysfunction,57,58 but with a low incidence of this undesirable side effect. PP

References

1. Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin Psychiatry. 2001;62(suppl 3):5-9.

2. Gitlin MJ. Effects of depression and antidepressants on sexual functioning. Bull Menninger Clin. 1995;59:232-248.

3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: A critical review. J Clin Psychopharmacol. 1999;19:67-85.

4. Croft H, Settle E, Houser T, et al. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther. 1999;21:643-658.

5. Coleman CC, Cunningham LA, Foster VJ, et al. Sexual dysfunction associated with the treatment of depression: A placebo-controlled comparison of bupropion sustained-release and sertraline treatment. Ann Clin Psychiatry. 1999;11:205-215.

6. Coleman CC, King BR, Bolden-Watson C, et al. A placebo-controlled comparison of the effects on sexual functioning of sustained-release bupropion and fluoxetine. Clin Ther. 2001;23:1040-1058.

7. Segraves RT. Antidepressant-induced sexual dysfunction. J Clin Psychiatry. 1998;59(suppl 4):48-54.

8. Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry. 1994;55:406-413.

9. Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry. 2001;62(suppl 3):22-34.

10. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry. 2001;62(suppl 3):10-21.

11. Jamerson B, Ashton AD, Houser TL, et al. Antidepressant compliance and side effects: results from a patient survey. Poster presented at: the 154th Annual Meeting of the American Psychiatric Association; May 2001; New Orleans, LA.

12. Modell JG, Katholi C, Modell JD, et al. Comparative sexual side effects of SSRIs and bupropion. Clin Pharm Ther. 1997;61:476-487.

13. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176-194.

14. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26:25-40.

15. Clayton AH, McGarvey EL, Clavet GJ. The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull. 1997;33:731-745.

16. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol. 2000;20:122-128.

17. Feiger A, Kiev A, Shrivastava RK, et al. Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry. 1996;57(suppl 2):53-62.

18. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63:357-366.

19. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance of male rats. Life Sci. 1989;45:1263-1270.

20. Rodriguez M, Castro R, Hernandez G, et al. Different roles of catecholaminergic and serotoninergic neurons of the medial forebrain bundle on male rat sexual behavior. Physiol Behav. 1984;33:5-11.

21. Nurnberg HG, Levine PE. Spontaneous remission of MAOI-induced anorgasmia. Am J Psychiatry. 1987;144:805-807.

22. Reimherr FW, Chouinard G, Cohn CK, et al. Antidepressant efficacy of sertraline: A double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry. 1990;51:18-27.

23. Patterson WM. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry. 1993;54:71.

24. Barton JL. Orgasmic inhibition by phenelzine. Am J Psychiatry. 1979;136:616-617.

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

26. Ferguson JM, Shrivastava RK, Stahl SM, et al. Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline. J Clin Psychiatry. 2001;62:24-29.

27. Zajecka J. Strategies for the treatment of antidepressant-related sexual dysfunction. J Clin Psychiatry. 2001;62(suppl 3):35-43.

28. Balogh S, Hendricks SE, Kang J. Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry. 1992;53:212-213.

29. Shrivastava RK, Shrivastava S, Overweg N, et al. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1995;15:83-84.

30. Balon R. Intermittent amantadine for fluoxetine-induced anorgasmia. J Sex Marital Ther. 1996;22:290-292.

31. Masand PS, Reddy N, Gregory R. SSRI-induced sexual dysfunction successfully treated with amantadine. Depression. 1995;2:319-321.

32. Ashton AD, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 1998;59:112-115.

33. Labbate LA, Pollack MH. Treatment of fluoxetine-induced sexual dysfunction with bupropion: a case report. Ann Clin Psychiatry. 1994;6:13-15.

34. Bodkin JA, Lasser RA, Wines JD Jr, et al. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry. 1997;58:137-145.

35. Landén M, Bjorling G, Agren H, et al. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59:664-668.

36. Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. Depression. 1994;2:109-112.

37. Othmer E, Othmer SC. Effect of buspirone on sexual dysfunction in patients with generalized anxiety disorder. J Clin Psychiatry. 1987;48:201-203.

38. Fava M, Rankin MA, Alpert JE, et al. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychother Psychosom. 1998;67:328-331.

39. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry. 1992;53:119-122.

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

41. Segraves RT. Treatment of drug-induced anorgasmia. Br J Psychiatry. 1994;165:554.

42. Feder R. Reversal of antidepressant activity of fluoxetine by cyproheptadine in three patients. J Clin Psychiatry. 1991;52:163-164.

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

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

45. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand. 1996;93:69-70.

46. Cohen AJ, Bartlick BD. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24:139-143.

47. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry. 1999;60:260-261.

48. Reynolds RD. Sertraline-induced anorgasmia treated with intermittent nefazodone. J Clin Psychiatry. 1997:58:89.

49. Roeloffs C, Barlick B, Kaplan PM, et al. Methylphenidate and SSRI-induced sexual side effects. J Clin Psychiatry. 1996;57:548.

50. Michael A, O’Donnell EA. Fluoxetine-induced sexual dysfunction reversed by trazodone. Can J Psychiatry. 2000;45:847-848.

51. Clayton AH, McGarvey E, Warnock J, et al. Bupropion sustained-release as an antidote to SSRI-induced sexual dysfunction. Available at: www.nimh.nih.gov/ncdeu/abstracts2000/ncdeu169.cfm. Accessed March 25, 2002.

52. Keller Ashton A, Hamer R, Rosen RC. Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients. J Sex Marital Ther. 1997;23:165-175.

53. Goldbloom DS, Kennedy SH. Adverse interaction of fluoxetine and cyproheptadine in two patients with bulimia nervosa. J Clin Psychiatry. 1991;52:261-262.

54. Kavoussi RJ, Segraves RT, Hughes AR, et al. Double-blind comparison of bupropion sustained-release and sertraline in depressed outpatients. J Clin Psychiatry. 1997;58:532-537.

55. Walker PW, Cole JO, Gardner EA. Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J Clin Psychiatry. 1993;54:459-463.

56. Clayton AH, McGarvey EL, Abouesh AI, et al. Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. J Clin Psychiatry. 2001;62:85-190.

57. Mulrow CD, Williams JW, Madjukar T, et al. Treatment of Depression: Newer Pharmacotherapies. Rockville, Md: Agency for Health Care Research and Quality; February 1999: Publication no. 99-E014.

58. Geddes JR, Freemantle N, Jason J, et al. SSRIs versus other antidepressants for depressive disorder.The Cochrane Library. 2000 (4)CD002791. Oxford: Update Software.

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Anita H. Clayton, MD
 
Primary Psychiatry. 2003;10(1):55-61

 

Dr. Clayton is professor and vice chairin theDepartment of Psychiatric Medicine at the University of Virginia Health Systems in Charlottesville.

Disclosure: Dr. Clayton receives grants from Boehringer-Ingelheim, Eli Lilly, Forest, GlaxoSmithKline, Organon, Pfizer, Pharmacia, Pherin, and Merck; is a consultant for Bayer, Boehringer-Ingelheim, Eli Lilly, GlaxoSmithKline, Pharmacia, and Vela; and is on the Speaker’s Bureau of Bristol-Myers Squibb, GlaxoSmithKline, Organon, and Pfizer. No financial, academic, or other support was received for this work.

Please direct all correspondence to: Anita H. Clayton, MD, Department of Psychiatric Medicine, University of Virginia, 2955 Ivy Rd., Northridge Suite 210, Charlottesville, VA 22908-0623; Tel: 434-924-2241; Fax:?434-924-5149; E-mail: ahc8v@virginia.edu


 

Abstract

How can the occurrence of antidepressant-associated sexual dysfunction be minimized? In prospective studies, sexual dysfunction has been reported by up to 70% of patients using serotonergic antidepressants, which are associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or minimally affect serotonergic neurotransmission. Three approaches to managing antidepressant-associated sexual dysfunction include reduction or elimination of antidepressant doses suspected of causing sexual dysfunction, use of a second medication to reverse sexual dysfunction, or substitution of a second antidepressant not associated with sexual side effects. The introduction of new antidepressants augments the options for controlling or avoiding sexual dysfunction. For symptoms of depression, the norepinephrine and dopamine reuptake inhibitor bupropion sustained-release and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective as serotonergic antidepressants, but with a much lower incidence of sexual dyfunction.

Introduction

Clinically depressed individuals often suffer from sexual dysfunction, which can arise from numerous causes, including the depression itself, comorbid psychiatric or medical disorders, antidepressant therapy, and concomitant medications.1 A primary role of antidepressant therapy in the etiology of sexual dysfunction has become increasingly recognized since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the late 1980s.2 While SSRIs and other medications that enhance serotonergic function are most strongly associated with orgasm dysfunction,3-6 they may also be associated with disorders of other phases of the sexual response cycle, including desire and arousal.7-9 As data from well-controlled studies on the sexual side effects of SSRIs and other serotonergic antidepressants have accumulated over the last decade and a half, health care providers’ concern about these side effects and interest in exploring treatment strategies that minimize or eliminate sexual side effects have grown. This review, based on MEDLINE searches and systematic review of congress abstracts, considers clinical aspects, prevalence, and possible mechanisms of antidepressant-associated sexual dysfunction with a discussion of strategies to minimize the occurrence of this side effect.

Antidepressant-Associated Sexual Dysfunction

Clinical Consequences

Sexual dysfunction can adversely affect quality of life, self-esteem, and interpersonal relationships. These effects are of particular concern among patients with depression, in whom these issues may already be compromised. Moreover, antidepressant-associated sexual dysfunction may lead to medication noncompliance and premature discontinuation and thereby may increase the risk of relapse or recurrence of depression.10,11

In an open-label study of 1,022 patients with a mean 40 years of age, 59.1% reported antidepressant-associated sexual dysfunction.10 The study analyzed the following antidepressants: citalopram, paroxetine, venlafaxine, sertraline, fluvoxamine, fluoxetine, mirtazapine, nefazodone, amineptine, moclobemide, clomipramine, imipramine, maprotiline, phenelzine, and trazodone. Of those with sexual dysfunction attributed to antidepressants, 38.3% rated themselves as being concerned enough about sexual dysfunction to discontinue antidepressant therapy (Figure 1). Another 34.5% indicated that, although they did not intend to discontinue antidepressant therapy because of it, they and/or their partner were concerned or distressed about sexual dysfunction. That nearly 4 of 10 patients in this study were concerned enough about their sexual dysfunction to discontinue their antidepressant is worrisome in view of the fact that noncompliance with the therapeutic regimen may result in relapse or recurrence of depression.

In a patient survey (N=350) reported in 2001, 60% of patients indicated that they had stopped taking their prescribed antidepressant at one time or another, and 22% of patients indicated that they did not always take their antidepressant medication exactly as prescribed.11 Sexual dysfunction was one of the top five reasons for stopping medication or failing to use medication as prescribed. When asked to rate the impact of specific side effects, one fourth of the patients indicated that it would be extremely difficult to live with the side effects of orgasm dysfunction or erectile dysfunction.

Assessment

Across studies in which sexual dysfunction is a prospectively defined endpoint, the condition has been reported in up to 70% of patients using antidepressants such as SSRIs.9,12 Lower frequencies of sexual dysfunction are reported in studies in which sexual function was not objectively assessed or patients were not specifically queried.3,9 Variance in estimates of the prevalence of sexual dysfunction arises primarily from the fact that some studies specifically queried patients regarding sexual dysfunction whereas other studies relied on patients’ spontaneous reports. Because patients are usually reticent to initiate discussion about sexual dysfunction with their health care provider, reliance on spontaneous report of sexual dysfunction underestimates the commonality of the condition. This fact is illustrated by the results of a study (N=344) that assessed sexual dysfunction both via patients’ spontaneous reports and with a questionnaire. Whereas only 14% (28 of 200) of patients spontaneously reported sexual dysfunction, 58% (200 of 344 patients) subsequently reported sexual dysfunction when specifically asked.13

From a practical perspective, these results emphasize the importance of having health care providers discuss sexual function with their patients both before antidepressant therapy is initiated (to obtain a baseline measure) and during antidepressant therapy. Normalizing the issue by opening with an explanation of the frequency of sexual disorders in the general population and among depressed patients, as well as the frequency of sexual disorders associated with specific treatments for depression, can help remove the barriers to discussing sexual functioning with patients.1

Using the medical model to evaluate each stage of the sexual response cycle (desire, arousal, orgasm, resolution) or employing an assessment tool such as the Arizona Sexual Experiences (ASEX) Scale14 or the Changes in Sexual Functioning Questionnaire-Clinical version (CSFQ-C)15 is also important in identifying and assessing sexual dysfunction. Once the presence of sexual dysfunction is confirmed, further evaluation is necessary to differentiate antidepressant-associated sexual dysfunction from sexual dysfunction that may be attributed to other causes.1 This evaluation should compare a sexual history with the current level of sexual functioning and should eliminate other contributing factors including comorbid medical or psychiatric conditions, medications, or substances of abuse. Because both erectile dysfunction and decreased libido commonly occur as symptoms of depression, it is important to determine the patient’s level of sexual functioning prior to the onset of depression to determine the relative contributions of depression and antidepressant therapy.1

Besides reliance on spontaneous reports, other factors that explain variability in estimates of the prevalence of sexual dysfunction include misattribution of depression-associated sexual dysfunction to antidepressant use, failure to account for other established correlates of decreased sexual function such as advancing age and physical illness, and variation among studies in the definition and measurement of sexual dysfunction. Moreover, many studies reporting on sexual dysfunction did not prospectively define it as an endpoint and were often not sufficiently powered to assess the influence of specific variables or interventions.

Several recent studies that have controlled for these methodological problems provide useful data on the prevalence of antidepressant-associated sexual dysfunction.4-6,16-18 The data from these recent studies are consistent in showing that the prevalence of sexual dysfunction differs by physiologic mechanism of the antidepressant: antidepressants affecting serotonergic neurotransmission are reliably associated with a higher frequency of sexual dysfunction than antidepressants that do not affect or only minimally affect serotonergic neurotransmission. For example, in the first study to employ a validated rating scale to assess the effects of the 10 new-generation antidepressants on sexual dysfunction in a large population of patients, 37% of 6,297 patients consulting 1,100 primary care physicians in the United States, reported sexual problems associated with antidepressant use.18 The lowest rates of sexual dysfunction across all antidepressant groups were in patients treated with bupropion (22% and 25%, for the immediate-release and sustained-release [SR] forms, respectively) and nefazodone (28%). Patients treated with bupropion SR or nefazodone had a statistically significantly lower prevalence rate of sexual dysfunction than patients taking SSRIs (citalopram, fluoxetine, paroxetine, sertraline), or venlafaxine extended-release. The mean prevalence rate of presumed antidepressant-associated sexual dysfunction was 24.4% among a prospectively defined subpopulation of patients free from other probable causes of sexual dysfunction (ie, patients were 18–40 years of age, had no history of sexual side effects on previous antidepressants, had used their current antidepressant for at least 3 months, were not taking concomitant medications affecting sexual functioning, had no comorbid illness that would affect sexual functioning, and had a history of at least some sexual enjoyment). Patients treated with bupropion SR had the lowest prevalence (6.7%) of sexual dysfunction (Table 1).

Manifestations

The four phases of the sexual response cycle are desire, arousal (erection in men, engorgement and lubrication in women), orgasm, and resolution. The aspect of sexual functioning most often affected by serotonergic antidepressants is the ability to achieve orgasm, which is either delayed or does not occur in many patients treated with antidepressants.7 Because orgasm dysfunction, unlike other sexual problems such as decreased libido, rarely occurs as a manifestation of depression per se, it is more easily attributed to pharmacotherapy than are sexual symptoms that frequently occur as manifestations of depression.3 In addition to orgasm dysfunction, the serotonergic antidepressants have been linked to erectile dysfunction and decreased libido, although the data associating these sexual side effects with antidepressant therapy are less consistent.7

Mechanisms of Action

The mechanism of antidepressant-associated sexual dysfunction has not been determined. The range of possible mechanisms includes (1) nonspecific neurologic effects (eg, sedation) that globally impair behavior including sexual function; (2) specific effects on brain systems mediating sexual function; (3) specific effects on peripheral tissues and organs, such as the penis, that mediate sexual function; and (4) direct or indirect effects on hormones mediating sexual function.8 It is probable that antidepressants impact several of these physiologic substrates of sexual function.

The association of some antidepressants and of depression itself with sexual dysfunction is not surprising in view of the fact that many of the neurotransmitter systems implicated in depression, including the serotonin, dopamine, and norepinephrine systems, are also implicated in control of sexual function. Animal research and data from studies in human subjects suggest that sexual behavior and function are enhanced by increases in brain dopaminergic function and inhibited by increases in brain serotonergic function.2,8,19,20 The latter observation is consistent with the association of serotonergic antidepressants with sexual dysfunction.

Management Strategies for Antidepressant-Associated Sexual Dysfunction

Four general approaches to managing antidepressant-associated sexual dysfunction have been adopted (Table 2). The first approach is deciding not to intervene for antidepressant-associated sexual dysfunction in the hope that spontaneous remission will occur. The second approach is to reduce or eliminate doses of the antidepressant suspected of causing sexual dysfunction. The third approach involves use of a second medication as an antidote to reverse sexual dysfunction. Finally, the fourth approach involves substitution of a second antidepressant unlikely to cause sexual side effects. Each of these strategies for managing antidepressant-associated sexual dysfunction is reviewed below.

No Intervention

Some health care providers decide not to intervene in the case of antidepressant-associated sexual dysfunction in the hope that sexual side effects may spontaneously remit over time.4 Spontaneous remission of antidepressant-associated sexual dysfunction has been reported in case studies.21,22 However, recent research suggests that it infrequently occurs within the first 6 months of initiation of therapy. In a prospective, open-label study of 1,022 outpatients taking antidepressants, 59% reported antidepressant-associated sexual dysfunction.10

Of the patients reporting sexual dysfunction, only 9.7% of them reported total improvement or spontaneous remission at the end of 6 months of antidepressant therapy; 79% of them reported no improvement. These data, suggesting that antidepressant-associated sexual dysfunction does not promptly remit, are consistent with data from the 16-week controlled comparison of sertraline and bupropion SR.16 In that study, sertraline-associated sexual dysfunction was observed at the end of the first treatment week (the initial assessment following the start of treatment) and was maintained throughout the 16-week treatment period. If spontaneous remission does not occur, failure to intervene may increase the likelihood of noncompliance with the antidepressant regimen—particularly among patients to whom sexual dysfunction is a significant concern.

Reducing or Eliminating Antidepressant Doses

Reducing the dose of antidepressant medication has been tried in attempts to ameliorate antidepressant-associated sexual dysfunction.8 This strategy has not been systematically assessed in controlled clinical studies but has been reported effective with an SSRI and a monoamine oxidase inhibitor.23,24 Depressive symptoms may reemerge with dose reduction.

Antidepressant drug holidays have also been employed as a strategy for reducing antidepressant-associated sexual dysfunction. Like the dose-reduction strategy, the efficacy of drug holidays in reducing antidepressant-associated sexual dysfunction has not been systematically studied. Positive results were obtained in one open-label, 30-patient study in which patients discontinued sertraline or paroxetine, but not fluoxetine, for the weekend. Discontinuation was associated with significant improvement in sexual functioning without a worsening of depressive symptoms.25

As drug holidays may result in antidepressant discontinuation syndrome and may provide a risk for relapse of depression, they are not an ideal strategy for most patients. Drug holidays may also limit patients’ spontaneity with respect to the timing of sexual activity. Furthermore, advising drug holidays for improvement of sexual dysfunction may encourage patients to be noncompliant with the treatment regimen during times when drug holidays are not advised or appropriate. Finally, in cases in which a drug holiday is effective in reducing sexual side effects, reinstatement of antidepressant therapy is likely to result in the reemergence of sexual dysfunction.

Reemergence of sexual dysfunction due to antidepressants was evaluated in a double-blind rechallenge study enrolling depressed patients who reported impairment in sexual function upon initiation of therapy with sertraline 100 mg OD.26 Patients discontinued sertraline for a 2-week period, and if their sexual functioning normalized during the 2-week period, were assigned to 8 weeks of double-blind treatment with sertraline 50 mg OD or the mixed serotonin antagonist/reuptake inhibitor nefazodone 100 mg BID. Beginning with the first week of reinstatement of sertraline therapy, sexual dysfunction reemerged. Whereas approximately 15% of patients were dissatisfied with sexual function before reinstatement of sertraline therapy, 50% were dissatisfied at week 1 of sertraline reinstatement. When doses were increased to 100 mg/day sertraline and 150 mg nefazodone BID during the second week of therapy, the proportion of sertraline-treated patients dissatisfied with sexual function increased to approximately 80%, which was consistently maintained through the remainder of the 8-week treatment period. These data suggest that drug holidays are not a viable long-term strategy for controlling antidepressant-associated sexual side effects, particularly for a chronic disease such as depression, which often requires life-long pharmacotherapy.

Adding an Antidote

Daily administration of pharmacotherapies that reverse sexual dysfunction and administration of antidotes acutely before sexual activity have also been tried. Agents used for this application are listed in Table 3.27-52 Although addition of an antidote can be successful in reducing the incidence of sexual side effects, it entails polytherapy, which relative to monotherapy increases the overall risk of side effects and drug interactions.

Of all of the agents administered as antidotes, only bupropion SR and buspirone have been demonstrated effective in placebo-controlled trials as well as open-label studies involving both sexes.27,32-37,51 Unlike some of the other augmentation therapies that have been tried, both bupropion SR and buspirone added to SSRI regimens appear to be well-tolerated. None of the other possible antidotes to antidepressant-associated sexual dysfunction have been evaluated in placebo-controlled studies. Evidence for their use is derived primarily from case reports and small, open-label investigations as follows:

• Several authors have reported that amantadine used for at least 2 days before sexual activity or on a regular basis reverses SSRI-associated sexual dysfunction.28-31 In a retrospective chart-review study involving records from 594 patients, amantadine was less effective than yohimbine at reversing SSRI-associated sexual dysfunction.52

• Sildenafil, which is currently approved only for management of erectile dysfunction in men, was reported in an open-label investigation to work as an antidote to antidepressant-induced sexual dysfunction in both men and women.38 Sildenafil is one of the only antidotes that can be taken on an as-needed basis shortly prior to sexual activity.

• Psychostimulants used intermittently or on a daily basis have been reported to be effective at reversing SSRI-associated sexual dysfunction.27,49 Possible drawbacks
of the use of psychostimulants include impairment of sexual function with increasing dose, the potential for abuse, and cardiovascular side effects.

• Ginkgo biloba has been reported in case reports and one uncontrolled study to counter SSRI-induced sexual dysfunction.27,46 As it is an over-the-counter herbal extract, its safety profile has not been assessed with the rigor that is applied to prescription medicines.

• Serotonin (5-HT)2 antagonists such as nefazodone and mirtazapine, as well as the 5-HT2 antagonist and antihistamine cyproheptadine, have been reported to be effective antidotes to antidepressant-associated sexual dysfunction.42-45,47,48 Cyproheptadine administered as daily therapy can interfere with the antidepressant efficacy of SSRIs.42,53 Administered acutely or chronically, it may also cause sedation, which can interfere with sexual function.

Substitution With an Antidepressant Unlikely to Cause Sexual Dysfunction

The development of new antidepressants with little or no adverse effects on sexual function has provided new opportunities for managing antidepressant-associated sexual dysfunction. Health care providers increasingly manage antidepressant-associated sexual dysfunction by starting new patients on an antidepressant shown to cause less sexual dysfunction than the SSRIs and venlafaxine. Similarly, in patients with antidepressant-associated sexual dysfunction, the sexually impairing antidepressant may be replaced with an antidepressant not associated with negative sexual side effects. These strategies have been shown to be effective with the nonserotonergic antidepressant bupropion SR as well as with the mixed serotonin antagonist/reuptake inhibitor nefazodone.7

Feiger and colleagues17 conducted a randomized, double-blind, parallel-group study to compare 6 weeks of treatment with nefazodone (n=71; mean modal end-of-treatment dose of 456 mg/day) and sertraline (n=72; mean modal end-of-treatment dose of 148 mg/day) with respect to efficacy, tolerability, and effects on sexual function. Sexual function was evaluated weekly via questionnaire. The results show that sertraline, but not nefazodone, significantly impaired sexual function, particularly among men. The following was noted among men during the last treatment week:

(1) 100% of those receiving nefazodone reported that they “fully enjoyed” or “sometimes enjoyed” sex compared with 57% of those receiving sertraline;

(2) 89% of those receiving nefazodone were at least moderately satisfied with sex compared with 50% of men receiving sertraline (Figure 2);

(3) 19% of those receiving nefazodone compared with 67% of those receiving sertraline reported difficulty with ejaculation; and

(4) 18% of those receiving nefazodone compared with 67% of those receiving sertraline indicated that they frequently, usually, or always took a long time to ejaculate.

Among women, 74% of those receiving nefazodone compared with 59% of those receiving sertraline were at least moderately satisfied with sex (Figure 2). Nefazodone-treated women achieved orgasm more easily and were more satisfied with the ability to achieve orgasm than were sertraline-treated women.

The effects on sexual function of bupropion SR have also been assessed in double-blind, head-to-head comparisons with SSRIs in patients with depression.4-6,16 In the first study, patients with moderate or severe depression received bupropion SR (100–300 mg/day) or sertraline (50–200 mg/day) for 16 weeks.16 To be included in the study, patients had to have normal sexual function (defined as absence of sexual arousal disorder, orgasm dysfunction, premature ejaculation, dyspareunia, or vaginismus) at baseline prior to the initiation of treatment, although sexual desire disorder associated with the depression could be present. The results demonstrate that the cumulative incidence of orgasm delay or failure was significantly (P<.001) greater among sertraline-treated patients (52%) than among bupropion SR-treated patients (8%), as was the overall incidence of sexual desire disorder (34% of sertraline-treated patients, 21% of bupropion-treated patients; P<.05) and the cumulative incidence of sexual arousal disorder (16% of sertraline-treated patients, 4% of bupropion SR-treated patients; P<.05). Consistent with these data, the percentage of patients satisfied with their sexual function at the end of the study increased substantially for bupropion SR (57% to 79%) but did not change for sertraline (57% to 58%). While bupropion SR had a better sexual tolerability profile than did sertraline, it conferred comparable efficacy for depressive symptoms measured with the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions Scale for Severity, and the Clinical Global Impressions Scale for Improvement.54

These data were substantiated by two double-blind, placebo-controlled, 8-week studies that replicated the findings of the first study.4,5 The placebo-controlled studies also extended the earlier findings by demonstrating that the effects of bupropion SR on the incidence of orgasm dysfunction, sexual desire disorder, and sexual arousal disorder did not differ from those of placebo (with the exception of sexual arousal disorder on day 56 of treatment in one study4) in patients with major depression. In both of these studies as in the first one, differences between bupropion SR and sertraline were most marked for orgasm delay or failure, which of the sexual problems assessed was the most common one reported with sertraline therapy (Figure 3).

In a similar placebo-controlled study prospectively designed to compare the effects of bupropion SR (100–400 mg/day) with those of fluoxetine (10–60 mg/day) on sexual dysfunction, significantly more fluoxetine-treated patients experienced orgasm dysfunction beginning by the second treatment week and continuing throughout the study compared with bupropion SR- or placebo-treated patients (P<.001, Figure 4).6 This effect was observed both in patients defined as clinical responders (ie, those with a 50% decrease in total HAM-D scores during treatment) and in patients experiencing remission (ie, those with total HAM-D scores improved to less than 8). Worsened sexual functioning, decreased sexual desire, sexual arousal disorder, and dissatisfaction with sexual functioning were more often associated with fluoxetine than with bupropion SR or placebo.

Similar differences between treatments were reported in two prospective clinical trials in which patients with antidepressant-associated sexual dysfunction were switched from an SSRI to bupropion.55,56 Sexual side effects resolved while antidepressant efficacy was maintained in both studies. In one study, bupropion SR was initiated prior to discontinuation of paroxetine, sertraline, fluoxetine, or venlafaxine while in the other, bupropion was initiated 2 weeks after discontinuation of fluoxetine. Both of these methods of switching from an SSRI to bupropion were generally well tolerated.

Conclusion

Health care providers increasingly recognize antidepressant-associated sexual dysfunction as a significant problem among some patients. Sound sexual function is important in maintaining the patient’s quality of life and self-esteem, preserving interpersonal relationships, and ensuring compliance with the antidepressant regimen. The introduction of new antidepressants augments the range of options for controlling or avoiding sexual dysfunction. In particular, the norepinephrine and dopamine reuptake inhibitor bupropion SR and the mixed serotonin antagonist/reuptake inhibitor nefazodone are as effective at controlling depressive symptoms as are antidepressants associated with sexual dysfunction,57,58 but with a low incidence of this undesirable side effect. PP

References

1. Clayton AH. Recognition and assessment of sexual dysfunction associated with depression. J Clin Psychiatry. 2001;62(suppl 3):5-9.

2. Gitlin MJ. Effects of depression and antidepressants on sexual functioning. Bull Menninger Clin. 1995;59:232-248.

3. Rosen RC, Lane RM, Menza M. Effects of SSRIs on sexual function: A critical review. J Clin Psychopharmacol. 1999;19:67-85.

4. Croft H, Settle E, Houser T, et al. A placebo-controlled comparison of the antidepressant efficacy and effects on sexual functioning of sustained-release bupropion and sertraline. Clin Ther. 1999;21:643-658.

5. Coleman CC, Cunningham LA, Foster VJ, et al. Sexual dysfunction associated with the treatment of depression: A placebo-controlled comparison of bupropion sustained-release and sertraline treatment. Ann Clin Psychiatry. 1999;11:205-215.

6. Coleman CC, King BR, Bolden-Watson C, et al. A placebo-controlled comparison of the effects on sexual functioning of sustained-release bupropion and fluoxetine. Clin Ther. 2001;23:1040-1058.

7. Segraves RT. Antidepressant-induced sexual dysfunction. J Clin Psychiatry. 1998;59(suppl 4):48-54.

8. Gitlin MJ. Psychotropic medications and their effects on sexual function: diagnosis, biology, and treatment approaches. J Clin Psychiatry. 1994;55:406-413.

9. Ferguson JM. The effects of antidepressants on sexual functioning in depressed patients: a review. J Clin Psychiatry. 2001;62(suppl 3):22-34.

10. Montejo AL, Llorca G, Izquierdo JA, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. J Clin Psychiatry. 2001;62(suppl 3):10-21.

11. Jamerson B, Ashton AD, Houser TL, et al. Antidepressant compliance and side effects: results from a patient survey. Poster presented at: the 154th Annual Meeting of the American Psychiatric Association; May 2001; New Orleans, LA.

12. Modell JG, Katholi C, Modell JD, et al. Comparative sexual side effects of SSRIs and bupropion. Clin Pharm Ther. 1997;61:476-487.

13. Montejo-Gonzalez AL, Llorca G, Izquierdo JA, et al. SSRI-induced sexual dysfunction: fluoxetine, paroxetine, sertraline, and fluvoxamine in a prospective, multicenter, and descriptive clinical study of 344 patients. J Sex Marital Ther. 1997;23:176-194.

14. McGahuey CA, Gelenberg AJ, Laukes CA, et al. The Arizona Sexual Experience Scale (ASEX): reliability and validity. J Sex Marital Ther. 2000;26:25-40.

15. Clayton AH, McGarvey EL, Clavet GJ. The Changes in Sexual Functioning Questionnaire (CSFQ): development, reliability, and validity. Psychopharmacol Bull. 1997;33:731-745.

16. Segraves RT, Kavoussi R, Hughes AR, et al. Evaluation of sexual functioning in depressed outpatients: a double-blind comparison of sustained-release bupropion and sertraline treatment. J Clin Psychopharmacol. 2000;20:122-128.

17. Feiger A, Kiev A, Shrivastava RK, et al. Nefazodone versus sertraline in outpatients with major depression: focus on efficacy, tolerability, and effects on sexual function and satisfaction. J Clin Psychiatry. 1996;57(suppl 2):53-62.

18. Clayton AH, Pradko JF, Croft HA, et al. Prevalence of sexual dysfunction among newer antidepressants. J Clin Psychiatry. 2002;63:357-366.

19. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance of male rats. Life Sci. 1989;45:1263-1270.

20. Rodriguez M, Castro R, Hernandez G, et al. Different roles of catecholaminergic and serotoninergic neurons of the medial forebrain bundle on male rat sexual behavior. Physiol Behav. 1984;33:5-11.

21. Nurnberg HG, Levine PE. Spontaneous remission of MAOI-induced anorgasmia. Am J Psychiatry. 1987;144:805-807.

22. Reimherr FW, Chouinard G, Cohn CK, et al. Antidepressant efficacy of sertraline: A double-blind, placebo- and amitriptyline-controlled, multicenter comparison study in outpatients with major depression. J Clin Psychiatry. 1990;51:18-27.

23. Patterson WM. Fluoxetine-induced sexual dysfunction. J Clin Psychiatry. 1993;54:71.

24. Barton JL. Orgasmic inhibition by phenelzine. Am J Psychiatry. 1979;136:616-617.

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

26. Ferguson JM, Shrivastava RK, Stahl SM, et al. Reemergence of sexual dysfunction in patients with major depressive disorder: double-blind comparison of nefazodone and sertraline. J Clin Psychiatry. 2001;62:24-29.

27. Zajecka J. Strategies for the treatment of antidepressant-related sexual dysfunction. J Clin Psychiatry. 2001;62(suppl 3):35-43.

28. Balogh S, Hendricks SE, Kang J. Treatment of fluoxetine-induced anorgasmia with amantadine. J Clin Psychiatry. 1992;53:212-213.

29. Shrivastava RK, Shrivastava S, Overweg N, et al. Amantadine in the treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. J Clin Psychopharmacol. 1995;15:83-84.

30. Balon R. Intermittent amantadine for fluoxetine-induced anorgasmia. J Sex Marital Ther. 1996;22:290-292.

31. Masand PS, Reddy N, Gregory R. SSRI-induced sexual dysfunction successfully treated with amantadine. Depression. 1995;2:319-321.

32. Ashton AD, Rosen RC. Bupropion as an antidote for serotonin reuptake inhibitor-induced sexual dysfunction. J Clin Psychiatry. 1998;59:112-115.

33. Labbate LA, Pollack MH. Treatment of fluoxetine-induced sexual dysfunction with bupropion: a case report. Ann Clin Psychiatry. 1994;6:13-15.

34. Bodkin JA, Lasser RA, Wines JD Jr, et al. Combining serotonin reuptake inhibitors and bupropion in partial responders to antidepressant monotherapy. J Clin Psychiatry. 1997;58:137-145.

35. Landén M, Bjorling G, Agren H, et al. A randomized, double-blind, placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59:664-668.

36. Norden MJ. Buspirone treatment of sexual dysfunction associated with selective serotonin reuptake inhibitors. Depression. 1994;2:109-112.

37. Othmer E, Othmer SC. Effect of buspirone on sexual dysfunction in patients with generalized anxiety disorder. J Clin Psychiatry. 1987;48:201-203.

38. Fava M, Rankin MA, Alpert JE, et al. An open trial of oral sildenafil in antidepressant-induced sexual dysfunction. Psychother Psychosom. 1998;67:328-331.

39. Jacobsen FM. Fluoxetine-induced sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry. 1992;53:119-122.

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

41. Segraves RT. Treatment of drug-induced anorgasmia. Br J Psychiatry. 1994;165:554.

42. Feder R. Reversal of antidepressant activity of fluoxetine by cyproheptadine in three patients. J Clin Psychiatry. 1991;52:163-164.

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

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

45. Lauerma H. Successful treatment of citalopram-induced anorgasmia by cyproheptadine. Acta Psychiatr Scand. 1996;93:69-70.

46. Cohen AJ, Bartlick BD. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24:139-143.

47. Farah A. Relief of SSRI-induced sexual dysfunction with mirtazapine treatment. J Clin Psychiatry. 1999;60:260-261.

48. Reynolds RD. Sertraline-induced anorgasmia treated with intermittent nefazodone. J Clin Psychiatry. 1997:58:89.

49. Roeloffs C, Barlick B, Kaplan PM, et al. Methylphenidate and SSRI-induced sexual side effects. J Clin Psychiatry. 1996;57:548.

50. Michael A, O’Donnell EA. Fluoxetine-induced sexual dysfunction reversed by trazodone. Can J Psychiatry. 2000;45:847-848.

51. Clayton AH, McGarvey E, Warnock J, et al. Bupropion sustained-release as an antidote to SSRI-induced sexual dysfunction. Available at: www.nimh.nih.gov/ncdeu/abstracts2000/ncdeu169.cfm. Accessed March 25, 2002.

52. Keller Ashton A, Hamer R, Rosen RC. Serotonin reuptake inhibitor-induced sexual dysfunction and its treatment: a large-scale retrospective study of 596 psychiatric outpatients. J Sex Marital Ther. 1997;23:165-175.

53. Goldbloom DS, Kennedy SH. Adverse interaction of fluoxetine and cyproheptadine in two patients with bulimia nervosa. J Clin Psychiatry. 1991;52:261-262.

54. Kavoussi RJ, Segraves RT, Hughes AR, et al. Double-blind comparison of bupropion sustained-release and sertraline in depressed outpatients. J Clin Psychiatry. 1997;58:532-537.

55. Walker PW, Cole JO, Gardner EA. Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J Clin Psychiatry. 1993;54:459-463.

56. Clayton AH, McGarvey EL, Abouesh AI, et al. Substitution of an SSRI with bupropion sustained release following SSRI-induced sexual dysfunction. J Clin Psychiatry. 2001;62:85-190.

57. Mulrow CD, Williams JW, Madjukar T, et al. Treatment of Depression: Newer Pharmacotherapies. Rockville, Md: Agency for Health Care Research and Quality; February 1999: Publication no. 99-E014.

58. Geddes JR, Freemantle N, Jason J, et al. SSRIs versus other antidepressants for depressive disorder.The Cochrane Library. 2000 (4)CD002791. Oxford: Update Software.

Articles

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Steven P. Wengel, MD, and William J. Burke, MD
 
Primary Psychiatry. 2003;10(1):67-70

 

Dr. Wengel is associate professor and director of medical student education in psychiatry and Dr. Burke is professor of psychiatry and vice chair for research, both in the Department of Psychiatry at the University of Nebraska Medical Center in Omaha.

Disclosure: The authors report no financial, academic, or other support of this work.

Please direct all correspondence to: Steven P. Wengel, MD, 985580 Nebraska Medical Center, Omaha, NE 68198-5580; Tel: 402-354-6380; Fax: 402-354-6896; E-mail: swengel@unmc.edu

 


Abstract

Where does escitalopram, the latest antidepressant, fit in the universe of selective serotonin reuptake inhibitors (SSRIs)? SSRIs, including fluoxetine, fluvoxamine, sertraline, citalopram, and paroxetine, are among the most commonly prescribed antidepressants due to their demonstrated efficacy and relatively benign side-effect profile. Citalopram is a racemic mixture of R- and S-enantiomers. The S-enantiomer, escitalopram, is the therapeutically active portion of the parent compound, whereas the R enantiomer does not contribute to clinical efficacy and may account for some of the side effects of citalopram. Escitalopram is the most serotonin-selective of the SSRIs, has relatively little effect on the cytochrome P450 system, and is less protein bound than other SSRIs. It is also well-tolerated and may offer a quicker onset of therapeutic action than citalopram in depressed patients. Like other SSRIs, it is also effective in relieving anxiety symptoms associated with depression.

Introduction

Selective serotonin reuptake inhibitors (SSRIs) are first-choice antidepressants for most depressed individuals. As a class, they possess demonstrated efficacy and a relatively low rate of side effects. In addition to existing SSRIs in the United States market (fluoxetine, fluvoxamine, sertraline, citalopram, and paroxetine), escitalopram was approved by the Food and Drug Administration in 2002 for treatment of major depressive disorder and for prevention of relapse. With existing agents already available, physicians may question why we need yet another SSRI. Does escitalopram offer a compelling reason for its existence on the market?

What Makes Escitalopram Unique?

Citalopram is a racemic mixture of R- and S-enantiomers; escitalopram is comprised of the S-enantiomer alone. To appreciate the impact of stereochemistry on psychopharmacology, a brief review of stereochemistry is helpful.

Chirality, Stereoisomers, and Enantiomers

Some organic molecules exist in two different forms which possess the same chemical formula but which are mirror images of one another. When one carbon atom binds to four different substituents, two three-dimensional configurations are possible. The two mirror-image compounds are referred to as stereoisomers and the carbon atom is described as the “chiral center” of each compound.1 The word chiral is derived from cheir, the Greek word for hand. Chiral compounds, like hands, are nonsuperimposable mirror images.2 Stereoisomers which are non-superimposable mirror images are called enantiomers.

Enantiomers are designated by at least three different systems of classification. Originally, enantiomers were differentiated on the basis of their ability to rotate plane-polarized light and this system uses prefixes of (+)/(-) or d/l. This system is still used when the absolute configuration of the molecule is not known. Another system uses prefixes of D and L (which have no relationship to the former d/l system) and compares compounds to certain reference molecules. However, the preferred system relies on knowledge of the structure of the molecule and uses the prefixes R (from the Latin rectus for right) and S (from the Latin sinister for left) to describe the order of atoms attached to the chiral center ranked by atomic number. This system has no relationship to either the d/l or D/L systems.2 Thus, escitalopram (or S-citalopram) is the enantiomer of citalopram in which the order of atoms attached to the chiral carbon is arranged in a counter-clockwise or sinister direction.

What is the Clinical Relevance of Enantiomers?

Despite the fact that enantiomers share physical and chemical properties, they may behave differently in the highly chiral environment of the human body. For example, the S-enantiomer of ketamine is an anesthetic, while the R-enantiomer can cause hallucinations.2 Another example is the proton pump inhibitor omeprazole, whose S-enantiomer is now marketed as esomeprazole and which maintains gastric pH at a higher level for a longer duration than other proton pump inhibitors.3

It should not be too surprising that enantiomers may have very different effects, since biological receptors require proper spatial orientation. A “right-handed” molecule may properly fit a receptor, while its “left-handed” enantiomer may not. In some cases, one enantiomer may be markedly more effective than another, or may have toxicity not shared by another, due to these differential spatial characteristics.

The Stereochemistry of Current SSRIs

Fluvoxamine does not possess a chiral center and, thus, does not have enantiomers. Sertraline and paroxetine are currently available as single enantiomers,2 while citalopram and fluoxetine are racemic mixtures. Fluoxetine’s enantiomers are roughly equivalent inhibitors of serotonin uptake, but its main metabolite, norfluoxetine, also exists as enantiomers which differ in reuptake inhibition. Also, the R(-) form of both fluoxetine and norfluoxetine are weaker inhibitors of the cytochrome P450 (CYP) 2D6 isoenzyme. Attempts to develop R(-)-fluoxetine for clinical use were thwarted by concerns about QT prolongation when this enantiomer was given alone.

Pharmacodynamic and Pharmacokinetic Properties of Escitalopram

SSRIs are believed to exert their clinical effects by binding to the serotonin transporter (SERT) protein, and in so doing, inhibiting the uptake of serotonin. In a study of binding affinity for the human SERT, escitalopram was found to be the most “SERT-selective” compound of those tested, and was about 30 times more potent in binding affinity than R-citalopram (Table 1).4



Mork and colleagues5 injected rats with escitalopram 2 mg/kg, R-citalopram 2 mg/kg, or citalopram 4 mg/kg and measured resulting serotonin levels in the frontal cortex of the subject rats via microdialysis. Rats receiving R-citalopram showed very little change in serotonin, while those that received escitalopram had roughly double the amount of serotonin released compared to that seen with the racemic mixture of citalopram. These results are quite surprising since racemic citalopram contains equal amounts of R-citalopram and escitalopram. If R-citalopram were simply inert, the groups receiving escitalopram and citalopram would be expected to have the same amount of serotonin released after injection. It is not possible to explain the mechanism of these results yet, but they suggest that R-citalopram plays some active role in interfering with escitalopram.

Speed of response to antidepressants can be investigated using various animal models. In one such model of stress,6 rats were trained to consume a 1% sucrose solution. They were then assigned to a control group or a “stressed” group. Rats in the stressed group were subjected to various forms of stress, such as stroboscopic lighting and food or water deprivation, over a 3-week period. In this phase, sucrose solution consumption declined from an average of 15 g/day to 8 g/day. Both groups were then given citalopram, pure saline, or escitalopram. Citalopram normalized sucrose solution consumption in the stressed rats after 2 weeks, and escitalopram did so after 1 week. By way of comparison, tricyclic antidepressants and monoamine oxidase inhibitors take at least 3–5 weeks to normalize stress-induced behavioral changes.

Time to response in human subjects was also examined by these investigators who administered citalopram, escitalopram, or placebo to 471 depressed patients. They found that those receiving escitalopram had a statistically significant improvement in depression rating scores starting at week 1, while those taking citalopram did not exhibit a statistically significant change compared to placebo for the entire 4-week duration of the study.6

The effects of escitalopram and R-citalopram on the CYP isoenzyme system were compared using human liver microsomes. The R-enantiomer is a weak to moderate inhibitor of CYP 2D6, comparable to sertraline, while escitalopram was found to be a weak or negligible inhibitor of human CYP 1A2, 2C9, 2C19, 2D6, 2E1, and 3A isoenzymes.7 Escitalopram is transformed into its main metabolite, S-desmethylcitalopram, via CYP 2D6, 2C19, and 3A working in parallel. In this regard, Von Motke and colleagues note the following:7

Any one of these isoforms due to a drug interaction or genetic poor metabolizer polymorphism is unlikely to have a large effect on net metabolic clearance.

Although there is only a limited amount of in vivo data available, there is no evidence yet of clinically significant interactions with escitalopram. At 20 mg/day of escitalopram, twice the recommended daily starting dose, there is some elevation in levels of co-administered desipramine and metoprolol which appear comparable to the effect of racemic citalopram.8

Clinical Evidence for Efficacy of Citalopram in the Treatment of Depression

There have been five randomized controlled trials of escitalopram to date. Two of these were fixed-dose trials, two were flexible-dose trials, and one was a continuation trial for subjects who had participated in an acute, 8-week trial. The first was a fixed-dose study in a primary care setting. Escitalopram 10 mg/day was compared to placebo in depressed outpatients recruited from primary care clinics in Canada, Estonia, France, the Netherlands, and the United Kingdom.9 Escitalopram-treated patients showed significant reductions in depressive symptoms measured by the Montgomery-Asberg Depression Rating Scale (MADRS)10 starting at week 2, and also demonstrated improvement in Clinical Global Impressions Improvement (CGI-I)11 scores by week 1. At week 8, 55% of the escitalopram-treated patients were classified as responders, compared to 42% of those receiving placebo.

In a study of 491 outpatients with major depression, Burke and colleagues12 compared clinical response in subjects taking fixed doses of escitalopram 10 mg, escitalopram 20 mg, citalopram 40 mg, or placebo once daily for 8 weeks. Patients in all three active treatment groups demonstrated statistically significant reductions in depressive symptoms as measured by the MADRS, the Hamilton Rating Scale for Depression (HAM-D),13 and the CGI-I and CGI-Severity scales.11 Response to treatment, defined as a 50% improvement in MADRS compared to baseline, was seen in 45.6% of patients treated with citalopram, 50% of those treated with escitalopram 10 mg, and 51% of those treated with escitalopram 20 mg; these differences were not statistically significant.

Although not reaching statistical significance, there was a trend for the 20 mg escitalopram group to separate from the citalopram group in terms of MADRS total score (P=.07) and the HAM-D (P=.06). Interestingly, escitalopram 10 mg/day was as effective as citalopram 40 mg/day on most of the efficacy measures. Also noteworthy was the fact that both escitalopram doses led to significant improvement in HAM-D and MADRS scores starting in week 2 of the study. Escitalopram also reduced anxiety symptoms, as rated by the Hamilton Rating Scale for Anxiety (HAM-A).14 In the case of the HAM-A, the 20 mg dose of escitalopram led to a greater reduction of anxiety symptoms at the 8-week study endpoint than the 10 mg dose.

A multinational flexible-dose trial of 310 patients with major depression revealed statistically significant improvement in both CGI and MADRS scores compared to placebo, starting at week 1.15 The other flexible-dose study in which both escitalopram and citalopram separated from placebo on observed cases but not on last observation carried forward analysis was conducted by Gorman and colleagues16 using the pooled data from the studies by Burke and colleagues12 and Lepola and colleagues.15 The study examined the clinical response to escitalopram compared to the parent compound; the studies by Burke and Lepola were chosen due to similarity of their designs (8-week duration, same outcome measures, and use of the active comparator citalopram). MADRS scores for those taking escitalopram were significantly improved compared to the placebo and citalopram groups after 1 week of treatment; citalopram-treated patients did not show statistically significant improvement over placebo until the week 6. CGI-I scores for those taking escitalopram also showed significant improvement over placebo starting at week 1, and also separated from the citalopram group at weeks 4 and 6. Gorman and colleagues16 also examined response in those with the most severe depressions (baseline MADRS scores >30) and found that escitalopram was statistically superior to citalopram at weeks 1, 6, and 8.

Escitalopram has also been demonstrated to be statistically superior to placebo for the prevention of recurrent depression.17 There are currently no published studies evaluating the use of escitalopram at doses above 20 mg/day.

Evidence for Escitalopram’s Efficacy in Anxiety Disorders

While not currently approved by the FDA for treatment of anxiety disorders, escitalopram’s efficacy in such disorders has been investigated. Preliminary evidence demonstrates that escitalopram significantly reduces symptoms of generalized anxiety disorder (GAD),18,19 social anxiety disorder (SAD),19,20 and panic disorder (PD).19,21 Doses of escitalopram range from 10–20 mg/day in the GAD and SAD studies, and 5–20 mg/day in the PD studies. Escitalopram was well tolerated in these studies.

What About Escitalopram’s Side-Effect Profile?

In the study by Burke and colleagues,12 4.2% of those receiving escitalopram 10 mg discontinued the study due to adverse events, compared to 10.4% of those receiving escitalopram 20 mg, 8.8% of those receiving citalopram 40 mg, and 2.5% of those receiving placebo. The discontinuation rates between the escitalopram 10 mg group and the placebo group were not statistically significant, while the escitalopram 20 mg and citalopram 40 mg groups did have a significantly higher dropout rate due to adverse events compared to placebo. Also, the overall rate of treatment-emergent side effects did not significantly differ between the placebo and escitalopram 10 mg groups.

Side effects reported in at least 10% of active treatment groups consisted of nausea, diarrhea, insomnia, dry mouth, and ejaculatory disorder (primarily delay). Other sexual side effects, including anorgasmia and loss of libido, were seen in <3% of actively treated subjects, although it should be noted that sexual side effects were self-reported and may thus underrepresent these symptoms.

Similar results were seen in a study of primary care patients conducted by Wade and colleagues.9 The only statistically significant finding was nausea seen in 8.9% of escitalopram patients compared to 3.7% of placebo-treated patients. Fewer than 4% of escitalopram-treated patients experienced nausea on any given day of treatment, and after the first 2 weeks of treatment, there was no difference in this side effect between groups. Ejaculation disorder affected 6% of male patients. Approximately 70% of those receiving escitalopram had no change in weight during the study.

In a study designed to examine tolerability of escitalopram in subjects unable to tolerate another SSRI, Rosenthal and colleagues22 randomly assigned patients with recurrent major depression to 8 weeks of open label treatment with citalopram, fluoxetine, paroxetine, or sertraline. Forty-six patients discontinued treatment from one of these four antidepressants due to adverse events. These patients were then given 8 weeks of open-label treatment with escitalopram, flexibly dosed from 10–20 mg/day. Eighty-five percent of those starting escitalopram were able to tolerate the drug despite their prior intolerance of the other SSRIs. Other side effects reported include dizziness, increased sweating, constipation, fatigue, and indigestion (Table 2).

Discussion

Escitalopram appears to be a well-tolerated and effective antidepressant. With a favorable side-effect profile, it appears to be well tolerated even in patients who are intolerant of other SSRIs. Additionally, escitalopram may possess safety advantages, in that it appears to have the potential for fewer drug-drug interactions due to little effect on the CYP system and is less highly protein-bound than other SSRIs.

While escitalopram is currently only approved for the treatment of major depression and preventing its recurrence, it has been shown to effectively treat anxiety symptoms associated with depression. Additionally, preliminary data suggest that it will be efficacious in the treatment of anxiety disorders, including GAD, SAD, and PD.

Data from clinical trials and an animal model of chronic stress suggest that escitalopram may have a more rapid onset of action than racemic citalopram.5 Both animal and human studies have demonstrated a separation from placebo and citalopram for subjects receiving escitalopram within the first 2 weeks of treatment.5 However, caution is appropriate in interpreting these data concerning rate of onset, for a number of reasons. First, although patients taking escitalopram separate from placebo relatively early in treatment, they nonetheless still have MADRS scores in the depressed range. Second, data on rate of improvement are post hoc analyses. Properly designed studies to detect early response are required to specifically address this issue.

Similar results have been reported with other antidepressants, including citalopram, which have not always been replicated. A good case in point is that subjects taking citalopram in these trials often took 4–8 weeks to separate from placebo, depending on the specific measure.

The issue of relative efficacy of escitalopram compared to citalopram is puzzling. It is interesting to observe that, as Burke and colleagues12 notes, patients receiving 40 mg of citalopram received twice as much escitalopram as those receiving 10 mg alone, yet there was no statistical superiority in the citalopram group. This raises the question of whether the presence of the R-enantiomer in citalopram might actually produce an impairment in efficacy compared to escitalopram alone. Although unproven, it is an intriguing hypothesis.

Single isomer drugs are not intrinsically superior to racemic mixtures. In some cases, the single isomer drug has clear disadvantages, as in the case of R-fluoxetine which was associated with QT prolongation, while racemic fluoxetine apparently does not cause this side effect. Also, the reduction in certain side effects may be a mixed blessing. Sedation with racemic citalopram is problematic for some patients but may be therapeutic for others.

Conclusion

Escitalopram appears to be an efficacious, well-tolerated antidepressant that has a low propensity for drug-drug interactions due to its low protein binding and minimal effect on the CYP system. It may offer a more rapid improvement in depressive symptoms, but additional data will be needed to reach a definitive conclusion on this issue. PP

References

1. Brocks DR, Jamali F. Stereochemical aspects of pharmacotherapy. Pharmacotherapy. 1995;15:551-564.

2. Burke WJ, Kratochvil CJ. Stereoisomers in psychiatry: the case of escitalopram. J Clin Psychiatry. 2002;4:20-24.

3. Johnson TJ, Hedge DD. Esomeprazole: a clinical review. Am J Health Syst Pharm. 2002;59:1333-1339.

4. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine. Biol Psychiatry. 2001;50:345-350.

5. Mork A, Kreilgaard M, Sanchez C. Escitalopram: in vitro and in vivo 5-HT uptake inhibition [abstract]. Presented at: the 12th World Congress of Psychiatry; August 24-29 2002; Yokohama, Japan.

6. Montgomery SA, Loft H, Sanchex C, Reines EH, Papp M. Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol. 2001;88:282-286.

7. Von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos. 2001;29:1102-1109.

8. Lexapro [package insert]. St. Louis, MO: ForestPharmaceuticals; 2002.

9. Wade A, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2002;17:95-102.

10. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382-389.

11. Guy W. ECDEU Assessment Manual for Psychopharmacology. US Dept of Health, Education, and Welfare publication (ADM) 76-338. Rockville, Md: National Institute of Mental Health; 1976:218-222.

12. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;3:331-336.

13. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56-62.

14. Hamilton M. Diagnosis and rating of anxiety. Br J Psychiatry. 1969;special publication:76-79.

15. Lepola U, Loft H, Reines EH. Escitalopram is efficacious and well tolerated for the treatment of depression in primary care [abstract]. Presented at: the Annual Meeting of the Scandanavian College of Neuropsychopharmacology; April 18-21, 2001; Juan Les Pins, France.

16. Gorman JM, Korotzer A, Su Guojin. Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder: pooled analysis of placebo-controlled trials. CNS Spectrums. 2002;7(suppl):40-44.

17. Rappaport M, Bose A, Zheng H, Korotzer A. Escitalopram prevents relapse of depressive episodes [abstract]. Presented at: the Annual Meeting of The American College of Neuropsychopharmacology; December 9-13, 2001; Waikoloa, Hawaii.

18. Davidson JD, Bose A, Su Guoqin. Escitalopram in the treatment of generalized anxiety disorder [abstract]. Presented at: the12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.

19. Pollack MH, Bose A, Zheng H. Efficacy and tolerability of escitalopram in the treatment of anxiety disorders [abstract]. Presented at: the 12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.

20. Kasper S, Loft H, Rico N. Escitalopram in the treatment of social anxiety disorder [abstract]. Presented at: the 12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.

21. Stahl S, Gergel I, Li D. Escitalopram in the treatment of panic disorder [abstract]. Presented at: the 12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.

22. Rosenthal MH, Li D. Efficacy and tolerability of escitalopram in patients intolerant of other SSRIs [abstract]. Presented at: the 12th World Congress of Psychiatry; August 24-29, 2002; Yokohama, Japan.


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Paul D. Wulkan, MSW
 

Primary Psychiatry. 2003;10(1):50-54

Dr. Wulkan is director of program evaluation and research at the Nevada Division of Mental Hygiene and Mental Retardation, South Nevada Adult Mental Health Services, in Las Vegas, Nevada.

Disclosure: This study was conducted under the auspices of the Nevada Division of Mental Health and Developmental Disabilities in Las Vegas, Nevada.

Please direct all correspondence to: Paul D. Wulkan, MSW, South Nevada Adult Mental Health Services, 6161 W. Charleston Blvd., Las Vegas, NV 89145; Tel: 702-486-6070; 702-486-6248; E-mail: pwulkan@govmail.state.nv.us


  

Abstract

What is the result of switching patients from tricyclic antidepressants to selective serotonin reuptake inhibitors (SSRIs) in terms of total direct care costs? With the advent of the new-generation medications came an economic impact on the delivery of mental health services. This was especially pronounced with major buyers of these medications, including health maintenance organizations, hospitals, all levels of government, and especially Medicaid. The benefit of these new-generations medications has been the subject of much research over the last decade. The general consensus has been that while more expensive, the benefits of these medications outweigh the costs. Legislative and governing bodies continue to ask the question of whether there is an overall money savings with the use of the new-generation medications. The results of this study confirmed the reduction in inpatient costs regarding readmission, episodes, and length of stay. However, there was an increase in community-based cost primarily due to the cost of medication. The implication is not that the SSRIs should not be used, but rather that administrators and policy makers need to be aware that the benefits of the SSRIs will result in a cost shift in the budgets of the mental health sector.

Introduction

The economic impact of new-generation medications on the mental health sector was felt first by the large buyers of these medications, including the state and federal governments, public and privates insurers, such as Medicaid and health maintenance organizations (HMOs), and hospitals. This study was initiated to determine the benefits and cost effectiveness of all new-generation medications, including the selective serotonin reuptake inhibitors (SSRIs). The new-generation medications have been touted as being more effective by improving quality of life1 and safety,2,3 preventing relapse,4 reducing side effects, physical health care costs,5 hospitalization days, and episodes.6 Due to their increased utilization, new-generation medications have also become the community standard. This article portrays a retrospective naturalistic mirror design study developed by the Nevada Division of Mental Health and Developmental Disabilities in Las Vegas, Nevada, to compare the cost of service utilization before and after switching patients from older tricyclic antidepressants (TCAs) to the SSRIs. Because the agencies studied were comprehensive full service agencies, the total costs of direct care could be measured including hospitalization, housing, medications, and all aftercare services. Since the Nevada State legislature approved the use of SSRIs and other new-generation medications, the overall budget for pharmaceuticals has increased significantly. The annual expenditure for antidepressants more than doubled from Fiscal Year (FY) 1998 ($1.6 million) to FY 2002 ($3.3 million). While much of the change in expenditures was in numbers of patients served, the expenditure for TCAs in that period increased 21.4% compared to a 102% for SSRIs. The percent of patients on SSRIs rose from 60% in 1998 to over 90% in FY 2002. This study focused on this transitional period where patients were switched from TCAs to SSRIs by policy.

At the time of the study, the average unit cost of the SSRIs was $1.50 compared with the older TCAs, which was only $0.17 for the average unit cost. Nearly 10 times higher. This study compared patients both before and after administration of SSRIs to determine if there was a change in utilization mental health or housing services as measured by service costs. The 221 patients in the sample were compared for equal numbers of days pre- and post-SSRI (Mean=218 days).

Background

It is estimated that depression, including direct costs, mortality (suicide), and morbidity (loss of productivity), costs Americans $43.7 billion annually. Direct costs alone amount to $12.4 billion.7 This study examined cost effectiveness based on direct care costs, including inpatient, outpatient, housing, and medications costs.

Cost effectiveness examines the intervention in the usual circumstance of service delivery, (in vivo) which is different from the cost-efficacy studies which are usually conducted by pharmaceutical manufacturers. Those studies evaluate the intervention (or drug) under optimal conditions.8 Effectiveness studies are limited in part because of the difficulty in finding psychiatric systems that are self contained, eg, where the patient remains in the same inpatient, outpatient, housing, and pharmacy system, and where all that information can be tracked.

Nevada’s mental health system is unique from most states in that hospital, community services, housing, and pharmacy are provided by the same entity. Gills and Crott noted:

Comparative cost-effectiveness/utility studies… have consistently shown a better cost-effectiveness ratio for the newer antidepressants over traditional antidepressants when all therapy-related costs are taken into account.9

Each of the settings in which these studies have been conducted has their own unique delivery systems and follow-up costs. To that degree, we know that there are decreases in inpatient utilization, but we do not know what the offsets in cost mean relative to the total service delivery to patients placed on the new-generation medications.

Objective

As part of a legislative mandate, this research project focused on what direct-cost changes occurred when patients were switched from TCAs to new-generation medications. The measure of these cost changes is based on the utilization of mental health services prior to and post the administration of the SSRIs.

Method

The criteria for inclusion in the study was that the patient had received one of the older antidepressants for at least 60 days and that they had switched to and received an NGM for at least 60 days. The prior medication had to have been a traditional antidepressant medication. Additionally, they must have made the switch in FY 1997 or 1998.

These particular years were selected because the Nevada legislature had just appropriated funds allowing for the general use of NGMs including the expanded use of SSRIs. This provided an opportunity for capturing a significant sample of patients who were switching from TCAs to SSRIs due to policy and economic change.

This was a retrospective study using a mirror design. If, for example, a patient had been on a new medication for 100 days, the service cost and utilization for the 100 days prior and 100 days post the new medication were considered. If the time periods were unequal, the shorter time period was used.

All data was reported in FY 1998 dollars. Costs were also computed on dollars per patient per day. This was calculated by dividing the cost by the total proxy patient days. (cost in dollars)/(patients X average number of days in the study).

Participants

The sample was drawn from two of the Division of Mental Health’s agencies in Las Vegas and Reno. To conduct this study, patients at both of Nevada’s comprehensive facilities were used in the sample. Both facilities provide a full range of mental health services with a high volume of active cases.

The strength of this study was that in many states the aftercare is conducted by multiple agencies and is not easily tracked. For example, in some states, inpatient services are operated by the state, while outpatient services are conducted by community mental health agencies and the housing by local welfare agencies. Because of Nevada’s unique operation of blending these into one agency, these costs and the cost of the pharmaceuticals can all be tracked.

Listed below are the agencies and their caseload at the time of the study for each respective service.

Description of the Agencies

Southern Nevada Adult Mental Health Services —Las Vegas

Programs and average annual caseloads (FY 1998) for inpatient and outpatient care were as follows.

Inpatient Care

There were 86 beds in the psychiatric hospital staffed for 79 beds; about 25% of patients were receiving long-term care.

Outpatient Care Programs

There were 437 patients in the case management program, 720 in counseling, 378 in housing and supportive living arrangements, 126 in psychosocial rehabilitation, 544 in 24-hour ambulatory crisis unit, 10 in the 10-bed observation unit, 3,706 in the medication clinic, and 2,157 in pharmacy.

Northern Nevada Adult Mental Health Services —Reno

Programs and average annual caseloads (FY 1998) for inpatient and outpatient care were as follows:

Inpatient Care

There were 74 patients in the psychiatric hospital staffed for 54 beds.

Outpatient Care Programs

There were 700 patients in the case management program, 286 in counseling, 149 in housing, 154 in psychosocial rehabilitation, 1,297 in medication clinics, and 763 in pharmacy.

Demographics of the Sample

Demographics and the length of time the patients were in the medication study are listed in Table 1.

The racial characteristics of the sample approximate that of the agencies’ caseload, however it is lower than the state percent for Hispanics. The average age is higher than for the agency as a whole, but about the same for persons who have been identified as severely mentally ill. Females were overrepresented, but that was expected for persons with a diagnosis of depression. The range of time on the medications was 62–422 days with a mean of 218 days.

Procedures

The classification of drugs into the categories of old- versus new-generation drugs were driven by cost rather than the chemical composition or the targeted neuroreceptors. The two general groups of medication studied were loosely called SSRIs and the traditional or older medications called TCAs in this study. While there is some technical difference in the action of some of the medications, the groupings have been made to differentiate older and less expensive drugs from the newer and more expensive medications. A listing of each drug by grouping is provided in Table 2.

Results

Inpatient Services

The number of inpatient episodes in the post-SSRI group decreased 37.5% or from 40 to 30 episodes, and the days spent in hospital beds decreased 31.9% from 1,003 to 683 bed days. Among the patients in the post-SSRI group who did return to the hospital, their average length of stay was longer than the pre-SSRI group, increasing from 20.9 to 22.8 days (9.1%).

The overall savings in the post-SSRI group was $121,104 in hospital bed costs (Table 3) and $2,535 in psychiatric observation unit cost (Table 4).

Residential Care: (Housing)

Following hospitalization, many patients are transferred to group care or other types of residential living situations that are paid for by the agencies. Some are transitional in nature and others are longer-term placements.

The housing bed days increased 6.2% for the patients placed on the SSRIs, which increased the agencies’ expenditure $6,325 for this group (Table 5).

Medications Costs

 

The cost of medications increased by 475.6% and the number of prescriptions dispensed increased by 190.8%. The increased cost was $192,894 to $8.01 per patient per day. The prescription day was computed by dividing the total costs of each patient’s prescription by the number of days in the study (Table 6).

All other outpatient services were combined including those listed in Table 7. Of these services, the use of the 24-hour crisis ambulatory unit decreased the most in terms of usage. The psychosocial rehabilitation unit and medication clinics increased the most in usage. There was an increase in medication clinic usage (excludes medication costs). Overall, there was only a 5.2% cost increase in these combined services for a total increase of $20,263 in aftercare costs (Tables 7 and 8).

Summary of Results

The following is a summarized listing of the study results:

• The number of inpatient episodes decreased from 48 to 30 (-37.5%) and the number of bed days decreased from 1008 to 688 (-31.9%). The savings were $121,104 or $2.51 per patient day savings on the new medications.

• The number of observation unit admissions decreased 13.3% from 60 to 52. The overall cost decreased just $2,535 totally for this category.

• Housing costs increased by $6,325 or 6.3% or a cost per patient per day of just $0.13.

• The number of prescriptions increased 190.8% and the cost of medications increased 475.6%. The increase in the gross cost was $192,894. The average cost per patient per day reduced from $0.84 to $4.85.

• Outpatient services increased by only 5.2% or $0.42 per patient per day. The largest decrease in this group was ambulatory crisis, which decreased 36.0%. The largest dollar increase was for medication clinic visits, which was expected.

• The overall cost of patient services increased by 10.3% or $96,389 for the 221 patients in the study. The patient per day cost rose by $1.99.

Discussion

Overall, there was a 10.3% increase in the total cost of services following the switch from TCAs to SSRIs. The assumption that a decrease in inpatient days and cost would offset the increase in cost of medications was not confirmed. The amount of decrease in hospital costs ($121,104) was not sufficient to offset the increased costs of the SSRIs ($192,894 [Figure]).

The limitations of this study are the fact that at the time of this study none of the drugs in the SSRI group had generic formulations yet, and the majority of SSRIs (93.8%) used were limited to fluoxetine, paroxetine, and sertraline. Had this switch from TCAs happened today, the end results may have been lower because the distribution in the use of newer antidepressants is much broader and because generic antidepressants have reached the market. Recent Canadian research suggested that when fluvoxamine, fluoxetine, paroxetine, and sertraline are equally used, drug expenditure will decrease by 8%.10 The agencies in this study now have a much broader dispensing pattern which may also influence the reduction in the overall cost of the SSRIs.

This study addressed only cost, but because of the minimal (10.3%) increase, the broader benefits of the SSRIs must be considered. Also, ongoing cost effectiveness must be conducted because of the changing cost of medications and the increased inventory of medications. Equally important, attention must be paid to the cost shifts in the delivery of mental health services.

Conclusion

In the last decade there has been much discussion about the effect of the cost of the next-generation medications. The oldest of this group are the antidepressants, generally reffered to as SSRIs. Because governmental bodies, hospitals and health maintenance organizations purchase large volumes of drugs, they were the first to feel the impact of the increased costs of these next-generation medications.

When the Nevada Division of Mental Health and Developmental Disabilities received approval and funding to place SSRIs into their formulary in 1998, an opportunity was created to measure the economic impact of the migration of patients from the older antidepressants, TCAs, to the newer SSRIs. This naturalistic study identified patients who had previously been on a TCA and had switched to an SSRI. The total cost of services were compared both before and after the switch from TCAs to SSRIs. The analysis was done in 1998 dollars.

The cost of service utilization had decreased for the post group by 31.6% for hospitalization and 14.4% for observation unit costs (<72 hour stays). There were minor increases for housing (6.3%) and other outpatient services (5.2%). The most significant increase was for medications, which rose 457.6% with the switch to SSRIs. When all costs were added together, there was a 10.3% increase in the post-SSRI group.

Because one third of the patients were taking fluoxetine, which is now generic, the overall cost would now be much lower had the study been conducted today. Due to better compliance, tolerance, and acceptance it is possible that the savings from generic drugs may be offset by increased use of SSRIs and other next-generation medications as increased numbers of patients are seeking treatment for depression. Better compliance means longer stays on the medications; increased off-label use of SSRIs also contributes toward a cost shift in public agency budgets. The public sector must be prepared for this cost shift in the distribution of how mental health dollars are spent. As additional next-generation medications reach the market the percent of dollars spent on pharmaceuticals will compete with other treatment dollars. PP

References

1. Taylor AT, Spruill WJ, Longe RL, Wade WE, Wagner PJ. Improved health-related quality of life with SSRIs and other antidepressants. Pharmacotherapy. 2001;21:189-194.

2. D’Mello DA, Finkbeiner DS, Kocher KN. The cost of antidepressant overdose. Gen Hosp Psychiatry. 1995;17:45-55.

3. Carlsten A, Warn M, Ekedahl A, Ranstam J. Antidepressant medication and suicide in Sweden. Pharmacoepidemiol Drug Saf. 2001;10:525-530.

4. Revicki DA, Sorensen SV, Shih YC. The economics of selective serotonin reuptake inhibitors in depression: a critical review. CNS Drugs. 2001;15:59-83.

5. Panzarino PJ Jr, Nash DB. Cost-effective treatment of depression with selective serotonin reuptake inhibitors. Am J Manag Care. 2001;7:173-184.

6. Wulkan PD. New generation psychiatric medications in Nevada. Nevada Division of Mental Health and Developmental Services; 2001. Available at: http://mhds.state.nv.us/pdfs/NGM021501.pdf. Accessed: December 2002.

7. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER. The economic burden of depression in 1990. J Clin Psychiatry. 1993;54:405-418.

8. Hargrave WA, Shumway M, Hu T, Cuffel B. Cost-Outcome Methods for Mental Health; San Diego, Calif: Academic Press; 1998.

9. Gills P, Crott R. Economic comparisons of the pharmacotherapy of depression: overview. Acta Psychiatr Scand. 1998:4:241-252.

10. Dewa CS, Hoch JS, Goering P. Using forcasting models to estimate the effects of changes in the composition of claims for selective serotonin reuptake inhibitors on expenditures. Clin Ther. 2001;23:292-306.

 

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Roger S. McIntyre, MD, FRCPC, Kari A. Fulton, BA, David Bakish, MD, FRCPC, J. Jordan, MD, CCFP, and Sidney H. Kennedy, MD, FRCPC
 
Primary Psychiatry. 2003;10(1):39-42

 

Dr. McIntyre is head of the Mood Disorders Psychopharmacology Unit at the University Health Network and assistant professor of psychiatry at the University of Toronto in Canada.

Ms. Fulton is a research coordinator at the Mood Disorders Psychopharmacology Unit at the University Health Network.

Dr. Bakish is adjunct professor in the Department of Psychiatry at the University of Toronto.

Dr. Jordan is program chair at the Byron Family Medical Centre, London Health Sciences Centre, and associate professor in the Department of Family Medicine at the University of Western Ontario, in London, Ontario.

Dr. Kennedy is professor of psychiatry and head of the Department of Psychiatry at the University of Toronto, and chief psychiatrist at the University Health Network.

Disclosure: The authors report no financial, academic, or other support of this work.

Please direct all correspondence to: Roger S. McIntyre, MD, University Health Network, 399 Bathurst St., ECW-3D-008, Toronto, Ontario M5T2S8; Tel: 416-603-5279; Fax: 416-603-5368; E-mail: Rmcintyr@uhnres.utoronto.ca

 



Abstract

Objective: To describe a brief depression rating scale capable of estimating depression symptom severity, establishing and comparing the efficacy of antidepressant treatment, and distinguishing a clinical response to treatment from full symptomatic remission.

Method: An extraction technique was employed attempting to identify the most commonly endorsed and sensitive depressive items from a standardized clinician-rated depression scale, the 17-Item Hamilton Rating Scale for Depression (HAM-D17). Data was harvested from a mood disorders clinical database within a tertiary university-affiliated hospital. Participants were comprised of patients (N=248) with a diagnosis of major depressive disorder who were receiving naturalistic treatment. The primary aim of this study was to identify a cutoff score to distinguish clinical response from remission.

Results: A score of ≤3 (out of a potential score of 26) would define a full remission of symptoms with the Toronto Hamilton Depression Rating Scale.

Conclusion: Family physicians prescribing antidepressant treatment should employ a brief valid comprehensive scale to assess depression severity at baseline and monitor patient response to treatment. The contemporary goal in treating depressed patients is full remission of symptoms. Full remission has been operationalized quantitatively inviting the need for depression rating scales in the routine management of all depressed patients.

Introduction

Major depressive disorder (MDD) is a highly prevalent heterogeneous disorder which imparts substantial illness burden and humanistic costs.1-3 Depression often coaggregates with other illnesses such as anxiety and cardiovascular disease.4-5 Persons with depressive and anxiety syndromes are consistently identified as high utilizers of primary care services.6 A recent study sponsored by the World Bank and Health Organization was launched in 1992 with an aim of quantifying the burden of disease. The metric disability-adjusted life years (DALYs) were employed and estimations of disability and mortality from over 100 diseases in all regions of the world were carried out.7 It was determined that depression is currently the leading cause of disability and premature death among those 18–43 years of age.3 An expanding corpus of data has described the staggering economic costs imparted by depression to the individual, their family, and society.8

This forgoing composite of MDD constitutes a very significant paradigm shift in conceptualizing MDD. These changes have invited the clinical community to redefine a therapeutic model with clear, practical, and consensually agreed upon treatment goals. The contemporary goal of antidepressant therapy is to achieve full remission of symptoms, prevent recurrence of illness, promote functional restoration, and enhance quality of life.9

Response to treatment in clinical research is arbitrarily defined as a 50% reduction in depressive symptom total score (with a clinician rated scale such as the 17-Item Hamilton Rating Scale for Depression [HAM-D17]).10 Results from clinical and prospective longitudinal studies converge and suggest that responding to antidepressant therapy but failing to achieve full abatement of all depressive symptoms comprises an adverse clinical outcome.11-13 Residual depressive symptoms (subsyndromal symptomatology) remaining in an antidepressant “responder,” powerfully predisposes and portends risk of overt affective recurrence. Moreover, the risk of cardiovascular morbidity and mortality in persons with and without preexisting cardiovascular disease and suicidal behavior is significantly enhanced by ongoing depressive symptoms.14

An inverse and parallel gradient between depressive symptom severity and psychosocial functioning has been described.15,16 Delineating refined therapeutic objectives and completely eliminating illness activity is a valid therapeutic target in depression. Clinicians require tools to assist them in navigating toward the destination of remission and functional restoration.17,18 Symptomatic remission has been defined as HAM-D17 total score of ≤7, which implies the clinician should employ a standardized depression rating scale.19

The HAM-D has been the most frequently employed scale in clinical research. The hegemony of this tool has been challenged by longstanding concerns over its psychometric deficiencies (internal/external validity, test-retest reliability), transferability across different medical settings, and general unacceptance by the clinical community (largely due to its length of time to administer).

We sought to determine whether we could develop a brief version of the HAM-D17, which would improve upon existing psychometric deficiencies. A further clinical aim of this study was to create a valid comprehensive depressive assessment tool that the clinician could administer within several minutes, which could purposefully estimate the severity of depression, monitor symptomatic progress, and distinguish clinician response from remission. A comprehensive validated scale would have clinical practice utility by virtue of its brevity.

Methods

Subjects were outpatients with unipolar, nonpsychotic depression who received uncontrolled antidepressant treatment in the Depression Clinic of the Centre for Addiction and Mental Health at the University of Toronto. Subjects were openly assigned to conventional first-line unimodal antidepressant treatment (fluoxetine, sertraline, citalopram, fluvoxamine, paroxetine, venlafaxine extended-release, nefazodone, and moclobemide). All subjects consented to having their clinical information used as part of a larger clinical database.

Criteria for entry into the database was a diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV),20 HAM-D17 total score of ≥16, no current active medical illness, and absence of antidepressant medication for a minimum of 2 weeks prior to treatment initiation. The clinical database protocol required participants to receive treatment for a minimum of 14 weeks to a maximum of 26 weeks. The mean time from treatment initiation to protocol termination for those included in this analysis was 20 weeks (SD=5.0).

HAM-D17 evaluations were available at the baseline and endpoint visits. Efficacy assessments were not determined between these two time points. The items on the HAM-D17 that were mostly sensitive to antidepressant treatment were identified and extracted to create a more brief yet comprehensive scale. We attempted to determine a remission cutoff score that would correlate with the remission score defined by the HAM-D17. A secondary analysis was carried out to compare our abbreviated scale with preexisting depression subscales.

Results

Depressive symptom ratings were obtained from 248 patients with diagnosed with MDD, as defined by the DSM-IV.20 Depressed mood, cognitive symptoms and guilt, suicidal ideation/plan, difficulty working and enjoying activities, psychological somatic symptoms, anxiety, and low energy were the seven items that were scored positive by more than 70% of patients in the database. With the exception of middle insomnia, the remaining seven items were also those that were most sensitive to change with treatment, exhibiting change scores calculated as the effects sizes of 0.83 to 1.84 (Table 1).

It was noted that the items included in the Toronto HAM-D7 (Table 2) were similar to those in other abbreviated scales which were based on disparate populations from diverse settings. To extend this work further, we calculated a remission cut score that would define a full remission comparable to that enumerated for the HAM-D17. It was determined that a total score of ≤3 would define a full remission of symptoms.  score of ≥4 (out of possible total score of 26) would imply that the patient had insufficiently responded to the index antidepressant intervention. This latter computation (eg, the determination of a remission cutoff score) extends the previous work with existing depression scales for assessing depression and suggests that the Toronto HAM-D7 could be a practical, standardized tool for use when the patient has achieved full symptomatic remission.

Discussion

The Toronto HAM-D7 is the first ever abbreviated depression scale requiring only minutes to perform which can estimate overall depressive symptom severity, be highly sensitive to antidepressant effectiveness, and offer a determination of full symptomatic remission. A myriad of deficiencies have been described in the management of the depressed patient (Table 3).29 Efficacy and effectiveness research in depression marvelously concatenates and suggests that responding to antidepressant treatment but failing to abolish all illness activity is a modifiable deficiency. Previous research has shown that clinical global impressions of depressive symptom response are imprecise as a decisive outcome measure.18 The brevity of the Toronto HAM-D7 is commensurate with a busy family practice setting and permits the determination of full symptomatic remission

The items identified in the HAM-D7 are almost identical to other shorter forms of the HAM-D17.21-26 These other scales have published demonstration of statistical unidimensionality.26-28 In other words, these items define a unidimensional depressive state. The lengthier HAM-D17 contains many items which are nonspecific to depression, and could artefacturally assess medical comorbidity and/or pharmacotherapy adverse events. This potential confound adds to the variability of the scale, decreasing its internal consistency and limiting its power to detect antidepressant effects.

One potential deficiency of abbreviated depression scales is statistically the presence of fewer items may result in lower reliability. However, our computed reliability estimates of overall depression severity are comparable to the lengthier HAM-D17. It has been shown by previous studies, that brief depression scales correlate highly with global psychopathology scales.28

It suggested that the Toronto HAM-D7 be employed at baseline and during the acute phase of treatment. If after 4–6 weeks of treatment the patient has achieved full remission (eg, Toronto HAM-D7 score ≤3) the clinician and patient can begin discussing maintenance treatment strategies. However, if the patient fails to achieve full remission with this scale (eg, Toronto HAM-D7 score >4) then alternate therapeutic avenues need to be considered. Recently, the Canadian Psychiatric Association published its clinical guidelines for treatment of depressive disorders (www.cpa-apc.org), which provides a reference for the clinician regarding the various available treatment strategies and recommended duration of longer-term treatments.1

The Toronto HAM-D7 has been validated at a mood disorders clinic affiliated with the University of Toronto, which raises questions regarding eneralizability. It is noted, however, that the items contained in this scale have high face validity and are commonly endorsed by primary care depressed patients. Furthermore, research efforts are under way to prospectively validate this scale in the family practice setting.

The diagnosis of depression remains a clinical endeavor buttressed by a careful history and diagnostic assessment. The Toronto HAM-D7 assesses depressive symptoms in a previously diagnosed depressed patient. The scale is to be administered by clinician incorporating both patient response and clinical observation. Clinician rating scales have been found to be more sensitive to antidepressant treatment effects than patient administered scales (eg, the Beck Depression Inventory). With increasing emphasis on humanistic- and patient-evaluated outcomes, the Toronto HAM-D7 may represent an integral tool for the clinician with the patient remaining an important ally in describing their symptoms. This would parallel with a hypertension assessment, insofar as the blood pressure score (mmHg) is combined with patient experience (exercise capacity) with an aim to provide careful and precise management of this chronic disease.

Conclusion

The Toronto HAM-D7 is a brief, validated comprehensive tool that can assist the clinician in assessing the overall severity of depressive symptomatology. This scale requires only several minutes to administer and objectively permits the clinician to monitor progress of depressive symptom across time, establish and compare the effectiveness of antidepressant interventions, and distinguish a clinical response from a full remission of symptoms. The items contained in this scale were the most frequently endorsed and most sensitive to change to a variety of commonly employed antidepressant treatments. PP

References

1. Canadian Psychiatric Association. Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry. 2001;46(suppl 1):77S-90S.

2. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of major depression and bipolar disorder. JAMA. 1996;276:293-299.

3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study. Lancet. 1997;349:1498-1504.

4. Silverstone PH, Salinas E. Efficacy of venlafaxine extended release in patients with major depressive disorder and comorbid generalized anxiety disorder. J Clin Psychiatry. 2001;62:523-529.

5. Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment. Arch Gen Psychiatry. 1998;55:580-592.

6. Katon W, Korff VM, Lin E, et al. Distressed high utilizers of medical care. DSM-III-R diagnoses and treatment needs. Gen Hosp Psychiatry. 1990;12:355-362.

7. Gredon JF. The burden of disease in treatment-resistant depression. J Clin Psychiatry. 2001;62:26-31.

8. Greenberg PE, Stiglin LE, Finlelstein SN, Berndt ER. The economic burden of depression in 1990. J Clin Psychiatry. 1993;54:425-426.

9. Nierenberg DW. Teaching clinical pharmacology: a process of ‘lifelong learning.’ J Clin Pharmacol. 1993;33:311-315.

10. Hamilton M. A rating scale for depression.
J Neuro Neurosurg Psychiatry. 1960;23:56-62.

11. Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as a predictor of rapid relapse. J Affect Disord. 1998;50:97-108.

12. Judd LL, Akiskal HS, Maser JD, et al. A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry. 1998;55:694-700.

13. Rapaport MH, Judd LL. Minor depressive disorder and subsyndromal depressive symptoms: functional impairment and response to treatment. J Affect Disord. 1997;48:227-232.

14. Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58:221-227.

15. Mintz J, Mintz LI, Arruda MJ, Hwang SS. Treatments of depression and the functional capacity to work. Arch Gen Psychiatry. 1992;49:7661-7668.

16. Judd LL, Akiskal HS, Zeller PJ, et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry. 2000;57:375-380.

17. Paykel ES. Remission and residual symptomatology in major depression. Psychopathology. 1998;31:5-14.

18. Ramana R, Paykel ES, Cooper Z, Hayhurst H, Saxty M, Surtees PG. Remission and relapse in major depression: a prospective follow-up study. Psychol Med. 1995;25:1161-1170.

19. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder; remission, recover, relapse and recurrence. Arch Gen Psychiatry. 1991;134:382-389.

20.Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:339-345.

21. Gibbons RD, Clark DC, Kupfer DJ. Exactly what does the Hamilton Depression Rating Scale measure? J Psychiatr Res. 1993;27:259-273.

22. Hooper CL, Bakish D. An examination of the sensitivity of the six-item Hamilton Rating Scale for Depression in a sample of patients suffering from major depressive disorder. J Psychiatry Neurosci. 2000;25:178-184.

23. Bech P, Gram LF, Dein E, Jacobsen O, Vitger J, Bolwig TG. Qualitative rating of depressive states. Acta Psychiatr Scand. 1975;51:161-170.

24. Maier W, Philipp M, Gerken A. Dimensions of the Hamilton Depression Scale. Eur Arch Psychiatry Clin Neurosci. 1985;234:417-422.

25. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br
J Psychiatry.
1979;134:382-389.

26. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry. 1999;60:221-225.

27. O’Sullivan RL, Fava M, Agustin C, Baer L, Rosenbaum JF. Sensitivity of the six-item Hamilton Depression Rating Scale. Acta Physiol Scand. 1997;95:379-384.

28. Faires D, Herrera J, Rayamajhi J, DeBrota D, Demitrack M, Potter WZ. The responsiveness of the Hamilton Depression Rating Scale.
J Psychiatr Res. 2000;34:3-10.

29. Rudolf RL. Goal of antidepressant therapy: response or remission and recovery? J Clin Psychiatry. 1999;60:3-4.

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Steven B. Gelfand, MD, Raj M. Eliazer, MD, David Laport, PhD,
Christina M. Shunk-Jones, DO, Rebecca Gamble, PA-C

Primary Psychiatry. 2002;9(12):51-53

Dr. Gelfand is director of  the Neuropsychiatric Institute at Indiana Regional Medical Center in Pennsylvania.

Dr. Eliazer is chief of the Neurology Department, Dr. Laport is director of psychiatry and neuropsychology, and Ms. Gamble is physician’s assistant at the Neuropsychiatric Institute at Indiana Regional Medical Center.

Dr. Shunk-Jones is in practice at Guthrie Clinic in Sayre, Pennsylvania.

Disclosure: The authors report no financial, academic, or other support of this work.


 

Abstract

This case study examines a patient who presented to the emergency room with an unknown delirium that subsequently was discovered to be anticholinergic in nature. Diagnosis was difficult because the anticholinergic medications were predominantly taken as over-the-counter medicines and the patient initially presented the problem as gastrointestinal rather than psychiatric. This case demonstrates the extreme difficulty in making a diagnosis of anticholinergic toxicity in patients without a straightforward presentation.

 

Case Patient

In February 2001, a 34-year-old patient presented to the emergency room (ER) at the Indiana Regional Medical Center with complaints of gastrointestinal (GI) upset and nausea. She was given prochlorperazine (Compazine) intramuscularly (IM) and diphenhydramine (Benadryl) intravenously (IV). She was told to follow up later in the day at her doctor’s office. During that visit she was given additional dosage of oral diphenhydramine and diazepam (Valium) for the nausea. Later that evening she presented back at the ER with tightening of her jaw and rigidity and was given benztropine (Cogentin) 2 mg IM to combat a possible extrapyramidal side effect from the prochlorperazine, and lorazepam (Ativan) 1.5 mg for her agitation. She was also given famotidine (Pepcid) 20 mg IV for her GI upset. When she continued to have difficulty turning her head or swallowing and had jaw-clenching tremors that were generalized in nature, an additional 2 mg of benztropine was tendered.
 

Her review of symptoms was negative for any cardiac pulmonary or genital urinary symptoms. She had no neurologic events prior to this episode. Her past medical history was positive for a hysterectomy with bilateral salpingo-oophorectomies and periods of gastroesophageal reflux. She had been on lansoprazole (Prevacid) 30 mg/day previously and Estradiol (Estrace) injections monthly. She had received prochlorperazine on several occasions previously in her medical history and these produced some tightening of the jaw but never required any visits to the emergency room.
 

At the time of her presentation the patient was separated but not divorced. Her family history was not contributory. Once the patient’s dystonic reaction was controlled with two doses of benztropine she showed evidence of extreme agitation. Her gait was broad based. Her deep tendon reflexes were +3 and equal for biceps, triceps, brachaoradialis, patellar, and achilles.
 

In addition to the acute dystonia, she had one episode of oculogyric crisis. She had difficulty with finger-to-nose testing and heel-to-shin testing. Rapid alternating movements were similarly poor. Funduscopic examination was benign. Her pupils were 6.5 mm and reactive to 4 mm. Her extraocular muscles movements were within normal limits in all six cardinal fields of gaze. There was a pronator drift. Her head was turned to the left secondary to the rigidity in the sternocleidomastoid and there was some tremor. She had difficulty swallowing. Her thyroid was not enlarged. Her mouth was moist. Her neck was supple. Her sclera was not anicteric. Her lymph nodes were not palpable. Cardiovascular examination revealed a pulse of 100 beats per minute (BPM) without evidence of murmur, rub, or gallop. Her lungs were clear to percussion and auscultation. The abdomen was soft and nontender. Her extremities showed no edema.
 

Treatment

The patient was admitted to the hospital from the ER and at that time had a right-handed tremor. After receiving lorazepam she was drowsy but arousable. She became unsteady approximately 4 hours after her admission and then had a small emesis. Shortly after the emesis she became markedly more tremulous and was given an additional l mg of lorazepam, this time via IV. By midnight she was confused but oriented. She was talking to herself and continued to be confused throughout the night. From midnight until 6am the next morning the patient was picking at things she was seeing in the air. She was tremulous and confused. She would get in and out of bed without any idea of her direction and was completely disoriented and psychotic.
 

At 6am that morning the patient showed obvious signs of delirium with bilateral external tremors and an inability to respond to questioning. She was attempting to get out of bed to pull out her IV. She had a complete blood count with differential, which was normal and a normal sedimentation rate. Her reflexes were now hyperactive and equal at –4/4 for biceps, triceps, brachioradialis, patellar, and achilles. Her Babinskis were down. Her pupils continued to be large at 6 mm and reactive to 4.5 mm. She had a temperature of 101° with a pulse ranging from 95–100 BPM and a blood pressure of 120/80. The diagnosis of organic delirium was made at that time.
 

At approximately 8am she showed evidence of a return of her acute dystonia with her head turning to the left and was given an additional 2 mg of benztropine. Forty-five minutes later she was again oriented only to person. Her speech was slurred. She was restless, inattentive, hyperactive, and unsteady on her feet. She became increasingly more agitated and by 9am had been given an additional 2 mg of lorazepam. This did not in any way control her.
 

The possibility that she had received an excessive dose of lorazepam was then considered. As a result, flumazenil (Romazicon) was given at 2/10 of a mL IV, an additional 3/10 1 minute later, and an additional 5/10 2 minutes after that. The patient continued to be agitated. Her gait continued to be unsteady and she was extremely psychotic. Olanzapine (Zyprexa) 5 mg was given at that point and the patient was sent for an emergency electroencephalogram (EEG), computed tomography, and lumbar puncture, as she was now expressing paranoid ideation, having visual, tactile, and auditory hallucinations, and appeared to be acutely psychotic. Her lumbar puncture was negative. Her computed tomography, with and without contrast, was normal. Her EEG showed an enormous amount of β activity.
 

Because the patient was so agitated, midazolam (Versed) was used to control her agitation in 1-mg IV pushes. From 12:08pm to 1:06pm she received midazolam 6 mg. Since the EEG was done after the midazolam was given, there was an enormous amount of β artifact noted.
 

Diagnosis

Since there was no other etiology for the patient’s delirium, the possibility existed that she was suffering from an anticholinergic delirium due to her elevated temperature, her large pupils, and her extreme delirious behavior. As a result, she was given physostigmine (Antilirium) 1 mg IV every 2 minutes until a total of 2 mg was given. Three minutes after the second IV instillation the patient was fully awake, no longer confused, and completely oriented. There was no dissociation. There were no tremors. She was coherent, conversed well, and was appropriate. Her pupils were now 3 mm instead of 6 mm. Her extraoccular eye movements continued to be normal. She had some mild GI upset secondary to the physostigmine but was otherwise well.
 

Her family visited her at 2:10pm and she did well until 4pm, at which point she became delirious again with thickened speech, tremors, and psychosis. She was given another 2 mg of physostigmine at that time and she had a brief episode of atrial fibrillation with a controlled ventricular rate. At that point it was decided that she had received as much physostigmine as was stable.
 

For the next 72 hours the patient’s tremors and disorientation waxed and waned. At this point it was decided that the only safe way to treat her was with midazolam 1 mg at a time separated by 5 minutes with a maximum of 3 mg in any 2-hour period. The Pittsburgh Poison Center suggested terminating further use of physostigmine and initiation of benzodiazepines to control her. When the patient was calm from the midazolam, a lorazepam drip at 2 mg/hour was started at 4am and continued for the next 4 days.
 

Thirty-six hours later the patient was able to verbalize what had caused the toxicity. She reported that since the breakup with her boyfriend she had been unable to sleep and was taking huge amounts of Tylenol PM—a combination of acetaminophen and diphenhydramine. She was taking 8–12 tablets every day for 10–15 days prior to the time she presented to the emergency room—a total in excess of 100 tablets over 7–10 days. Although her liver enzymes were within normal limits, it was thought that the patient was unable to tolerate the anticholinergic load of the diphenhydramine.
 

The patient ultimately was transferred to Transitional Care—an intermediate unit—and was discharged from the hospital on February 8, 2001, after being hospitalized for 1 week. Two subsequent follow-up examinations showed the patient to be completely normal. She had normal mental status, normal neurologic examination, and no sequelae whatsoever from her delirium.
 

Discussion

This is an extremely unusual presentation of a patient with an unknown anticholinergic delirium, in which medical treatment added to and ultimately peaked her anticholinergic delirium. The primary problem occurred as a result of the patient taking very large amounts of over-the-counter diphenhydramine. This produced GI upset, which was treated with prochlorperazine, which then produced the acute dystonic reaction. Once the dystonia was treated aggressively with diphenhydramine and benztropine, the patient’s anticholinergic load was unacceptable and she was pushed into a delirium that in many ways was iatrogenic. She was acutely delirious for a period of 3 days and seriously ill for a period of 5 days.
 

It is very important to consider the possibility that over-the-counter drugs may produce delirium with anticholinergic agents. Were it not for the patient’s large pupils and low-grade temperature, diagnosis may have been impossible and treatment might have been delayed endangering the patient’s life.
 

It is our feeling that this case expertly demonstrates the danger of over-the-counter medications, and more significantly, the danger of anticholinergic medications. The addictive cholinergic effects of the diphenhydramine with its concurrent anticholinergic properties, the benztropine used to treat the extrapyramidal symptoms precipitated by prochlorperazine, and the famotidine used to treat the patient’s gastrointestinal symptoms, all contributed greatly to this patient’s delirium.

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Citalopram in the Treatment of Depression and Anxiety Complicated By Tremors?

Gail Fernandez, MD

Primary Psychiatry. 2002;9(12):54-55

Dr. Fernandez is assistant clinical professor in the Department of Psychiatry and Human Behavior at the University of California, Irvine Medical Center in Orange.

Disclosure: The author reports no financial, academic, or other support of this work.


 

Abstract

This report presents a complex case in which a 17-year-old female patient presenting with panic disorder without agoraphobia, generalized anxiety, severe tremors, and depressive symptoms responded to the selective serotonin reuptake inhibitor citalopram after nonresponse to and/or intolerance of propranolol, paroxetine, and venlafaxine.  The depressive symptoms emerged 4 months after the patient’s initial visit. A 2-year history of severe tremor complicated psychiatric treatment and prompted neurologic evaluation to determine the origin of the tremors. Trials of paroxetine and venlafaxine were discontinued due to severe sedation and gastrointestinal upset, respectively. Positive response, consisting of improved mood and anxiety level, was achieved with citalopram.

 

Case Report

A 17-year-old Caucasian female presented with a long history of tremors that had worsened over the last 2 years. Tremors increased with physical activity or anxiety and interfered with daily functioning. The patient reported feeling anxious but denied having depressed mood. Her tremors precipitated teasing by her peers, which increased her anxiety.

Propranolol 60 mg/day and propranolol 10 mg PRN were prescribed to decrease tremors. Neither dose was effective. Propranolol was discontinued and the patient was started on paroxetine 5 mg/day to mitigate anxiety. Dosage was titrated up to 20 mg/day over a 1-week period. Sedation occurred immediately and worsened to the point that the patient felt she could not function in her daily activities. Paroxetine was discontinued and venlafaxine 25 mg BID was initiated. Dosage was increased over a 10-day period to a final dose of 75 mg BID. After the dose was increased, the patient experienced gastrointestinal upset, which she felt was intolerable. Venlafaxine dosage was reduced to 25 mg/day. Approximately 3 months later, venlafaxine was discontinued due to gastrointestinal upset.

After unsuccessful treatment with propranolol, paroxetine, and venlafaxine, the patient was started on citalopram 10 mg/day, which was increased to 20 mg/day after 1 week. After 25 days, the patient reported a much improved mood and anxiety level, with a slight improvement in tremors. She was referred to a pediatric neurologist for a second opinion of her tremors. The evaluation was negative for neurologic problems, and it was suspected that the tremors were psychologically mediated. Family history was positive for benign essential tremors, which were experienced by the patient’s biological mother during early adulthood and then resolved. Therefore, both psychological and biological factors may have contributed to the development of tremors in this patient.

Primidone 25 mg/day was prescribed to mitigate tremors. However, the patient experienced sedation and dosage was reduced to 12.5 mg/day. Over the course of the next few months, primidone dosage was increased to a total dose of 100 mg/day with some improvement in sedation. However, as the patient felt the tremors did not respond to primidone, she discontinued the medication on her own with no adverse effects or change in tremors.

A few months later, the patient was seen for follow-up and presented with depressive symptoms including sadness, tearfulness, irritability, and anger over family issues, social isolation, decreased interest in activities, and decreased energy. She also reported increased anxiety with panic attacks and some obsessive-compulsive symptoms such as counting objects. Citalopram dosage was increased to 40 mg/day, and alprazolam 0.25 mg PRN was initiated to mitigate anxiety.

Since this time, the patient has been doing well. Depressive symptoms, generalized anxiety, panic attacks, and compulsion to count objects have resolved. Her energy level and social interactions also have improved. Although tremors are still present, they are less severe. The patient is enrolled in college, works part-time, and attends weekly psychotherapy sessions. Alprazolam has been used rarely due to the effectiveness of the 40 mg/day citalopram dosage.

 

Discussion

This case illustrates several issues relevant to the treatment of depression and anxiety in adolescence. It is common for individuals with anxiety disorders to manifest physical symptoms. In this case, the patient’s family history of tremors may have led to the patient’s initial diagnosis of a familial tremor rather than a psychiatric disorder. By focusing only on tremors, the patient underwent trials of propranolol, which were not effective for tremors, anxiety, or depression. She also appeared to be sensitive to medication side effects, causing treatment failure with both paroxetine and venlafaxine.
 

Due to its low side-effect profile and efficacy for both anxiety and depression, citalopram was well-tolerated and led to significant symptom reduction. Further studies with citalopram in adolescent depression and anxiety are warranted.

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Ralph Ryback, MD, Victoria E. Lund, PhD, Lewis Brodsky, MD

Primary Psychiatry. 2002;9(12):42-44

Dr. Ryback is medical director of the Adolescent Partial Hospitalization Program, Charter Behavioral Health in Potomac Ridge, Maryland.

Dr. Lund is clinical nurse specialist and consultant in pratice in Talahassee, Florida.

Dr. Brodsky is in private practice in Talahassee.

Disclosure: This work was supported in part by a grant from Parke Davis. 


 

Abstract

Could gabapentin relieve some of the disabling symptoms of dementia? This open-label, nonblinded study evaluated the effectiveness of gabapentin in the symptomatic treatment of dementia, since γ-aminobutyric acid is deficient in the brains of such patients. The study demonstrated improvement in affective lability, depression, behavioral dyscontrol, cognition, and psychotic symptoms in a sample involving 37 subjects. The results were statistically valid. Gabapentin was well tolerated when titrated slowly, with the most frequent optimal dose being 900 mg/day. The drug was compatible with other pharmacologic agents and likely offered neuroprotective benefits.

 

Introduction

A number of open-label studies and case reports suggest that valproate may reduce behavioral agitation in some demented patients.1-4 Verbal aggression, restlessness, and physical aggression were all ameliorated, whether dementia was of the Alzheimer’s type, multi-infarct, or a combination of both. This would typically occur at serum concentrations lower than those traditionally used in controlling seizures. Deficits in γ-aminobutyric acid (GABA)5 and other neurotransmitters and receptors6-9 have been demonstrated in the brains of patients suffering from Alzheimer’s dementia. Valproate stimulates GABA synthesis, potentiates postsynaptic effects of GABA, and inhibits GABA catabolism, resulting in enhanced central GABAergic neurotransmission.10,11 GABA, which is deficient in the brains of patients with dementia, is the major inhibitory neurotransmitter within the central nervous system. GABA agonists have anxiolytic, anticonvulsant, and aggressive-diminishing properties.12-17 These might actually reduce demented agitation by central GABAergic neurotransmission enhancement.
 

Behavioral agitation in demented patients usually results in the use of more costly levels of treatment from home, residential treatment settings (nursing homes), or psychiatric hospitalization.18-20 In addition, particularly in the elderly, untreated agitation often results in head trauma, hip fractures, and physical assault, necessitating the need for one-to-one supervision, restraints, or seclusion. Agitation, which can be defined as socially inappropriate verbal, vocal, or motor activity,21 can be costly and painful. Due to its GABAergic profile, its favorable side-effect profile, and its mood-stabilizing, anxiolytic action, assessing the efficacy of gabapentin in demented patients was believed to potentially be of clinical value.

Methodology

In the following open, nonblinded study, we evaluated the effectiveness of gabapentin in the symptomatic treatment of dementia. This included obtaining initial demographic information, Axis I diagnosis, 30-point Mini-Mental Status Examination (MMSE) before and after treatment, use of adjunctive medications, and the use of a subjective likert scale performed by the treating psychiatrist where 1=none and 4=severe. This scale was used to grossly measure affective lability, behavioral dyscontrol, cognitive impairment, depression, and psychotic signs and symptoms, before and after gabapentin treatment. The endpoint utilized in the study was also after a clinically stable dose of gabapentin had been established.

Results

There were 37 subjects, ranging from 49–91 years of age, where 16.2% (n=6) were African American; 2.7% (n=1) were Asian; and 81.8% (n=30) were Caucasian. Gender distribution was 30% male and 70% female. The most frequent Axis I diagnosis was Alzheimer’s type dementia with delusions, depressed mood, and behavioral disturbance. This was followed by vascular dementia with depressed mood. Several subjects had more than one Axis I diagnosis. There were single subjects who had dementia due to Parkinson’s disease, Pick’s disease, and/or chronic substance abuse.

The duration of gabapentin treatment ranged from 2–40 months with dosage varying from 200–3,200 mg/day. The most frequent dosage was 900 mg/day (13.5%). Eight participants (21.6%) reported side effects including ataxia, somnolence, dizziness, edema, agitation, anxiety, panic, and increased blood pressure, and three discontinued gabapentin. The data of the three dropout participants were included in the statistical computation of this study, hence the overall mean scores were decreased. Thirty-five subjects (94.6%) had received other medications prior to the initiation of gabapentin or had additional medications added after the second assessment. At the initial assessment, or prior to gabapentin, 73% (n=27) were on neuroleptic medications and/or donepezil, and 51% were taking regular vitamin supplements. Following the second assessment, two patients (5.4%) benefited from the addition of antidepressants and five (13.5%) from a second mood stabilizer.

Table 1 demonstrates a significant difference in MMSE scores before and after gabapentin treatment. These were all completed by an independent psychologist. All of the subjects demonstrated an improvement.

Table 2 demonstrates a positive difference between pre- and posttreatment scores for affective lability, behavioral dyscontrol, cognitive impairment, depression, and psychotic symptoms. These findings, though not placebo controlled, suggest that gabapentin at least temporarily improved cognitive, emotional, and behavioral functioning in patients with dementia.

Discussion

For the brain, stress constitutes an excitatory injury or an overwhelming overflow of activity. Stress is mediated in its final pathway neurochemically, whether due to psychic trauma or physical trauma, such as stroke, head trauma, dementia, or epilepsy. In all of these situations, the normal inhibitory processes are out of control and we see the release of glutamate, a neurotransmitter, which in overabundance can behave as a deadly neurotoxin (ie, excitatory neurotoxicity). In dementia, there is clearly a combination of both psychic (intense anxiety or the loss of one’s psychological capacities), and physical trauma (ie, the breakdown of connections between different systems and subsystems of the brain). Since inhibition is a major brain function that allows for control of thoughts, emotions, and movement, brain injury such as that seen in dementia, can certainly lead to disinhibition. This occurs not only because the “hard wire” is damaged as a connection, but because the system can no longer modulate inhibitory processes, including the inhibitory neurochemicals, to counteract the effects of the excitatory injury.

GABA is an inhibitory neurotransmitter. It is increased more than 3-fold by gabapentin in rat hippocampal brain slices which would have the functional effect of neuronal inhibition during periods of hyperexcitability.22 These findings are consistent with studies in humans where gabapentin appears to increase brain GABA levels as measured by magnetic resonance spectroscopy.23 Like the comparison between a standard and cellular telephone system, even when the “hard wiring” is broken, gabapentin can get the inhibitory neurotransmitters, such as GABA, to the sites where it is needed and useful. This may be part of what is reflected in the clinical observations made in this study.

Conclusion

The purpose of this study was to evaluate the effectiveness of gabapentin in relieving some of the disabling symptoms of dementia. Although this was an open, nonblinded study, gabapentin appeared to have improved affective lability, relieved depression, ameliorated behavioral dyscontrol, improved cognition, and diminished psychotic symptoms, in a small sample of patients who suffer from dementia.

The results of the study were statistically valid. When gabapentin was slowly titrated to dosages lower than generally utilized for the treatment of chronic pain or bipolar illness, it appeared to be well tolerated with minimal transient side effects. From a pharmacokinetic perspective, gabapentin appeared to be “user-friendly” in its compatibility with other pharmacologic agents. This is particularly important for a population that typically receives multiple medications. In addition, we can speculate that the neuroprotective benefit from gabapentin would make it ideal for use immediately after psychic or physical trauma to optimize the effects in decreasing symptomatology and perhaps even minimizing damage due to release of neuroexcitatory transmitters.

Future research is warranted, including double-blind studies, to assess the effects of gabapentin on patients with dementia. Studies focusing on relief of symptoms and quality of life would also be important, as people are living longer and as families become more involved in assuming a more active role in the caregiving of relatives suffering from dementia. The findings of this study support the use of gabapentin to treat some of the behavioral and emotional sequelae of the dementia process. In addition, it appears that the drug may assist in improving, albeit transiently, cognitive functioning.
 

References

1.    Sival RC, Haffmans PMJ, Van Gent PP, et al. The effects of sodium valproate on disturbed behavior in dementia [Letter]. J Am Geriatr Soc. 1994;42:906-909.
2.    Mellow AM, Solano-Lopez C, Davis S. Sodium valproate in the treatment of behavioral disturbance in dementia. J Geriatr Psychiatry Neurol. 1993;6:203-209.
3.    Horne M, Lindley SE. Divalproex sodium in the treatment of aggressive behavior and dysphoria in patients with organic brain syndromes. J Clin Psychiatry. 1995;56:430-431.
4.    Lott AD, McElroy SL, Keys MA. Valproate in the treatment of behavioral agitation in elderly patients with dementia. J Neuropsychiatry Clin Neurosci. 1995;7:314-319.
5.    Ellison DW, Beal MF, Mazurek MG, et al. A postmortem study of amino acid neurotransmitters in Alzheimer’s disease. Ann Neurol. 1986;20:616-621.
6.    Hardy J, Cowburn R, Barton A, et al. A disorder of cortical GABAergic innervation in Alzheimer’s disease. Neurosci Lett. 1987;73:192-196.
7.    Middlemiss DN, Palmer AM, Edel N, Bowen DM. Binding of the novel serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin in normal and Alzheimer brain. J Neurochem. 1986;46:993-996.
8.    Palmer AM, Stratmann GC, Procter AW, Bowen DM. Possible neurotransmitter basis of behavioral changes in Alzheimer’s disease. Ann Neurol. 1988;23:616-620.
9.    Blass JP. Pathophysiology of Alzheimer’s syndrome. Neurology. 1993;43(suppl):S25-S38.
10.    McElroy SL, Keck PE Jr. Antiepileptic Drugs. In: Nemeroff CB, Schatzberg AF, eds. American Psychiatric Press Textbook of Psychopharmacology. Washington, DC: American Psychiatric Press; 1995.
11.    Pope HG, JR, McElory SL. Valproate. In: Kaplan T, Saddock BE, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams & Wilkins; 1995.
12.    Simler S, Puglisi-Allegra S, Mandel P. Effects of N-dipropylacetate on aggressive behavior and brain GABA level in isolated mice. Pharmacol Biochem Behav. 1983;18:717-720.
13.    Eichelman B. Neurochemical and Psychopharmacologic aspects of aggressive behavior. In: Meltzer HY, ed. Pyschopharmacology: the Third Generation Progress. New York, NY: Raven Press; 1987.
14.    Giakas WJ, Seibyl JP, Mazure CM. Valproate in the treatment of temper outburst [letter]. J Clin Psychiatry. 1990;51(suppl):S25.
15.    Szymanski HV, Olympia J. Divalproex in posttraumatic stress disorder [letter]. Am J Psychiatry. 1991;148:1086-1087.
16.    Mazure CM, Druss BG, Cellar JS. Valproate treatment of older psychotic patients with organic mental syndromes and behavioral dyscontrol. J Am Geriatr Soc. 1992;40:914-916.
17.    Geracioti TD. Valproic acid treatment of episodic explosiveness related to brain injury [letter].
J Clin Psychiatry. 1994;55:416-417.
18.    Haupt M, Kurz A. Predictors of nursing home placement in patients with Alzheimer’s disease. Intl J Geriatr Psychiatry. 1993;8:741-746.
19.    Rabins PV, Mace NL, Lucas MJ. The impact of dementia on the family. JAMA. 1982;248:333-335.
20.    Chenoweth B, Spencer B. Dementia: the experience of family caregivers. Gerontological Soc Am. 1986;26:267-272.
21.    Cohen-Mansfield J, Betlig N. Agitated behaviors in the elderly. I: a conceptual review. J Am Geriatr Soc. 1986;34:711-721.
22.    Honmou O, Koesis JD, Richerson GB. Gabapentin potentiates the conductance increase induced by nipecotic acid in CA1 pyramidal neurons in vitro. Epilepsy Res. 1995;39:193-202.
23.    Petroff OAC, Rothman DL, Behar KL, et al. The effects of gabapentin on brain gamma-aminobutyric acid patients with epilepsy. Ann Neurol. 1996;39:95-99.

Articles

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William Coryell, MD

Primary Psychiatry. 2002;9(12):47-50

Dr. Coryell is professor in the Department of Psychiatry at the University of Iowa College of Medicine in Iowa City.

Disclosure: This work was supported by an unrestricted educational grant from GlaxoSmithKline.


 

Abstract

How does the clinician best manage side effects associated with mood stabilizers used for bipolar affective disorder? Informed management of side effects can improve a drug’s tolerability and therefore increase the likelihood that patients will continue to take the drug most effective for their illness. Placebo-controlled studies have supported the prophylactic use of lithium, carbamazepine, valproate, and lamotrigine for bipolar disorder. This review summarizes the case reports and controlled studies pertinent to the management of side effects for each of these agents.

 

Introduction

While the importance of pharmacotherapy in the management of bipolar affective disorder has been established, all of the useful agents have also been associated with side effects. Side effects may be endured, they may lead to treatment noncompliance, or they may result in the replacement of a drug that is effective in controlling illness symptoms with an alternative that is possibly less so. Any of these possibilities will diminish the patient’s quality of life.
 

In comparison with efforts to demonstrate the efficacy of mood stabilizers in the acute and prophylactic treatment of bipolar affective disorder, the literature concerning the management of side effects is small, largely anecdotal, and rarely reviewed. The following undertakes such a review, with suggestions relevant to each of the mood stabilizers for which placebo-controlled trials have shown efficacy. The side effects discussed are the ones more commonly described and particular emphasis is given to those for which corrective measures other than drug discontinuation have been proposed.
 

Lithium

Despite recent shifts in prescribing patterns, the efficacy of lithium in bipolar affective disorder is more thoroughly established than the efficacy of any other medication. Because its use was widespread before the advent of most of the other drugs now being prescribed for bipolar affective disorder, lithium’s side effects have been more fully characterized and a number of strategies for managing them
have emerged.
 

Nausea

Nausea may be the first side effect encountered when lithium is introduced, particularly when doses are rapidly increased. Because nausea tends to reflect the rapidity with which plasma levels are increasing,1 loading procedures will increase its likelihood and this may adversely bias the patient’s attitude toward lithium therapy. An obvious solution would therefore be a temporary decrease in dose, followed by a more gradual approach to the targeted plasma level range. Also, nausea often improves when lithium is consistently taken with meals. A slow-release preparation may reduce nausea, but may also increase difficulties with diarrhea.2
 

Tremor

A fine tremor, increased by voluntary movement, is often another early development in lithium therapy. It is often tolerated but may be quite distressing for the patient. If the tremor is seen to peak in intensity within several hours of each dose, a sustained-release preparation may be helpful. Also potentially helpful is a reduction in caffeine intake and the elimination of other drugs, such as tricyclic antidepressants, that may produce or worsen tremor. Because maintenance lithium levels at the lower end of the conventional therapeutic range produce less tremor,3,4 doses should be titrated against symptom control to determine whether lower doses provide relief.
 

When a distressing tremor persists despite dosing changes, modest doses of a β-blocker are indicated. According to a number of reports, propranolol 30–80 mg/day is often effective.5-7 β1 blockers, such as atenolol and metoprolol, have been used for patients at risk for bronchospasm.7,8
 

Polyuria and Polydipsia

Polydipsia is typically nonprogressive9 but may substantially interfere with sleep, and may lead to significant weight gain if the patient is relieving thirst with sugared drinks. As with tremor, symptoms are more likely at higher doses, and the problem often subsides when careful titration is used to determine the patient’s lowest effective dose.
 

According to several authors, polyuria is less likely with single daily dosing than with multiple-dose schedules.10-13 At least one study demonstrated that a shift from multiple dosing to single dosing reduced urinary volume,14 but another applied random assignment to alternate dosing schedules and found no difference in urine volume.15
 

If changes in dose and timing are unhelpful, the addition of a diuretic may produce a paradoxical reduction in urine volume. Hydrochlorothiazide 50 mg/day has been recommended, but amiloride,16 in doses titrated to 10 mg BID, is less likely to produce hypokalemia.
 

Weight Gain

Weight gain attributed to lithium can be an important issue for long-term compliance and may lead a clinician to consider alternative mood stabilizers. The results of randomized, prophylactic studies are pertinent. In the only comparison of lithium, valproate, and placebo, patients taking valproate, but not those taking lithium, experienced significantly more weight gain than those taking placebo.17 A randomized comparison of lithium and carbamazepine, on the other hand, indicated that carbamazepine resulted in significantly less weight gain.18 Existing evidence does not support a switch from lithium to valproate to limit weight gain.
 

As an alternative to switching mood stabilizers, clinicians should consider whether coadministered drugs may be contributing to the problem and whether these are necessary. Atypical antipsychotics are often used adjunctively to hasten symptom control in acute mania and then continued out of concern that monotherapy with lithium may be insufficient for prophylaxis. A gradual discontinuation is warranted to determine whether this is so.
 

Patients should also be asked whether they are drinking high-calorie beverages to relieve thirst or to counteract the metallic taste often experienced with lithium. A regular exercise program should be encouraged as this may enhance the control of both weight and depressive symptoms.19
 

Cognitive Impairment

Goodwin and Jamison20 found that  the most frequently cited reason for lithium noncompliance was “memory problems.” Clinicians often attribute complaints of mental sluggishness to residual depressive symptoms. However, placebo-controlled studies  have shown that at conventional therapeutic levels, lithium produces similar complaints in normal individuals21 and that deficits are measurable objectively as a slowing in cognitive performance.22
 

Lithium treatment is well-known to cause hypothyroidism. This is most commonly reflected in elevated thyroid-stimulating hormone (TSH) levels, but approximately 4% of patients on chronic lithium treatment develop abnormally low T3 and T4 levels.23 It is also well-known that depressive symptoms and complaints of sluggishness are typical concomitants of clinical hypothyroidism. Most clinicians who use lithium screen for hypothyroidism routinely and provide thyroid replacement when thyroxin levels are below normal limits.
 

However, subclinical hypothyroidism may also be a factor in both persistent depression24-26 and cognitive impairment.27,28 A trial of thyroid replacement is therefore warranted when either of these coexist with elevated TSH levels. T4 is commonly given but converging evidence now suggests that T3 provides more benefit in this role. Patients given T3 to augment antidepressant treatment in one study had significantly better outcomes than did those randomized to T4.29 In another study, those patients undergoing thyroid replacement with T4, who were randomized to receive part of their replacement as T3, reported significantly better mood and energy than did those who continued to receive T4 alone.30
 

Valproate

As with lithium, many of the side effects associated with valproate are dose-dependent and can be reduced through attention to plasma levels. Bowden and colleagues31 identified 45 mcg/mL as the minimum therapeutic level. Changes in manic symptoms did not correlate with plasma levels above this threshold, but side effects increased markedly when levels exceeded 125 mcg/mL. This increase reflects dose-dependent protein binding and therefore, conditions that affect protein binding conditions may shift the threshold downward. Thus, older patients, especially those with liver disease, and those taking other drugs that compete for protein binding, may experiencea nonlinear increase in side effects beginning at a lower plasma level.
 

Sedation

Anticonvulsants that increase γ-aminobutyric acid, as valproate does, tend to cause more sedation than do anticonvulsants, such as lamotrigine, which operate through the modulation of glutamatergic neurotransmission.32 While sedation offers an advantage in the acute control of manic symptoms, it becomes problematic during prophylaxis. Because this complaint does not seem to correlate with plasma levels within the therapeutic range, dose decreasing is often not helpful. If sedation is a problem during maintenance, the clinician should consider whether concomitant drugs, such as antipsychotics or benzodiazepines, can be eliminated at this stage.
 

Gastrointestinal Symptoms and Weight Gain

The most frequent side effects encountered by patients taking valproate are gastrointestinal in nature.33 Such complaints are less likely with divalproex than with valproic acid.33 If nausea persists with divalproex, a histamine2 blocker may prove helpful.34
 

Weight gain is at least as likely with valproate as with lithium.17 If weight gain is a prominent concern for a particular patient, the alternative mood stabilizers carbamazepine18,35 and lamotrigine36 should be considered. The continuation of any antipsychotics being given concomitantly should be reconsidered. As noted previously,a regular exercise program can have a number of benefits beyond weight control.
 

Hyperammonemia

Valproate inhibits urea synthesis and the resulting elevations in serum ammonia levels can have clinical consequences varying from mild fatigue to coma.37 The neurology literature contains many references to this effect, though the psychiatric literature does not. This effect does not appear to be dose dependent and its manifestations—fatigue, cognitive slowing, and sedation—may be misinterpreted as depressive symptoms or even viewed as a positive response.38 Moreover, the tendency of valproate to increase ammonia levels is probably common rather than idiosyncratic.
 

Hjelm and colleagues39 showed that ammonia levels increased by an average of 101% among five healthy subjects given valproate at doses tapered to 1,500 mg/day over 1 week. Thus, an increase in lethargy after the establishment of valproate therapy warrants a check of ammonia levels. Some have suggested the administration of carnitine 1 g BID as a remedy.40 This may work by altering the effect of valproate on urea synthesis.
 

Carbamazepine

Carbamazepine was the first anticonvulsant to be widely used in bipolar affective disorder. There have been no direct comparisons of efficacy between carbamazepine and valproate, and little is known regarding which patients can be expected to respond to one rather than the other. This makes the differing side-effect profiles a relatively important factor as clinicians choose among the anticonvulsants.
 

Blood Dyscrasias

Carbamazepine has a well-known tendency to lower white cell counts. In perhaps the largest survey of this effect,41 carbamazepine was five times more likely to produce leukopenia than was valproate, though it was not more likely to produce severe leukopenia, defined as a white blood cell (WBC) count <3,000 mm3. The onset of leukopenia is most likely during the first 30 days of treatment and is unlikely after 60 days. The WBC threshold42 below which discontinuation is recommended has varied from 3,000 to 4,000 mm3. Notably, 11 of the cases with moderate leukopenia described by Tohen and colleagues41 continued on carbamazepine without adverse consequences. Lithium is known to stimulate leukocyte production and may serve to correct the leukopenia induced by carbamazepine.43 This combination would be particularly appropriate in cases of incomplete clinical response to carbamazepine monotherapy.
 

Hyponatremia

Hyponatremia is a relatively common side effect of carbamazepine and may be symptomatic.44 The patient’s medical regimen should be reviewed when low sodium values are noted. Discontinuation of carbamazepine may be averted by adjusting or eliminating coadministrated diuretics.
 

Lamotrigine

Lamotrigine offers advantages over valproate and carbamazepine in terms of such side effects as fatigue, somnolence, and weight gain.32 Weight, on average, has been shown to remain stable or to decrease during lamotrigine treatment.45 Although lamotrigine has only recently come into use as a mood stabilizer, it has been widely used as an antiepileptic and more than 583,000 patient-years of experience have accumulated.46 Lamotrigine also lacks most of the side effects associated with the antidepressants developed for use in major depressive disorder. Several recent placebo-controlled studies have shown lamotrigine to have both acute and prophylactic benefits for bipolar depression,47,48 suggesting that this agent is an alternative to the more traditional antidepressants in the management of bipolar depression.
 

The most frequent adverse events leading to discontinuation in controlled trials have been skin rashes. Indeed, reports of toxic epidermal necrolysis or Stevens-Johnson syndrome have made some clinicians reluctant to use lamotrigine. An expert panel estimated that rashes occur in approximately 10% of patients given lamotrigine and that those severe enough to result in hospitalization occur in 0.3% of adults and 1% of children.46 Established risk factors for lamotrigine-induced rash are use in childhood, use in combination with valproate, and most importantly, a rapid progression in dose. Recognition of this last risk factor led to revisions in the recommended dose-progression.49 A large-scale comparison of rates before and after the adoption of these revisions shows that the risk for severe rash (associated with systemic disturbances) was seemingly eliminated, though the risk for nonserious rashes remained at 9%.49
 

Conclusion

Only a few medicines have demonstrated effectiveness in the maintenance of bipolar affective disorder. Because of this, and the fact that most patients with bipolar illness require maintenance for an indefinite period, side effects should be managed with particular care to prevent the unnecessary abandonment of a potentially valuable treatment.
 

Treatment options fall into four categories. The most obvious category is dose adjustment to titrate symptom prophylaxis against side effects within therapeutic plasma level ranges. An often neglected but frequently rewarding intervention is the trial elimination of concomitant medications which may no longer be necessary. The optimization of thyroid status may improve cognitive slowing or fatigue, particularly during lithium maintenance. Emphasis on a regular exercise program is often preferable to switching medication in the face of weight gain. Finally, modest doses of adjunctive medication have been reported as useful in the management of certain side effects. Most of these apply to lithium side effects, doubtless because lithium has been in use far longer than the alternatives.
 

References

1.    Persson G. Lithium side effects in relation to dose and to levels and gradients of lithium in plasma. Acta Psychiatr Scand. 1977;55:208-213.
2.    Persson G. Plasma lithium levels and side effects during administration of a slow release lithium sulphate preparation and lithium carbonate tablets. Acta Psychiatr Scand. 1974;50:174-182.
3.    Maj M, Starace F, Nolfe G, Kemali D. Minimum plasma lithium levels required for effective prophylaxis in DSM-III bipolar disorder. Pharmacopsychiatry. 1986;9:420-423.
4.    Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med. 1989;321:1489-1493.
5.    Kirk L, Baastrup PC, Schou M. Propranolol treatment of lithium-induced tremor [letter]. Lancet. 1973;2:1086-1087.
6.    Lapierre YD. Control of lithium tremor with propranolol. Can Med Assoc J. 1976;114:619-624.
7.    Zubenko GS, Cohen BM, Lipinski JF. Comparison of metoprolol and propranolol in the treatment of lithium tremor. Psychiatry Res. 1984;11:163-164.
8.    Dave M. Treatment of lithium induced tremor with atenolol. Can J Psychiatry. 1989;34:132-133.
9.    Smigan L, Bucht G, von Knorring L, Perris C, Wahlin A. Long-term lithium treatment and renal functions. Neuropsychobiology. 1984;11:33-38.
10.    Plenge P, Mellerup ET, Bolwig TG, et al. Lithium treatment: does the kidney prefer one daily dose instead of two? Acta Psychiatr Scand. 1982;66:121-128.
11.    Bowen RC, Grof P, Grof E. Less frequent lithium administration and lower urine volume. Am J Psychiatry. 1991;148:189-192.
12.    Hetmar O, Brun C, Ladefoged H, Larsen S, Bolwig TG. Long-term effects of lithium on the kidney: functional-morphological correlations. J Psychiatr Res. 1989;23:285-297.
13.    Hetmar O, Povlsen UJ, Ladefoged J, Bolwig TG. Lithium: long-term effects on the kidney. Br J Psychiatry. 1991;158:53-58.
14.    Perry PJ, Dunner FJ, Hahn RL, Tsuang MT, Berg MJ. Lithium kinetics in single daily dosing. Acta Psychiatr Scand. 1981;64:281-294.
15.    O’Donovan C, Hawkes J, Bowen R. Effect of lithium dosing schedule on urinary output. Acta Psychiatr Scand. 1993;87:92-95.
16.    Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med. 1985;312:408-414.
17.    Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57:481-489.
18.    Coxhead N, Silverstone T, Cookson J. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Acta Psychiatr Scand. 1992;85:114-118.
19.    Babyak M, Blumenthal JA, Herman S, et al. Exercise treatment for major depression: maintenance of therapeutic benefit at 10 months. Psychosom Med. 2000;62:633-638.
20.    Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press; 1990.
21.    Judd LL, Hubbard B, Janowsky DS, Huey YH, Attewell PA. The effect of lithium carbonate on affect, mood, and personality of normal subjects. Arch Gen Psychiatry. 1977;34:346-351.
22.    Judd LL, Hubbard B, Janowsky DS, Huey LY, Takahashi KI. The effect of lithium carbonate on the cognitive function of normal subjects. Arch Gen Psychiatry. 1977; 34:355-357.
23.    Amdisen A, Andersen CJ. Lithium treatment and thyroid function: a survey of 237 patients in long-term lithium treatment. Pharmacopsychiatry. 1982;15:149-155.
24.    Frye MA, Denicoff KD, Bryan AL, et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry. 1999;156:1909-1914.
25.    Joffe RT, Levitt AJ. Major depression and subclinical (grade 2) hypothyroidism. Psychoneuroendocrinology. 1992;17:215-221.
26.    Joffe RT, Marriott M. Thyroid hormone levels and recurrence of major depression. Am J Psychiatry. 2000;157:1689-1691.
27.    Prohaska ML, Stern RA, Mason GA, Nevels CT, Prange AJ. Thyroid hormones and lithium-related neuropsychological deficits: A preliminary test of the lithium-thyroid interactive hypothesis. J Int Neuropsychol Soc. 1995;1:134.
28.    Prohaska ML, Stern RA, Nevels CT, Mason GA, Prange AJ. The relationship between thyroid status and neuropsychological performance in psychiatric outpatients maintained on lithium. Neuropsychiatry Neuropsychol Behav Neurol. 1996;9:30-34.
29.    Joffe RT, Singer W. A comparison of triiodothyronine and thyroxine in the potentiation of tricyclic antidepressants. Psychiatr Res. 1990;32:241-251.
30.    Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340:424-429.
31.    Bowden CL, Janicak PG, Orsulak P, et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry. 1996;153:765-770.
32.    Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(5 suppl 2):S53-67.
33.    Zarate CA, Tohen M, Narendran R, et al. The adverse affect profile and efficacy of divalproex sodium compared with valproic acid: a pharmacoepidemiology study. J Clin Psychiatry. 1999;60:232-236.
34.    Stoll AL, Vuckovic A, McElroy SL. Histamine subscript 2-receptor antagonists for the treatment of valproate induced gastrointestinal distress. Ann Clin Psychiatry. 1991;3:301-304.
35.    Placidi GF, Lenzi A, Lazzerini F, Cassano GB, Akiskal HS. The comparative efficacy and safety of carbamazepine versus lithium: a randomized, double-blind 3-year trial in 83 patients.
J Clin Psychiatry. 1986;47:490-494.
36.    Isojarvi JI, Rattya J, Myllyla VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol. 1998;43:446-451.
37.    Kifune A, Kubota F, Shibata N, Akata T, Kikuchi S. Valproic acid-induced hyperammonemic encephalopathy with triphasic waves. Epilepsia. 2000;41:909-912.
38.    Eze E, Workman M, Donley B. Hyperammonemia and coma developed by a woman treated with valproic acid for affective disorder. Psychiatr Serv. 1998;49:1358-1359.
39.    Hjelm M, Oberholzer V, Seakins J, Thomas S. Valproate-induced inhibition of urea syntheseis and hyperammonaemia in healthy subjects [letter]. Lancet. 1986;2:859.
40.    Raby WN. Carnitine for valproic acid-induced hyperammonemia [letter]. Am J Psychiatry. 1997;154:1168-1169.
41.    Tohen M, Castillo J, Baldessarini RJ, Zarate C, Kando JC. Blood dyscrasias with carbamazepine and valproate: a pharmacoepidemiological study of 2,228 patients at risk. Am J Psychiatry. 1995;152:413-418.
42.    Joffe RT, Post RM, Roy-Byrne PP, Uhde TW. Hematological effects of carbamazepine in patients with affective illness. Am J Psychiatry. 1985;142:1196-1199.
43.    Brewerton TD. Lithium counteracts carbamazepine-induced leukopenia while increasing its therapeutic effect. Biol Psychiatry. 1986;21:677-685.
44.    Yassa R, Iskandar H, Nastase C, Camille Y. Carbamazepine and hyponatremia in patients with affective disorder. Am J Psychiatry. 1988;145:339-342.
45.    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;20:607-614.
46.    Guberman AH, Besag FM, Brodie MJ, et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children. Epilepsia. 1999;40:985-991.
47.    Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of the lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
48.    Calabrese JR, Suppes T, Bowden CL, et al.
A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61:841-850.
49.    Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother. 1999;33:1037-1042.