Raphael J. Leo, MD

The selective serotonin reuptake inhibitors are employed to treat an array of disorders, including depression, social phobia, panic disorder, posttraumatic stress disorder and obsessive-compulsive disorder. With generally fewer side effects and better tolerability than tricyclic antidepressants and monoamine oxidase inhibitors, the SSRIs have become the most widely prescribed antidepressants in the United States.

Owing to this popularity, adverse drug events previously unappreciated in premarketing clinical trials have gained increasing attention. The most notable of these has been the effect on sexual functioning. Less well-known, yet clinically significant, are movement disturbances that can occur with SSRI use. This should be of concern to clinicians, as movement disorders are uncomfortable, can adversely impact compliance, and can undermine the alliance between clinician and patient. 

In a review of the literature, 71 cases of SSRI-associated extrapyramidal symptoms (EPS) were found (Leo, 1996) (Table). Akathisia was most common, followed by dystonia, parkinsonism and tardive dyskinesia-like states. In addition, 16 cases of worsening parkinsonism were found in patients with pre-existing Parkinson's disease.

Any review of case reports is subject to inherent limitations. First, some case reports are limited by ambiguous descriptions that make movement disorders difficult to distinguish from other psychiatric disorders or other potential SSRI side effects. This is most notable in case reports of akathisia attributed to SSRI use. At times, it becomes difficult to differentiate akathisia from anxiety or jitteriness (Amsterdam et al., 1994; Maany and Dhopesh, 1990). Mistaking comorbid anxiety for SSRI-associated akathisia may delay or interfere with the appropriate treatment of the patient's anxiety disorder.

Second, in only limited numbers of case reports was the SSRI the sole agent administered. Often, the coadministered medications were also capable of producing EPS. Since the movement disturbances did not appear to occur until after addition of the SSRI, it is possible that pharmacokinetic interactions may have occurred -- leading to increased bioavailability of the SSRI, the concurrently administered drug or both -- thus leading to the emergence of the dyskinesia (Leo, 1996). For example, when coadministered with paroxetine (Paxil), serum perphenazine (Trilafon) levels were significantly increased and accompanied by increased rates of akathisia and parkinsonism (Ozdemir et al., 1997). In addition, medications that normally do not produce EPS may, when combined with an SSRI, predispose patients to dyskinesia (Leo et al., 1995).

Third, in several reports, the presence of pre-existing neurologic disease was evident. Conditions such as head trauma (Coulter and Pillans, 1995) or Parkinson's disease (Jimenez-Jimenez et al., 1994; Steur, 1993) can account for the development or emergence of movement disorders. It is also unclear how many of the patients reported in the literature had undiagnosed or overlooked neurologic conditions coincidentally manifesting around the time of SSRI exposure.

Fourth, reports of SSRI rechallenges are rare (Coulter and Pillans, 1995; Reccoppa et al., 1990). Despite the presence of confounding variables, re-exposure to the SSRI would establish a stronger causal relationship between SSRI treatment and the emergence of movement disorders. These factors limit the ability to draw firm conclusions about a causal relationship between SSRI use and the emergence and/or exacerbation of movement disorders.

A simple schematic model of movement disorders is provided in the Figure. Normally, voluntary movements arise when corticospinal tracts generate impulses to anterior horn cells in the spinal cord, modulated by basal ganglia output. Gamma-aminobutyric acid (GABA) from the basal ganglia is inhibitory, refining the corticospinal tract activation. Deficiency of GABA outflow, e.g., Huntington's disease, is characterized by herky-jerky and extraneous movements. 

The GABA outflow from the basal ganglia is, in turn, controlled by the balance between two neurotransmitter systems, i.e., dopamine (DA) arising from the substantia nigra and acetylcholine (ACh). The latter have opposing influences on the activity and, therefore, the outflow from the basal ganglia. Disturbance in the balance between ACh and DA alters the net outflow from the basal ganglia, producing movement disturbances (Figure). Thus, idiopathic parkinsonism arises from cell loss in the substantia nigra, reducing the amount of inhibitory DA input to the basal ganglia. The ACh, now relatively less opposed, stimulates the basal ganglia, increasing the inhibitory output to the corticospinal tracts, producing the bradykinesia, rigidity, mask-like facies, shuffling gait and other symptoms characteristic of Parkinson's disease.

The (Figure) also depicts, therefore, the effect of conventional high-potency antipsychotics in producing dyskinesia. These agents, such as haloperidol (Haldol), bind DA receptors in the basal ganglia, thereby preventing access to DA arising from the substantia nigra. The net effect, like that in Parkinson's disease, is unopposed excitatory input from ACh-containing neurons. Consequently, treatment consists of the addition of an anticholinergic agent like benztropine (Cogentin) restoring balance between DA and ACh and re-establishing the normal inhibitory outflow from the basal ganglia.

Serotonin (5-HT)-containing raphe nuclei extend diffuse interconnections to the DA-rich substantia nigra (Dray, 1981). Neurophysiologic and electric stimulation studies demonstrated that the 5-HT released by the raphe nuclei inhibit striatal neurons, an effect which is reversed by 5-HT antagonists (Davies and Tongroach, 1978). Thus, it is plausible that inhibitors of neuronal 5-HT reuptake, by increasing the availability of 5-HT, might be expected to produce an effect similar to that of DA-blocking agents (Figure). In fact, high doses of fluoxetine (Prozac) have been shown to inhibit DA synthesis in the forebrain, hippocampus and portions of the basal ganglia, specifically the caudate-putamen (Baldessarini and Marsh, 1990). Hence, it can be expected that movement disturbances might arise from SSRI use.

The physiologic processes underlying the development of akathisia may involve the interaction of serotonergic and DA pathways innervating mesolimbic systems. While not depicted here, it is suggested that the inhibitory input to these DA pathways produces the overt and covert restlessness characteristic of akathisia. Noradrenergic mechanisms may also be involved.

The mechanisms underlying SSRI-induced movement disorders are likely to be more complex than has been suggested above. A few case reports suggest improvement of parkinsonism and dystonia with the addition of SSRIs (Durif et al., 1995; Keppel Hesselink, 1993; Meerwaldt, 1986). It is possible that other interconnections between 5-HT containing innervations with those of GABA and ACh may contribute to the development of movement disturbances (Fibiger and Lloyd, 1984; Schreiber and Pick, 1995). However, these interconnections have yet to be clarified.

Just how SSRIs induce EPS and other movement disorders in some patients, but potentially improve parkinsonism and dystonia in others, remains unclear. Furthermore, were the mechanisms underlying SSRI-induced movement disorders as simple as illustrated here, the expectation would be that SSRI-induced movement disorders would be common. In fact, the rates of such movement disturbances remain quite low.

It is possible that some patients are more vulnerable to SSRI-induced movement disorders than are others. Included in the higher-risk category are a) the elderly; b) those exposed to high levels of SSRIs (due to high doses or altered metabolism due to drug interactions); c) patients with concurrent neuroleptic exposure; and d) patients with compromised nigro-striatal functioning. Elder patients may be susceptible to neuronal loss, rendering them vulnerable to the effects of enhanced 5-HT input to nigro-striatal pathways. In addition, due to decreased hepatic functioning, they may be vulnerable by virtue of increased levels of exposure to administered SSRIs. Clearly, neuroleptic exposure increases one's risk of movement disorders, and such exposure may increase the vulnerability of patients who are simultaneously administered SSRIs.

One can only speculate on the influence of gender. While reports featuring female patients who developed dyskinesia associated with SSRI use outnumber those featuring males (Table), one cannot assume that females are more vulnerable. On the one hand, the gender differences observed may merely reflect another trend, i.e., the prevalence of depression is greater among females and more females than males seek treatment for depression (Weissman and Klerman, 1977). In fact, it may be possible that males may be more susceptible than females to dyskinesia associated with SSRI use. Among SSRI-treated patients in a New Zealand medication monitoring program, females (n=3,539) exceeded males (n=1,917) (Coulter and Pillans, 1995). Nevertheless, the proportion of males developing movement disorders (n=8, 0.42%) exceeded the proportion of females (n=7, 0.2%) who did so.

While a majority of cases of SSRI-induced movement disorders involved fluoxetine, at the time of my initial review, fluoxetine had exceeded the other SSRIs in sales and had been available longer than the others. Consequently, the numbers of reports involving fluoxetine may simply have been an artifact of these trends.

On the other hand, there are differences among the effects of SSRIs on DA-reuptake inhibition. For example, sertraline (Zoloft) exhibits a direct augmenting effect on DA-reuptake inhibition (Koe et al., 1983); inhibitory serotonergic input to dopaminergic systems would be mitigated by such direct augmentation. Paroxetine and fluoxetine have lower potencies than sertraline for DA-reuptake inhibition in vitro (Richelson, 1994). Paroxetine also has anticholinergic properties in vitro, which may contribute to reducing the likelihood of EPS as compared to some of the other SSRIs.

The most prudent treatment measures might be dose reduction or discontinuation of the SSRI, switching to an alternate antidepressant, and/or reducing the coadministered medications that may have led to drug interactions and potentiation of the movement disturbances after SSRI administration. Other interventions employed to mitigate dyskinesia associated with SSRI use are summarized in the Table.

Given that patient exposure to the aforementioned SSRIs is currently estimated to exceed 85 million, movement disorders associated with SSRI use are rare. Certain patients may be more vulnerable to the emergence of dyskinesia after SSRI treatment, e.g., the elderly or those with neurological insults. Clinicians may need to pay particular attention to patients treated with SSRIs who require multiple medications for co-existing medical conditions or complicating psychiatric symptoms. Because pharmacokinetic interactions may occur that render patients susceptible to dyskinesia, patients should be examined frequently for signs of an emerging movement disorder.

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Coulter DM, Pillans PI (1995), Fluoxetine and extrapyramidal side effects. Am J Psychiatry 152(1):122-125 [see comment].
 

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The SSRIs have become the most widely prescribed antidepressants in the United States. With this increased use has come more information on adverse events associated with their use, such as sexual dysfunction. However, movement disturbances associated with SSRI use can adversely impact treatment. This article explains the pathology of movement disorders and describes confounding variables such as other medications, pre-existing neurological insults and the nature of case reviews. Those at risk include the elderly, patients taking neuroleptics and those exposed to high levels of SSRIs.

Movement Disturbances Associated With SSRIs

In the early 1970s, influenced by the supporters of the feminist movement, educators increasingly recognized the potential of the instructional materials employed from grade school through college in influencing gender role stereotypes. Hence, there was an impetus to introduce Title IX of the 1972 Education Amendments Act to reduce gender stereotypes in educational materials used in federally funded primary and secondary schools (Minority Health Improvement Act, 1994).

The increased awareness of sexism and the role of training and professional development in perpetuating sexist values similarly compelled many professionals to examine the ideologies and methodologies employed in their disciplines for the potential of gender bias. Often, such bias conveyed stereotypic representations of men and women, but nonetheless, imparted strong value messages to trainees. For example, in a review of psychology texts, Denmark (1982) observed that women were presented in photographs as mentally ill or as passive participants in psychological research, e.g., looking on while a male investigator conducted an experiment. Males were more often depicted as therapists or researchers.

Gender disparities in the provision of medical care have recently received increased attention. The causes for such disparities are multi-factorial and may emanate from educational experiences and attitudes presented in medical training (Table 1). Overtly or covertly expressed attitudes toward women conveyed by instructors and supervising attendings are potentially influential on medical trainees also.

More subtle influences on the medical trainee include the amount of attention devoted to the study of clinically relevant issues and disorders predominantly affecting, or specific to, women. This can include the extent to which these topics are addressed in texts, lectures and reviews of relevant clinical literature.

Women's health-related topics may not be incorporated into basic medical training, as they are viewed as more specialized, possibly resulting in their omission from basic health care provisions. For example, it is not uncommon to note that breast and pelvic examinations are routinely omitted on patients admitted to hospitals despite the mandate of "complete physical examinations."

It is common for clinical research to overlook or exclude women to avoid hormonal influences on study results and omit women of reproductive age to avoid potential fetal risks. Consequently, results of clinical investigations based upon samples of men may be inappropriately generalized to women (Cotton 1990a, 1990b).

There have been increasing efforts on clinical and research levels to address gender bias. The early 1990s saw the National Institutes of Health establish the Office of Research on Women's Health and the Women's Health Initiative. Medical journals, such as the 

, have been established to address issues pertaining to women. There has been some discussion of the development of a specialty in women's health, and several medical centers have been established nationwide with an exclusive focus on women's health.

Gender bias in medical training, and its influence on the medical trainee, is not readily amenable to scientific inquiry. Of those items listed in Table 1, only a few can be objectively studied. Furthermore, the resulting influence on the trainee remains unclear.

There are concerns that gender-biased instructional materials can impart values that are subsequently incorporated into clinical practice, as a great deal of a medical student's time is spent reviewing such texts. Gender bias in text content, unlike some items listed in Table 1, can be objectively quantified, e.g., by social role and stereotypic representations and in the frequencies with which men and women are portrayed in case scenarios or as models.

Previous investigations of gender bias in anatomy or physical diagnosis texts have noted that illustrations of male models exceeded those of female models (Giacomini et al., 1986; Mendelsohn et al., 1994). Consequently, investigators have suggested that medical students may be less familiar with female anatomy and are at risk for developing biases such as the male body being the "norm" (Mendelsohn et al., 1994; Nechas and Foley, 1994).

In 1999, Leo and Cartagena examined whether bias was present in psychiatric texts. Introductory-level texts were selected, as these are more apt to be used by medical students in psychiatry courses and during clinical clerkships.

Of the clinical case vignettes examined in this study, a disproportionate number featured male protagonists (Table 2). In five of the six texts reviewed, the use of the male protagonist exceeded that of females; significantly fewer female subjects were employed in four texts.

The propensity to use the male subject was not an artifact of depicting psychiatric disorders with higher prevalence rates among males. In fact, females tended to be subjects of vignettes illustrating disorders with higher prevalence rates among women, and likewise for males. Thus, protagonist gender was generally consistent with known epidemiologic trends of psychiatric disorders. Vignettes illustrative of disorders in which the prevalence rates are unknown or are equal among men and women, however, tended to feature male subjects.

Interestingly, only two texts dealt with disorders unique to women. One featured a single vignette describing premenstrual dysphoric disorder, and the other featured a single case of postpartum psychosis.

In summary, research has shown that women, who comprise more than half the population, and the psychotic disturbances unique to them are underrepresented in clinical vignettes in psychiatric texts despite their predominance in psychiatric practice.

The tendency to employ male subjects for illustrative examples has been observed in a variety of texts from grade school through college and subsequent professional training. The study on gender bias in psychiatric texts expands on work focusing on gender disparities in other disciplines, such as anatomy and clinical medicine, taught to medical students (Giacomini et al., 1986; Mendelsohn et al., 1994). The trends observed among psychiatric texts are, therefore, not unique to psychiatry but appear to reflect broader social biases. Nonetheless, several measures can be undertaken to correct the problem of gender bias in psychiatric education (Table 3).

Editors and authors of psychiatric texts can, in future editions, ensure that selection of subject gender in case vignettes parallels known epidemiologic trends or patterns of psychiatric service utilization. In this way, subject gender will be consistent with trends observed in the clinical setting. When these trends are unknown or unclear, a gender equitable approach can be a consideration (Scott and Schau, 1985).

Whether or not authors and publishers of psychiatric texts respond to the above suggestions, psychiatry instructors will likely have the more critical role in addressing gender bias. First, the problem of gender bias can be surmounted when one considers that gender can enrich our understanding of psychiatric principles. Clearly, gender differences exist with regard to epidemiologic and prognostic information regarding psychiatric disorders; therefore, every effort should be made to describe how the presentation, course and prognosis of psychiatric disorders differ for women and men. Second, students may benefit from having their attention drawn to the gender bias in educational materials and clinical research. The heightened awareness will attract a critical review of the limitations in clinical research and training and may impart the importance of greater sensitivity to the issues of gender as students advance in their careers, some or all of which may involve teaching of subsequent generations of medical trainees. Third, incorporating a section on women's health into the psychiatry curriculum may foster increased sensitivity to the full spectrum of issues and experiences affecting women's health (Spielvogel et al., 1995).

Previous research has demonstrated that physicians react to, evaluate or treat complaints made by male and female patients differently. For example, men receive more extensive evaluations and investigative studies than women, despite presenting with identical complaints (Bernstein and Kane, 1981; Council on Ethical and Judicial Affairs, 1991; Tobin et al., 1987). The differences in treatment and evaluation of men and women may be, in part, attributable to prejudices and misrepresentations of disorders as manifested by women in the medical literature (Lennane and Lennane, 1973; Scully and Bart, 1973). Whether a patient's gender influences the assessment and treatment of their condition, and how this might be communicated in psychiatric texts, warrants investigation.

Ultimately, it is hoped that when men and women are treated differently by physicians, it is based upon an awareness of the aforementioned gender differences and not faulty assumptions, attributions or misperceptions about men and women conveyed, implicitly or explicitly, in medical training.

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There is a history of gender bias in medical education and practice. Research has shown that this bias extends to the psychiatric field as well. Through material presented to medical trainees-in classes, textbooks, research reviews and the like-subsequent thoughts and actions may be negatively biased against women. A review of the ways in which biases are conveyed is explored, as well as suggestions for reducing, eliminating and preventing these biases in medical education.

Author | Raphael J. Leo, MD

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