The introduction of chlorpromazine in the 1950s was quickly followed by a series of reports on its adverse effects (1). Over the next 2 decades, extensive worldwide use of neuroleptics led to a compendium of systemic, neurological, and psychological adverse effects. During this period, considerable controversy and confusion existed with regard to naming and classifiying adverse events, especially the subtle and underrecognized subjective effects such as dysphoria, cognitive deficits, and loss of motivation resulting from neuroleptic use. The “lumpers” included them among extrapyramidal side effects (EPSEs), since drug-induced parkinsonian syndrome was already well recognized, systematically studied, and better understood at the time (2). Consequently, all the other neurological and psychological side effects whose nature and mechanisms were not clearly understood came to be included in the category of EPSEs. The “splitters” preferred to categorize them as psychic, behavioural, or mental side effects solely to distinguish them from somatic and neurological side effects (3). The nature of these subjective adverse effects and their clinical implications were carefully studied by some researchers, whereas the subjective nature of these responses created a sense of uncertainty and disinterest among many others. This article examines the original notion that neuroleptic dysphoria is a variant of EPSEs and considers recent findings that could help to redefine the relation between neuroleptic-induced dysphoria and EPSEs.
Neuroleptic dysphoria refers to the unpleasant subjective responses reported during neuroleptic therapy. Patients’ descriptions often include terms such as “feeling blah, listless, tired, and lacking interest and ambition.” Dysphoric feelings have been reported to occur within a few hours of administering the first dose of neuroleptic medications and seem to persist over the following weeks and months, leading to several important clinical consequences (4–8). Immediate clinical manifestations include complaints of subjective intolerance, reluctance to take antipsychotic drugs, and even outright treatment refusal (9). Failure to address these problems may lead to long-term consequences such as nonadherence to treatment, clinical instability characterized by relapses and rehospitalizations, suicidal behaviour, comorbid substance abuse, and compromised quality of life (7,10–15).
In the 1970s, neuroleptic dysphoria was considered by some to be a form of an affective syndrome, while others included it in the cluster of extrapyramidal syndromes (for example, akinesia, dystonia, and akathisia). The notion that dysphoric responses were a variant of EPSEs was supported by clinical observations: both phenomena occurred during the first week of neuroleptic therapy, they were often induced by high-potency neuroleptics, and their severity seemed to be related to the degree of dopaminergic blockade. It was also noted by others that dysphoria and EPSEs did not always coincide. EPSEs were relieved by antiparkinsonian drugs, whereas dysphoria was not, and dysphoric responses were noted much earlier than EPSEs during the course of neuroleptic therapy. By the 1980s, it became obvious that clinical observations alone were not adequate to resolve the issue of defining and classifying the status of neuroleptic dysphoria.
Because dysphoria is subjective, it seemed difficult to study the phenomenon using modern scientific principles and rigour. The enthusiasm for studying dysphoria subsided by the 1980s and research stagnated. In the 1990s, 3 significant developments helped to rejuvenate interest in dysphoria, especially interest in exploring its neurobiological under- pinnings. These developments were the popularity of clinical experiments involving chemical probes, progress in the area of neuroimaging, and the introduction of second-generation antipsychotic drugs.
Experimental Studies Involving Chemical Probes
Research into studying the role of dopamine took a major leap with the use of alpha-methyl paratyrosine (AMPT) as a chemical probe to manipulate neurotransmitter dynamics in the brain. The technique was perfected by Laruelle and colleagues, primarily for in vivo studies aimed at studying dopamine function in schizophrenia (16). The experimental protocol involved administering AMPT for 48 hours to induce a dramatic, but temporary and reversible, depletion of dopamine and studying consequent changes in receptor occupancy. Clinical rating scales administered during the experiment included a visual analogue scale to measure changes in emotional status. Results indicated significant changes in anxiety, depression, and extrapyramidal symptoms ensuing from the AMPT-induced dopamine depletion. These findings, along with the other biological indices of dopamine depletion (homovanillic acid and D2 receptor occupancy), resurrected the putative link between impaired dopamine function and dysphoric subjective responses.
Recently, we reported data from a comprehensive study of the phenomenology of dysphoria, including its relation to other extrapyramidal symptoms and striatal dopamine D2 binding ratio, which was carried out using the same experimental AMPT paradigm (17). In this focused investigation, subjective responses to AMPT ingestion were systematically monitored and documented through serial administration of the Addiction Research Center Inventory (18), the Drug Attitude Inventory (19,20), and the Profile of Mood States (POMS) (21). Subjective (dysphoric) responses were the earliest to be captured by the rating scales, followed by the emergence of akathisia and parkinsonian symptoms, respectively. Perceived psychomotor slowing, lack of pleasure, and preference to remain isolated were reported within 6 hours of receiving AMPT; akathisia was noted after 24 to 36 hours; rigidity and tremor became evident toward the end of 48 hours.
These observations were again substantiated by Verhoeff and colleagues (22), who noticed distinctive shifts in various POMS subscales that suggested emergence of dysphoria during AMPT-induced dopamine depletion.
The AMPT studies consistently demonstrated that rapid depletion of dopamine brings about a range of profound systemic, neurological, psychological, cognitive, and affective changes, the latter being in the form of dysphoria. In particular, our study indicated that the time of onset of these changes follows a distinctive pattern. This differential onset of the manifestations of impaired dopamine function is also consistent with the onset of side effects during the course of neuroleptic treatment.
Cross-sectional as well as long-term follow-up switch studies in schizophrenia indicate better subjective tolerability and less-frequent dysphoria on second-generation, compared with first-generation, antipsychotics (23–25). The topic is reviewed in greater detail in this issue (26).
Why are the novel antipsychotic drugs tolerated better, compared with the neuroleptics? A review of the concept of atypicality and the proposed mechanisms of action of second- generation antipsychotic drugs may provide some clues toward their low dysphoria liability and improved tolerability. The “dopaminergic” theories of atypicality are based on the following themes: the extent of dopamine D2 receptor blockade (27,28); the degree of affinity of drug molecules to D2 receptors (29,30); the contribution of other dopamine receptors, such as D1, D3, and D4, toward subjective attributes such as sensation-seeking behaviour (31); prefrontal dopamine release, either through serotonergic action or independently (32); and selective dopaminergic blockade in the shell of the nucleus accumbens that does not affect the core (33). The original speculation was that the ratio of D2 and 5-HT2 receptor blockade is crucial in determining EPSE liability or the lack of it (28,34).
Advances in neuroimaging made it feasible to explore the neurochemical basis of subjective responses, especially the pivotal role of dopamine. We include here a summary of the seminal studies (for a detailed review, see de Haan and colleagues; 35).
Employing various experimental techniques, several receptor-imaging studies in the recent past have attempted to address the relation between altered dopaminergic function and disturbed mood in schizophrenia. Fujita and colleagues used a protocol consisting of AMPT administration and single photon emission computed tomography (SPECT) imaging with [123I]epidepride in healthy volunteers and were able to demonstrate an association between increased D2 binding potential in the temporal cortex and a corresponding worsening of dysphoric mood (36). Hietala and others examined the striatal dopamine levels of 10 drug-naïve, first-episode schizophrenia patients with [18F]-6-L-fluorodopa ([18F]DOPA) positron emission tomography (PET) imaging and found a strong correlation (r = 0.86 to 0.9) between low striatal dopamine and scores on the depressive items on the Positive and Negative Symptom Scales (37).
De Haan and colleagues used [123I]iodobenzamide ([123I]IBZM) SPECT imaging to estimate striatal D2 occupancy rates in schizophrenia patients treated with olanzapine or risperidone and found a significant correlation between the percentage of D2 occupancy and dysphoric responses (38). In another recent study, a group of drug-free schizophrenia patients (n = 13) were administered AMPT (4 to 5 g daily) over a 48-hour period, and the progressive changes in their mental status were measured with standardized rating scales at 12-hourly intervals. Changes in their striatal D2 receptor occupancy were simultaneously quantified with [123<I]IBZM SPECT imaging (17). The severity of dysphoric responses correlated inversely with the incremental changes in D2 receptor binding ratios (r = –0.82, P < 0.01).
Cumulative knowledge acquired from anatomical and histological studies in rodents and primates has further enhanced our ability to decipher the neural substrates of neuroleptic effects. Intracranial electrical stimulation, chemical lesioning studies with 6-hydroxy dopamine, histochemistry, autoradiography, and immunoreactivity techniques have not only facilitated mapping of dopamine projections but have also identified meaningful anatomical-functional links. Of all the different projections described, perhaps the ones most relevant to the present discussion are the nigrostriatal and mesoaccumbens projections. Dopaminergic blockade in the nigrostriatal system is responsible for the occurrence of parkinsonian syndrome, whereas the same impairment in the accumbens complex seems to give rise to dysphoric responses.
The nucleus accumbens is a part of the basal forebrain and is closely linked to the ventral striatum and extended amygdala, both anatomically and functionally. Recent anatomical studies have shown that the accumbens has 2 vaguely defined anatomical components—a central core and a peripheral shell—that have histological and functional specificity (39). The nucleus accumbens has been identified as a critical component of the brain’s reward system and is significantly implicated in determining motivational behaviour and its disorders, such as drug abuse. Drugs of abuse, including cocaine, amphetamines, and morphine, preferentially stimulate the release of dopamine and increase the energy metabolism in the shell of the nucleus accumbens. Recent neurotensin and Fos immunoreactivity studies have also demonstrated that neuroleptics seem to exert their actions on the core as well as on the shell, while the new atypical antipsychotic drugs have a preferential effect on the dorsomedial aspects of the shell (32,33).
A review of recent developments (40) suggests 2 predominant themes: 1) provocation studies involving AMPT and neuroimaging studies confirm that dopaminergic blockade is responsible for both dysphoria and extrapyramidal syndromes; 2) clinical and neuroanatomical studies are, however, able to distinguish between dysphoria and EPSEs in terms of their neural substrates and time of onset. These observations neither clearly support nor refute the notion under discussion, but they have helped to redefine the relation between dysphoria and EPSEs with an improved level of scientific sophistication.
The Oxford English Dictionary defines variant as “a form or version of something differing in some respect from other forms of the same thing” (41). The notion that neuroleptic-induced dysphoria is a variant of EPSEs carries a connotation that EPSEs are a well-defined core phenomenon, whereas dysphoria is an alternative presentation of the same entity. As afflictions of the motor system, akinesia, rigidity, tremor, and dystonia share common characteristics and may be considered variants of neuroleptic-induced extrapyramidal syndrome. Conversely, neuroleptic dysphoria is primarily characterized as a subjective or psychological response, albeit caused by the same pathophysiology, that is, impaired dopamine function. Based on the review of recent literature, it would be more appropriate to consider both dysphoria and EPSEs as variants or manifestations of drug-induced dopaminergic blockade.
How relevant is it to ask whether or not dysphoria is a variant of neuroleptic-induced EPSEs? With the arrival of the second-generation antipsychotic drugs, neuroleptic-induced dysphoria and EPSEs are becoming less frequent, giving the false impression that this discussion has become somewhat academic. However, academic pursuits have heuristic value, and the study of neuroleptic dysphoria has implications for new drug development and for understanding the patho- physiology of a spectrum of dysphoric states, including substance abuse. Subjective tolerability is recognized as a desirable characteristic of an ideal antipsychotic drug, setting a new standard for the development of antipsychotic compounds. Also, recognition of the nucleus accumbens as the putative neural substrate for both dysphoria and substance abuse provides scope for understanding the neurobiological underpinnings of schizophrenia–substance abuse comorbidity.
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Manuscript received and accepted February 2004.
1. Associate Professor and Head, Schizophrenia Research Program, McMaster University, Hamilton, Ontario.
2. Chief of Psychiatry, Humber River Regional Hospital, Toronto, Ontario.
Address for correspondence: Dr LP Voruganti, Department of Psychiatry, McMaster University, 100 West 5th Street, Hamilton, ON L8N 3K7
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