Is Neuroleptic Dysphoria a Variant of Drug-Induced Extrapyramidal Side Effects?

Abstract

Objectives: Neuroleptic drugs induce psychological side effects such as dysphoria, cognitive impairment, and loss of motivation. These side effects were largely underrecognized and trivialized in the past as variants of extrapyramidal side effects (EPSEs). We review the recent literature on the subject and clarify the relation between neuroleptic-induced dysphoria and EPSEs. Methods:We critically examined clinical, interventional, neuroimaging, and basic science studies published in the past 10 years, delineating the temporal, phenomenological, biochemical, and neuroanatomical relation between dysphoria and EPSEs.Results: Subjective responses occur within 4 to 6 hours of neuroleptic use, whereas acute dystonia is often observed within 24 hours and parkinsonian syndrome after 5 to 7 days. Neuroleptic-induced dopaminergic blockade mediates both dysphoria and EPSEs. However, impaired dopamine function in the nucleus accumbens seems to give rise to dysphoria, whereas blockade of D 2 receptors in the nigrostriatal system is responsible for EPSEs. Conclusion:The earlier notion that neuroleptic dysphoria is a variant of EPSEs was simplistic and speculative. Exploring the differences rather than dwelling on the similarities will likely enhance our understanding of dopamine's role in the origin of varied side effects and in their distinctive characteristics. Clinical Implications· Clinical monitoring of the side effects of antipsychotic drugs should include specific inquiry into aspects of subjective tolerability. · If unchecked, poor subjective tolerability may lead to nonadherence to prescribed treatment, clinical instability, and other adverse consequences. · Exploring the nature of both spontaneous and iatrogenic dysphoria outside the context of schizophrenia and neuroleptic therapy will broaden our understanding and appreciation of its implications. Limitations· Studies of neuroleptic dysphoria in particular and subjective responses to medications in general have been few and far between. · In vivo studies involving neurochemistry of the brain are hampered by technical limitations, which prevents the drawing of firm associations between clinical events and neurobiological correlates. · Little has been known about the nature of dysphoria occurring in clinical situations apart from neuroleptic therapy.

The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment

“…Our finding that an increase of EFs can be elicited by subthreshold catalepsy doses of antipsychotics is in agreement with the clinical studies showing that neuroleptic dysphoria can present without the presence of EPS (Voruganti and Awad 2004b). However, given clinical reports that people often experience neuroleptic dysphoria at the same doses of drugs causing EPS (Gerlach 2002), it would not be surprising if catalepsy contributes to, or coexists with, dysphoria and likewise increased EFs.…”

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy

“…This suggests that overblockade of D 2 receptors can be detected clinically with a movement disorder examination. A specific examination for movement disorders will also permit identification of emergent psychiatric symptoms caused by movement disorders [1]: akinesia producing depression and dysphoria [143,144,145], facial mask, blunted affect, rigidity, motor retardation [1,81], akathisia, agitation/anxiety/insomnia, and suicidal ideation [146,147]. It will permit early recognition of iatrogenic psychiatric symptoms confounded with movement disorders [1], akinesia confounded with psychomotor retardation, akathisia with agitation, and TD with mannerisms and schizophrenic abnormal movements [1,81], symptoms which will often trigger dose increases and a consequent overblockade of D 2 receptors.…”

“…Most SGAs have been reported to be efficacious at doses that are associated with less movement disorders, including parkinsonism and TD compared to FGAs [1,167], and less dysphoric responses [1,145]. FGAs, that induce less movement disorders (thioridazine, pimozide, and benzamides: sulpiride, amisulpride, metoclopramide, cisapride, and remoxipride) were found to have significant cardiac and pro-arrhythmic effects, which led to their restricted use (US boxed warning), withdrawal, or nonapproval in several countries (Table 5).…”

Allostatic Load as a Tool for Monitoring Physiological Dysregulations and Comorbidities in Patients with Severe Mental Illnesses

“…Specifically, antipsychotic drug treatment is reported to provoke (1) neuroleptic dysphoria, 142,143 primarily via high D2 blocking agents, (2) sedation/drowsiness that impairs judgment, thinking, or motor skills, 125,144 (3) altered reward functions, 145,146 and (4) misbalanced dietary preferences. 81 We propose that using AL indices could provide insights into PAL.…”