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

Abstract

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D₂-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D₂ receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D₂ receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

Iatrogenic Factors in Psychopathology

“…At times, its effects on illness course are clear-cut. Examples are switching from unipolar to bipolar course with antidepressant drugs [6, 31] and supersensitivity psychosis, the onset of psychotic symptoms and co-occurring movement disorder with antipsychotic medications [4]. Paradoxical reactions may also occur, such as increased agitation, excitement, insomnia, and talkativeness with benzodiazepines, particularly in children and the elderly [33].…”

“…Withdrawal symptoms, which may follow discontinuation of psychotropic drugs, such as benzodiazepines [36], antipsychotic medications [4, 37], and antidepressant treatment [38-40], are also a form of behavioral toxicity. Discontinuation symptoms typically appear within 3 days of stopping antidepressant medication or initiating a medication taper.…”

“…Untreated symptoms may be mild and resolve spontaneously in 1–3 weeks; in other cases, they may persist for months or even years [38-40]. Persistent postwithdrawal disorder has been described with different classes of psychotropic substances (e.g., mood fluctuations and anxiety disorders with antidepressant drugs, tardive dyskinesia and supersensitivity psychosis with antipsychotic medication, protracted insomnia for alcohol and benzodiazepine withdrawal, and major depression for cocaine and amphetamine withdrawal) [4, 38-40]. Events related to withdrawal with psychotropic drugs may thus be limited to the period of drug administration and/or persist long after their discontinuation.…”

“…At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity, such as with weight gain and sexual side effects [6]. Similar considerations apply to antipsychotic medications [4]. …”

“…In psychiatry, iatrogenesis has traditionally been concerned with medical complications of psychotropic drug treatment [3], such as tardive dyskinesia [4] and insulin resistance [5] with antipsychotic drugs, and cardiac and metabolic disturbances with antidepressant medications [6-8]. The complications may occur due to direct toxicity, drug-drug interactions, intoxication, or withdrawal from psychotropic medications [3].…”