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ACEI: angiotensin-converting enzyme inhibitor

AUC: area under the curve

CBC: complete blood cell count

CNS: central nervous system

COX-2: cyclooxygenase 2

CV: cardiovascular

DA: dopamine

DAAO: D-amino acid oxidase

DAT: DA transporter

DM: diabetes mellitus

ECG: electrocardiogram

ECT: electroconvulsive therapy

eGFR: estimated glomerular filtration rate

EM: extensive metabolizer

ENaC: epithelial sodium channel

EPS: extrapyramidal symptom

FDA: Food and Drug Administration

G-CSF: granulocyte colony-stimulating factor

GFR: glomerular filtration rate

GlyT: glycine transporter

GSK: glycogen synthase kinase

5HT: serotonin

Ikr: inwardly rectifying K+ channels

IM: intramuscular

LAI: long-acting injectable

MAO: monoamine oxidase

mGlu: metabotropic glutamate

NDI: nephrogenic diabetes insipidus

NE: norepinephrine

NMDA: N-methyl-D-aspartate

NMS: neuroleptic malignant syndrome

ODT: oral dissolving tablet

PDP: Parkinson disease psychosis

PET: positron emission tomography

PGP: P-glycoprotein

PK_: protein kinase _, as in PKA, PKC

PP2A: protein phosphatase 2A

SCD: sudden cardiac death

T4: levorotatory thyroxine

TD: tardive dyskinesia

TH: tyrosine hydroxylase

TSH: thyrotropin (previously thyroid-stimulating hormone)

VMAT2: vesicular monoamine transporter 2


Psychosis is a symptom of mental illnesses characterized by a distorted or nonexistent sense of reality. Psychotic disorders have different etiologies, each of which demands a unique treatment approach. Common psychotic disorders include mood disorders (major depression or mania) with psychotic features, substance-induced psychosis, dementia with psychotic features, delirium with psychotic features, brief psychotic disorder, delusional disorder, schizoaffective disorder, and schizophrenia.

Schizophrenia has a worldwide prevalence of 1% and is considered the prototypic disorder for understanding the phenomenology of psychosis and the impact of antipsychotic treatment, but patients with schizophrenia exhibit features that extend beyond those seen in other psychotic illnesses. Hallucinations, delusions, disorganized speech, and disorganized or agitated behavior are psychotic symptoms found individually, and occasionally together, in all psychotic disorders and are typically responsive to pharmacotherapy. In addition to positive symptoms, schizophrenia patients also suffer from negative symptoms (apathy, avolition, alogia) and cognitive deficits, with the latter the most disabling aspect of the disorder (Young and Geyer, 2015).

The Dopamine Hypothesis

The syntheses of chlorpromazine (1950) and haloperidol (1958) allowed Carlsson to deduce that postsynaptic DA receptor antagonism was their common mechanism. Carlsson’s discovery informed the development of numerous typical or first-generation antipsychotic drugs that were found to act specifically at D2 receptors (Seeman, 2013). The discovery of clozapine’s unique clinical features and binding profile stimulated development of second-generation antipsychotics that potently antagonize the 5HT2A receptor while possessing less affinity for D2 receptors than typical antipsychotic agents, resulting in antipsychotic efficacy with lower potential for extrapyramidal side effects. Subsequent research led to the development of agents with D2 partial agonist properties that act as modulators of dopaminergic neurotransmission (Meyer and Leckband, 2013).

The DA model of antipsychotic action has limitations: It does not explain the psychotomimetic effects of ...

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