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Abbreviations
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
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TREATMENT OF PSYCHOSIS
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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.
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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).
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The Dopamine Hypothesis
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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).
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The DA model of antipsychotic action has limitations: It does not explain the psychotomimetic effects of ...