Adverse Subjective Experience With Antipsychotics and Its Relationship to Striatal and Extrastriatal D ₂ Receptors: a PET Study in Schizophrenia

Abstract

Higher D(2) receptor occupancy is associated with negative subjective experience in patients taking risperidone or olanzapine. These negative subjective effects may be related to the high discontinuation rates seen in usual practice. Understanding the neurobiological mechanism of these negative subjective experiences and developing antipsychotics with novel (i.e., non D(2)) mechanisms may be critical in improving the treatment of psychosis.

Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism

“…Despite a surge in its recreational use (Griffin et al, 2008), the neural correlates mediating these effects are unknown. Decreased dopamine signaling in the dorsal and ventral striatum is implicated in the induction of dysphoria and the pathogenesis of depression (Mizrahi et al, 2007). KOR agonists decrease dopamine concentrations in these regions; an effect attributed to inhibition of dopamine release (Shippenberg et al, 2007; Spanagel et al, 1990).…”

Acute-Onset Type 1 Diabetes that Developed During the Administration of Olanzapine

“…The mechanisms underlying the onset of glucose intolerance are reported to be as follows. 1) increased insulin resistance caused by weight gain as a result of overeating due to the principal activity of SDAs, which increase the ghrelin levels by blocking the 5-HT 2C (25), D2 (26), α1 (23), and H1 receptors (23). 2) Pancreatic β-cell dysfunction (27) 3) increases the insulin resistance caused by impaired glyconeogenesis and the insulin signal transduction in L6 skeletal muscle cells (28).…”

Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia

“…Also consistent with our results, human pharmacological studies show that anhedonia is attenuated by chronic D2/D3R agonism in Parkinson disease (Lemke et al, 2006) and chronic, partial D2R agonism in schizophrenia (Liemburg et al, 2011). Finally, greater striatal D2/D3R occupancy with antipsychotics relates to dysphoria in patients (Mizrahi et al, 2007) and antipsychotic use induces dysphoria in healthy individuals (King et al, 1995). Of note, DA receptor sensitivity is positively related to affective flattening, but not anhedonia per se , in depressed patients (Schmidt et al, 2001).…”

“…Alternatively, symptom severity may more strongly relate to D2/D3R availability than patient status. Low striatal D2/D3R availability in patients, either at baseline or due to receptor occupancy by antipsychotics, has been associated with greater negative symptom severity (de Haan et al, 2000; Heinz et al, 1998; Lataster et al, 2011; Martinot et al, 1994; Pickar et al, 1996; Uchida et al, 2009) and dysphoria (Mizrahi et al, 2007). However, it has also been associated with greater positive and less negative symptom severity (Pogarell et al, 2012) and some studies did not show any relationship (Agid et al, 2007; Graff-Guerrero et al, 2009; Kegeles et al, 2008; Klemm et al, 1996; Talvik et al, 2006).…”