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LB-102

Schizophrenia

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Product information and disease descriptionPlace of product in therapyDisease description

Pathophysiology

10 evidence topics · 14 sources

Dopamine hypothesis: presynaptic striatal dopamine dysfunction

“Forty-four studies were identified that compared in vivo striatal dopaminergic function in 618 patients with schizophrenia with 606 controls using positron emission tomography or single photon emission computed tomography.” (opens the source at this quote in a new tab)

“There was a highly significant elevation (p<0.0001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen’s d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D2/3 receptor availability (Cohen’s d=0.26), but this was not evident in drug-naïve patients and was influenced by the imaging approach used.” (opens the source at this quote in a new tab)

“The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic-affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release.” (opens the source at this quote in a new tab)

“Mean dopamine synthesis (g = 0.65, p = .004) and release (g = 0.66, p = .03) capacities, as well as synaptic levels (g = 0.78, p = .0006), were greater in patients overall, but mean synthesis capacity did not differ from that of control subjects in treatment-resistant patients (p > .3).” (opens the source at this quote in a new tab)

Dopamine hypothesis: dysregulation as the final common pathway to psychosis

“The hypothesis has 4 distinctive components.” (opens the source at this quote in a new tab)

“interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia.” (opens the source at this quote in a new tab)

“Second, the locus of dopamine dysregulation moves from being primarily at the D2 receptor level to being at the presynaptic dopaminergic control level.” (opens the source at this quote in a new tab)

“Excessive dopamine activity in the mesolimbic pathway, which runs from the ventral tegmental area to the limbic regions, is thought to contribute to the positive symptoms of schizophrenia. Reduced dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, may underlie negative symptoms and cognitive deficits.” (opens the source at this quote in a new tab)

Dopamine D2 receptor blockade as the common mechanism of antipsychotics

“These show that at clinical doses all currently licensed antipsychotic drugs block striatal D2 receptors. Furthermore, a threshold striatal D2 blockade is required for antipsychotic efficacy, but this is not sufficient—some patients show little improvement despite high D2 occupancy.” (opens the source at this quote in a new tab)

“all licensed first‐line treatments for schizophrenia operate primarily via antagonism of the dopamine D2 receptor” (opens the source at this quote in a new tab)

“In particular, dopamine blockade is not an effective treatment for negative and cognitive symptoms” (opens the source at this quote in a new tab)

“Current pharmacological treatments operate using the same mechanism, blockade of dopamine D2 receptor, which contribute to their adverse effects.” (opens the source at this quote in a new tab)

D2 receptor occupancy thresholds for response and adverse effects

“The patients showed a wide range of D(2) occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D(2) occupancy exceeded 65%, 72%, and 78%, respectively.” (opens the source at this quote in a new tab)

“Additionally, the nigrostriatal pathway is linked to extrapyramidal motor side effects caused by D2 receptor blockers, while the tuberoinfundibular pathway is associated with the hyperprolactinemia observed with D2 receptor blocker use.” (opens the source at this quote in a new tab)

Dopamine synthesis capacity in treatment-resistant schizophrenia

“Patients who had responded to antipsychotic treatment showed significantly higher K(i)(cer) striatal values than did patients with treatment-resistant illness (effect size=1.11) and healthy volunteers (effect size=1.12).” (opens the source at this quote in a new tab)

“There were no significant differences between patients with treatment-resistant illness and healthy volunteers in the whole striatum or any of its subdivisions.” (opens the source at this quote in a new tab)

Dopamine D3 receptor

“The D3 receptor is expressed in brain regions controlling reward, emotions, and motivation. Antipsychotics bind in vitro to the D3 receptor with similar affinity as to the D2 receptor, and occupancy of D3 receptors in vivo by these compounds given acutely at clinical dosage have been demonstrated in Positron Emission Tomography (PET) studies.” (opens the source at this quote in a new tab)

“In animals, D3 receptor antagonists reverse behavioral manifestations of NMDA receptor blockade and improve cognitive performances in various paradigms.” (opens the source at this quote in a new tab)

Serotonin 5-HT7 receptor: antagonism by amisulpride

“In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties.” (opens the source at this quote in a new tab)

“We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated here could explain its antidepressant actions in vivo.” (opens the source at this quote in a new tab)

“These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.” (opens the source at this quote in a new tab)

Role of the 5-HT7 receptor in the pathophysiology of schizophrenia

No evidence found.

Glutamate and NMDA receptor hypofunction

“The administration of NMDA receptor antagonists, such as phencyclidine and ketamine, to healthy controls has been repeatedly shown to induce manifestations similar to the positive, negative and cognitive symptoms of schizophrenia” (opens the source at this quote in a new tab)

“Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder.” (opens the source at this quote in a new tab)

“Reduced NMDAR activity on inhibitory neurons leads to disinhibition of glutamate neurons increasing synaptic activity of glutamate” (opens the source at this quote in a new tab)

“In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia.” (opens the source at this quote in a new tab)

Muscarinic acetylcholine receptor pathways

“Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia.” (opens the source at this quote in a new tab)

“Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity.” (opens the source at this quote in a new tab)

“muscarinic receptor 4 positive allosteric modulators specifically inhibit dorsal striatal dopamine release, with efficacy demonstrated in some clinical trials” (opens the source at this quote in a new tab)

Structural brain changes

“Lateral ventricle enlargement by about 25%, coupled with an approximate 2% reduction in overall brain volume, primarily in the grey matter, is seen in schizophrenia.” (opens the source at this quote in a new tab)