Where exactly is the Dopamine dysfunction in schizophrenia? Archives Gen Psych. Aug 2012

14.09.2012

The dopamine hypothesis of schizophrenia is more than 30 yrs old with support from indirect evidence. PET  and SPECT imaging have been used to investigate dopaminergic parameters in schizophrenia.

D2/3 receptors and their presynaptic function, including dopamine synthesis capacity, dopamine release, and transporters are widely studied.

This review focused on the striatum as 1. it has the highest density of dopamine projections in the brain 2. dopaminergic dysfunction in the striatum can be reliably imaged 3. it is  linked to the severity of symptoms, response to treatment, and the onset of the disorder.

Researchers  grouped the findings  of  studies on presynaptic dopaminergic function  in to  three : namely: 1.dopamine synthesis capacity, dopamine release, and synaptic dopamine levels 2. dopamine transporter availability 3. dopamine receptor availability.

A total of 17 studies described in 15 publications  met inclusion criteria with 231 patients and 251 controls.There is evidence for possible publication bias and low to moderate heterogeneity between studies.

Results: There was no evidence of a significant difference between patients with schizophrenia and controls  on  dopamine transporter availability.The pre- synaptic dopaminergic function is altered in schizophrenia, with a large effect size (d = 0.79),  and a small elevation in D2/3 receptor availability, although the latter finding was not consistent.

There was low to moderate heterogeneity in the studies of presynaptic dopaminergic function, which suggests that there is consistency across studies. However, there was moderate to large heterogeneity in the studies of dopamine transporter and D2/3 receptor availability

Mechanism:  the presynaptic studies thus suggest that there is increased dopaminergic activity reflected in increased dopamine synthesis capacity and increased dopamine release. This is consistent with evidence of increased turnover of striatal dopamine in schizophrenia.

The authors argue that that the major dopaminergic abnormality in schizophrenia is a presynaptic one, affecting dopamine synthesis capacity and release, and that, in contrast, the overall effect on D2/3 receptor availability is small.

They do not address the issue of what drives the presynaptic striatal alterations. One candidate is decreased D1-mediated dopaminergic neurotransmission in the frontal cortex (see Fusar-Poli et al  and Meyer- Lindenberg et al  and review by Heinz et al). Another candidate, supported by preclinical models and some human findings is glutamatergic dysfunction.

Future? : Future treatments could be targeting presynaptic control of dopamine synthesis and release. (remember  reserpine, and more recently-methylparatyrosine is associated with a rapid and profound reduction in psychotic symptoms). Because dopamine and norepinephrine share part of the same synthetic pathway, treatments that interfere with dopamine also risk affecting norepinephrine synthesis, leading to undesirable adverse effects. We should also need to have medications with regional selectivity  to avoid altering dopamine neurotransmission in the frontal cortex and potentially worsening negative symptoms and cognitive impairments.

In conclusion, there is consistent evidence of presynaptic dysfunction in schizophrenia with a large effect size but no evidence of a compensatory increase in dopamine transporter availability to buffer the system. D2/3 receptor upregulation is small and not detected in antipsychotic-naive patients. These findings suggest that drug development should target the presynaptic regulation of dopamine synthesis and release.

The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies.

Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. Arch Gen Psychiatry. RCH GEN PSYCHIATRY/VOL 69 (NO. 8), AUG 2012

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