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Arch Gen Psychiatry. 2012 Apr 2;
Authors: Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S
Abstract
CONTEXT: Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia.
OBJECTIVE: To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies.
DATA SOURCES: The MEDLINE, EMBASE, and PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.
STUDY SELECTION: A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.
DATA EXTRACTION: Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables.
DATA SYNTHESIS: There was a highly significant elevation (P < .001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d = 0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d = 0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.
CONCLUSIONS: The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
PMID: 22474070
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QUOTES FROM THE ARTICLE:
The elevation in presynaptic dopaminergic function could be due to … increased dopamine synthesis capacity and dopamine release.
This view is supported by findings of elevated dopamine synthesis capacity in drug-naive individuals in the prodrome to schizophrenia and of a further increase associated with the onset of the psychotic disorder.
Interestingly, patients who respond less well to antipsychotic drugs have been found to show lower synaptic dopamine levels, and findings indicate that treatment-resistant patients show normal dopamine synthesis capacity.
For too long the Dopamine-Hypothesis of Schizophrenia has been the focus of antipsychotic medication development. This is supported by the fact that currently “effective” antipsychotics work by primarily blocking dopamine receptors. Even new generation antipsychotics which involve blockade of Serotonin 2A receptors focus on how this changes dopamine signaling.
However, the response in the vast majority of patients with schizophrenia to antipsychotics – new and old – is very poor. At best, there is a 20% reduction in the severity of symptoms in the average patient if you catch them early in the illness. As the illness progresses, there is much less of a response to treatment. The vast majority of patients are treatment resistant since a maximum 20% reduction in symptom severity is totally inadequate.
A 20% reduction in severity of symptoms means that patient is STILL SEVERELY ILL. In my book, this reflects a failure of the Dopamine-Hypothesis. Yes, it helps some. And if you are lucky, it may help a lot. But for most patients, it is inadequate to explain their illness.
Despite 50 years of drug research, we still do not have adequate single medication treatments for schizophrenia. I seriously doubt focusing on a single signaling system will be successful. From my point of view, the pathophysiology is more complex than dopamine dysfunction. A multi-modal, multi-systemic evaluation and treatment is necessary to achieve greater improvement in the mental health of our patients.