12 April 2012. A meta-analysis of dopamine imaging studies in schizophrenia reports elevated presynaptic dopamine function. By contrast, no change in dopamine transporter activity and a small, antipsychotic-dependent increase in dopamine 2/3 (D2/3) receptor availability were found. The study, published online April 2 in the Archives of General Psychiatry, suggests that future antipsychotic drugs might target the presynaptic regulation of dopamine synthesis and release, rather than block D2 receptors, as most current drugs do.
The dopamine hypothesis is schizophrenia’s most venerable (see SRF Hypothesis), and was initially based on the observation that antipsychotic drugs are dopamine antagonists. The hypothesis posits that hyperactive dopamine signaling in subcortical brain regions is responsible for the positive symptoms of the illness, and has been bolstered by findings of increased striatal D2/3 receptor density and dopamine in postmortem tissue (Mackay et al., 1982), and elevations in cerebrospinal fluid (CSF) dopamine levels (Widerlöv et al., 1988). Positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) studies have enabled the in-vivo measurement of dopamine function in the illness, and the large number of these studies affords the opportunity for meta-analysis.
Probing dopamine function
Led by Oliver Howes of King’s College London, U.K., researchers in the current study combed databases for PET and SPECT dopaminergic imaging studies published between 1960 and 2011. The researchers limited their meta-analysis to studies of striatal dopamine function, since this region can be reliably imaged and is where dopamine dysfunction in schizophrenia has been linked to illness onset, symptom severity, and treatment response (Laruelle et al., 1999). Howes and colleagues analyzed different aspects of dopaminergic function in schizophrenia using three separate meta-analyses measuring: 1) presynaptic function (including dopamine synthesis capacity, dopamine release, and synaptic dopamine levels); 2) dopamine transporter availability; and 3) D2/3 receptor availability.
A total of 17 studies examining 231 patients and 251 control subjects were included in the meta-analysis of presynaptic dopamine function, which found a significant elevation with a large effect size in schizophrenia subjects. Importantly, this effect does not seem to be mediated by antipsychotics, as a similar result was obtained after exclusion of medicated subjects. This elevation is likely due to a functional change in dopamine synthesis and release, rather than a change in axon terminal or neuron number, since there is no evidence that dopamine terminal density and neuron number are altered in schizophrenia (Taylor et al., 2000; Bogerts et al., 1983).
By contrast, no significant difference was observed between the 152 schizophrenia subjects and 132 controls used in a second meta-analysis of dopamine transporter availability. This finding persisted when antipsychotic-treated subjects were excluded. Unlike the analysis of presynaptic dopaminergic functioning, moderate to large heterogeneity between studies was observed, likely due to differences in the radiotracers utilized across studies.
The largest sample size (337 patients and 324 controls) was available to examine D2/3 receptor availability, and a significant elevation was observed. However, the effect size was much smaller than for presynaptic dopamine function, and appeared to be due to antipsychotic treatment, as no difference was seen between control antipsychotic-free schizophrenia subjects. Moreover, moderate to large heterogeneity between studies was present, and in over half of the iterations of a leave-one-out analysis, there was no difference between patients and controls, indicating that the difference was not robust.
Overall, the results of this in-vivo meta-analysis support the dopamine hypothesis of schizophrenia, and point to a specific abnormality in presynaptic dopamine function. Interestingly, this effect appears to be specific to schizophrenia, as alterations are not observed in non-psychotic affective and anxiety disorders (Howes et al., 2007). Howes and colleagues also examined subregions of the striatum, finding that presynaptic function was elevated in the putamen but not the caudate. Neither dopamine transporter nor D2/3 receptor availability was altered in either subregion alone. More work will be needed to address whether the presynaptic alterations are also present in other brain regions besides the striatum.
Implications for treatment
Since all current antipsychotics block D2 receptors, the results of the present study suggest that these treatments are acting downstream of the major dopamine abnormality, and thus that new drugs should target presynaptic dopamine synthesis and release. Interestingly, reserpine and α-methylparatyrosine, drugs that reduce presynaptic dopamine levels, can ameliorate psychotic symptoms (Hollister et al., 1955; Abi-Dargham et al., 2000), suggesting that this mechanism may be useful in schizophrenia.
However, as noted by the authors, several challenges with this treatment strategy remain. For example, given that part of the synthetic pathway for dopamine overlaps with that of norepinephrine, altering dopamine synthesis may create adverse side effects from abnormal norepinephrine signaling. Moreover, regional specificity of the drug target may be necessary to avoid worsening the negative and cognitive symptoms that are thought to result, in part, from alterations in frontal dopamine function through D1 receptors (see SRF related news story).—Allison A. Curley.
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S. The Nature of Dopamine Dysfunction in Schizophrenia and What This Means for Treatment: Meta-analysis of Imaging Studies. Arch Gen Psychiatry. 2012 Apr 2. Abstract