Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis. Schizophrenia Research. Your Privacy Rights. To change or withdraw your consent choices for VerywellMind. At any time, you can update your settings through the "EU Privacy" link at the bottom of any page.
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We are therefore confident that our patient group is representative of first episode psychosis patients. We have found that subjects taking typicals have significantly larger basal ganglia volume than drug-free subjects. This finding is in accordance with a large number of studies that have reported an increase in size and blood flow of these subcortical structures in patients taking typical antipsychotics Chakos et al, ; DeLisi et al, ; Gur et al, b ; Miller et al, This volume increase can be reverted by suspension of the drug or switching to clozapine, an atypical antipsychotic Chakos et al, ; Keshavan et al, It remains unclear what mechanisms underlie the basal ganglia increase.
Structural MRI studies may highlight a change in brain volume, but any explanation of the pathophysiological mechanisms underlying these volume changes can only be speculative. In fact, what is detected as a change in volume could be for example the consequence of changes in tissue perfusion, fat, or water content Weinberger and McClure, This is particularly important when using voxel-based methods of image analysis, and when studying the effect of pharmacological treatment, as different duration of exposure may induce different changes.
We believe that these issues need to be taken into account when interpreting our findings. Still, some mechanisms have tentatively been put forward in the literature to try and explain the increase in basal ganglia volume in association with typical antipsychotics use.
For example, typical antipsychotics have an antagonistic effect on D2 receptors that could explain changes in structures rich in these receptors, such as the basal ganglia. The chronic block of D2 may lead to a proliferation of D2 receptors, and the resulting increased metabolism and blood flow may lead to an increase in size of the ganglia Miller et al, a.
It is also possible that this D2 proliferation induces changes in the dendritic tree that then lead to an increase in volume Miller et al, a. Indeed, atypical drugs also bind to D2, and the lack of differences in basal ganglia volume between subjects on typicals and subjects on atypicals suggest that basal ganglia may also be enlarged in association with atypicals use, although the effect may be less marked. Interestingly, subjects taking atypical antipsychotics showed a significant enlargement of another subcortical area, the thalamus, when compared with drug-free subjects.
This finding is similar to a previous report, using a region of interest technique, of an enlargement of thalamic volume associated with use of atypical antipsychotics Gur et al, b ; Miller et al, It also supports the description of thalamic enlargement in association with symptoms improvement following treatment with atypical antipsychotics Strungas et al, The thalamus is part of brain circuits that modulate perception, emotion, and thinking Crosson and Hughes, , and its volume seems to be reduced in patients with schizophrenia Andreasen et al, Owing to its role in integrating brain functions, the thalamus could be involved in mediating the clinical effects of antipsychotic drugs, and it has been indicated as one of the sites of action of both typical and atypical antipsychotic drugs Cohen et al, , Again, the fact that the thalamus volumes were not different between typicals and atypicals groups would support that both classes of drugs may affect this region, but to a different extent.
For example, differences between the effects of typical and atypical drugs have been described in thalamic GABA-mediated neural transmission Sakai et al, , monoamine metabolism Kikumoto et al, , in thalamic cerebral blood volume Cohen and Yurgelun-Todd, , and in the expression of the protein Fos, which is a marker of cellular activation Cohen et al, We found that typical antipsychotics are associated with a reduction of volume of frontal areas paracentral lobule, anterior cingulate, superior and medial frontal gyri , temporal-insular areas, and precuneus.
A volume reduction of frontal lobe has been described by Gur et al a in a region of interest study, in correlation with higher typical antipsychotic dose.
To our knowledge, ours is the first report to indicate regional reductions in the frontal lobe in first episode psychotic patients taking typical antipsychotics in comparison with drug-free subjects.
These cortical changes are difficult to interpret and again they might be interpreted as reflecting differences in tissue hydration or metabolism. In fact, use of haloperidol a typical antipsychotic has been associated with decreased frontal cerebral blood flow possibly bringing a reduction in size in comparison to risperidone Bartlett et al, ; Miller et al, Different effects of typical and atypical antipsychotics on N -acetylaspartate NAA signal a measure of neuronal viability in frontal areas has been reported by spectroscopy studies, with typicals being associated with NAA signal reduction in comparison to atypicals Ende et al, ; Heimberg et al, An increase in functional activation of the frontal lobe following substitution of a typical with an atypical antipsychotic has also been reported using fMRI Honey et al, Once again, the lack of difference between subjects on typicals and subject on atypicals may be interpreted as showing some, albeit smaller, effects of atypicals on these structures.
In our study, a reduction in temporal areas seems to be specifically associated with treatment with typical antipsychotic, as it is present in comparison with both the drug-free and the atypicals group. The temporal lobe has been identified as a site rich in extrastriatal cortical D2 receptors, which may have pathophysiological significance for schizophrenia and therefore be possible sites of action for antipsychotics Okubo et al, Our finding of a grey matter deficit in the insula may be the structural manifestation of insular hypometabolism in subjects on treatment or previously treated with haloperidol Desco et al, ; Kim et al, Also, insular activity has been reported as improved following switch from haloperidol to risperidone Molina et al, However, other studies on the effect of haloperidol did not show any selective decrease of insular activity Bartlett et al, ; Holcomb et al, Finally, we observed a reduction of the cortex of the precuneus, again predominantly associated with typicals.
This is an area involved with attention, imagery, and memory processes, and it has been reported as reduced in volume Shapleske et al, and altered in function Kumari et al, ; Shapleske et al, in schizophrenia. The precuneus may be involved in the psychopathology of schizophrenia, and as such could be a potential site of action for antipsychotics.
On the basis of our findings, we would like to suggest that, even after short-term treatment, both typical and atypical antipsychotics affect brain structure. Although these two classes of drugs may share some common effects on brain structure, there seem to be important quantitative differences in the extent of these effects, which may explain some of the differences in their clinical profile and side effects.
The hypotheses proposed in this paper will need to be tested in future ad hoc studies using a randomized design. Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging.
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The effect of acute administration of risperidone on local cerebral glucose utilization in the rat. Eur J Pharmacol : — Structural gray matter differences between first-episode schizophrenics and normal controls using voxel-based morphometry. Background: Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms EPS.
They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs.
Method: This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin 5-HT receptors, both in the test tube and in live patients. Results: Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine.
The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine.
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