The neurobiology of subjective tolerability to antipsychotic medications in Schizophrenia - is it also relevant to the genesis of comorbid addiction?
Bibliographic record
Abstract
One of the frequent but unrecognized side-effects of antipsychotic medications is the subtle alterations in subjective tolerability to these medications, including feelings of anxiety, distress and lack of pleasure, and which often lead to dislike and aversion to medications, with known serious clinical consequences. Yet, those very patients take to frequent abuse of illicit drugs. One popular and frequently accepted explanation for such a high association has been the self-medication hypothesis, which proved inadequate to explain all aspects of this phenomenon. Until recently, the neurobiological basis for alteration in subjective tolerability and the negative dysphoric responses to antipsychotic medications has not been clear, though it was generally understood that somehow it relates to dopamine, since all antipsychotic medications have antidopaminergic properties. In a series of studies, including our recent experimental dopamine depletion SPECT study, we demonstrated for the first time the relationship between negative subjective tolerability and dopamine-binding ratio in the nigro-striatal area. Our findings explain to a large part why only some patients, not all receiving antipsychotic medications, experience dysphoric responses, since only those who have low baseline dopamine function are more susceptible to further dopamine-blocking effects. Meanwhile, emerging evidence from research in the addiction field has implicated dopamine in the same neural circuitry in motivational and reinforcement behaviour, which is central to initiation and continuation of dependency states. It's plausible, then, that what links vulnerability to addictions and negative subjective tolerability lies in a dysregulated dopamine signaling in the nucleus acumbens, resulting from frontal cortical and hippocampal dysfunction. Such a proposal, though many aspects of it have not yet been worked out clearly, and if confirmed represents a new rethinking of the concept of schizophrenia and its varied domains and manifestations and also has clinical implications in management.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".