Non-stimulant Psychosis

In purine theory of bipolar, excess guanine-derivatives activate the D2/D3 receptor, presenting as psychosis.

G-derivatives are converted to other purines via GMP reductase (producing IMP) or guanase (producing xanthine).

Excess xanthine-similar molecules would be expected to inhibit guanase as part of a process called product inhibition, resulting in build-up of guanine and (secondarily), other G-derivatives, presenting as psychosis.

Steroid psychosis is common and well recognized PMID 31656440: the shared chemical structure with other schizophrenia-similar medication-induced psychoses is not commonly appreciated. Greater similarity to xanthine correlates with greater frequency of insomnia (adenosine receptor blockade) as a concurrent side-effect. Prednisone, prednisolone, dexamethasone, etc. are differentiated from physiologic steroid hormones by increased (compare to corisol, aldosterone, testosterone), but not full (estradiol), aromaticity in the first six-member ring. IMG

I recently attended a case of apparent metronidazole- induced psychosis: family & patient reported first ever auditory hallucinations within 48 hours of starting metronidazole, followed by complete resolution within 48 hours of metronidazole discontinuation. Although home medication included an off-label antipsychotic, no changes were made to home regimen during the episode. There are several case reports of metronidazole-induced psychosis in the literature: e.g. PMID 24388629. 

Most applications will allow for substitution with tinidazole, which is not xanthine-similar (although S is similar to O, this S has two O atoms pulling electron density away) and is not associated with psychosis, despite being in use since 1978. Secnidazole is a single-dose alternative: methyl group may or may not prevent induced psychosis, but single dose may limit consequences.

Efavirenz is an anti-retroviral that has been associated with psychosis: PMID 32920783 and is a xanthine-analogue.

Combined with a guanine-analogue metformin and an IMP/inosine-analogue fluoxetine, PNP inhibition may be sufficient to act as a chemotherapy 36588385

Indomethacin has a xanthine-similar chemical structure and is associated with psychosis: PMID 3559156. The clinical use of indomethacin is mostly for gout: excess production of uric acid.

Xanthine-similar product inhibition may be a shared mechanism between the anti-gout and pro-psychotic effects of indomethacin.

Reports of topiramate PMID 10452922 or levetiracetam PMID 32920785 psychosis often cite co-administration of valproate e.g. PMID 12875956. One lacosamide psychosis case report cites concurrent vaproate and felbamate: PMID 26366962 another cites concurrent phenytoin: PMID 23334072. These may share guanase product inhibition as mechanism with cumulative effects leading to psychosis.

The psychosis associated with xanthine-similar levetiracetam is described as "schizophrenia-like": PMID 32920785, distinct from the manic-similar symptoms of guanosine analogues: e.g. PMID 17651180.

Note that inadequate guanase activity would be expected to cause schizophrenia-like psychosis without any additional substance, and without a compensatory decreased need for sleep typical of manic psychosis.

Inadequate GMP reductase activity would also be expected to cause psychotic symptoms, due to excess guanine, but would also reduce IMP production, the precursor to adenosine. This would be expected to present clinically as schizophrenia-type psychosis with intermittent manic or depressive symptomatology: consistent with schizoaffective disorder. IMG

Porphobilinogen is identified as the psychosis-causing compound in porphyria. Note the xanthine-similar structure.

I have attended cases of psychosis following subarachnoid hemorrhage that responded well to  (xanthine reducing?) chlorpromazine. IMG

Z-drugs cause hallucinations and also dissociative symptoms.

Suvorexant was intended to herald a new modality for treating insomnia, but patients report intolerable dissociative symptoms.

Parapsychosis is a syndrome which combines both dissociations and psychotic elements and may guide treatment of BPD, PTSD, and certain cases of schizophrenic psychosis.