Table 7.
Clozapine
| Source (1st author, year) | Study design |
No. of participants (males) | Population | Drug, dosage, and route of administration | Ketamine dosage, route of administration (and duration) | Clinical outcome | Possible mechanism | Remarks |
|---|---|---|---|---|---|---|---|---|
| Lipschitz et al. (1997) | Randomized, double-blind, placebo-controlled, crossover trial | 7 (4) | Healthy individuals | Clozapine, 50 mg or placebo pretreatment | Ketamine IV, 0.5mg/kg over 60 minutes | Clozapine pretreatment did not reduce the BPRS 5 key positive or 3 key negative scores, but there was a trend for a reduction in perceptual alteration as measured by the CADSS (P = .09). | No hypothesis described. | Conference abstract. |
| Malhotra et al. (1997) | Randomized, double-blind, placebo-controlled, crossover trial | 10 (6) | Patients meeting DSM-III-R criteria for schizophrenia or schizoaffective disorder (2 patients entered the study APD free) | Clozapine, [mean dose = 430 (±48.3) mg/d for 51.8 (±17.7) d] followed by ketamine/placebo infusion after drug-free period (mean drug-free period = 20.5 [±9.0] d for 8 patients) | Ketamine IV, bolus of 0.12 mg/kg followed by infusion of 0.65 mg/kg of ketamine (maximum dose of 58 mg) vs placebo (saline) bolus followed by infusion of total dose of 0.77 mg/kg over 1 h | Clozapine treatment significantly blunted the ketamine-induced BPRS positive symptoms (P = .05), but not negative symptoms, paranoia, or anxiety–depression. Clozapine specifically blunted ketamine-induced conceptual disorganization. (P = .05) |
It is tempting to speculate that these patients’ resistant psychotic symptoms may be related to NMDAR dysfunction and are therefore more amenable to clozapine, rather than typical, antipsychotic therapy. | |
| Vollenweider et al. (2012) | Randomized, double-blind, placebo-controlled trial | 20 (20) | Healthy individuals | Clozapine, 30 mg oral or placebo | S-ketamine, 0.006mg/kg/min | S-ketamine produced positive symptoms and cognitive disturbances that were differentially associated with increased brain activity in an extended neural network including prefrontal regions, anterior cingultate, putamen, thalamus and temporomedial and insular cortex (as measured with H125O-PET). Reduced activity was found in parietal and occipital cortex regions, and cerebellum (P < .00001). Pretreatment with clozapine moderately reduced some S-ketamine-induced symptoms and partially reversed alterations in anterior cingulate, insula, temporomedial cortex, and cerebellum. | These findings suggest disruption of NMDAR but not of 5HT2AR- mediated neurotransmission within fronto-temporal-striato-thalamic pathways mainly contributes to ketamine-induced psychotic symptoms. | Conference abstract. |
Abbreviations: 5-HT2AR, 5-hydroxytryptamine 2A receptor; APD free, Antipsychotic drug free; BPRS, Brief Psychiatric Rating Scale; CADSS, Clinician-Administered Dissociative States Scale; DSM, Diagnostic and Statistical Manual; H215O-PET, H215O-positron emission tomography; IV, Intravenous; NMDAR, N-methyl-D-aspartate receptor.