Subanesthetic Doses of Ketamine Stimulate Psychosis in Schizophrenia

Abstract

We administered ketamine to schizophrenic individuals in a double-blind, placebo-controlled design using a range of subanesthetic doses (0.1, 0.3, and 0.5 mg/kg) to evaluate the nature, dose characteristics, time course, and neuroleptic modulation of N-methyl-D-aspartate (NMDA) antagonist action on mental status in schizophrenia. Ketamine induced a dose-related, short (< 30 minutes) worsening in mental status in the haloperidol-treated condition, reflected by a significant increase in BPRS total score for the 0.3 mg/kg (p = .005) and 0.5 mg/kg (p = .01) challenges. Positive symptoms (hallucinations, delusions, thought disorder), not negative symptoms accounted for these changes. These ketamine-induced psychotic symptoms were strikingly reminiscent of the subject's symptoms during active episodes of their illness. Results from six patients who were retested in the same design after being neuroleptic-free for 4 weeks failed to indicate that haloperidol blocks ketamine-induced psychosis. Several subjects evidenced delayed or prolonged (8-24 hours) psychotomimetic effects such as worsening of psychosis with visual hallucinations. These data suggest that antagonism of NMDA-sensitive glutamatergic transmission in brain exacerbates symptoms of schizophrenia.

The Neuropsychopharmacology of Phencyclidine From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia

“…Several groups have reported moderate effects after administration of typical antipsychotic drugs to PCP-abusing individuals with psychotic symptoms (Castellani et al 1982;Giannini et al 1984); whereas, other studies have failed to find such results (Rainey and Crowder 1975;Allen and Young 1978;Bowers et al 1990). Recently, several groups have examined neuroleptic effects on ketamine-precipitated psychotic episodes in schizophrenic subjects; Lahti et al (1994) reported that haloperidol was ineffective at attenuating NMDA antagonist-induced symptoms; whereas, Malhotra et al (1997b) demonstrated that clozapine significantly blunted ketamine-precipitated psychoses. In view of the limited, but positive, data, it is clear that further studies of the response of PCP psychosis to clozapine and other atypical antipsychotic drugs are warranted.…”

“…In addition, NMDA receptor binding in the hippocampus is transiently decreased (at 3 h) and subsequently increased (for approximately 2 days) after single-dose PCP administration (Gao and Tamminga 1996). Interestingly, the transient metabolic and glutamatergic effects of PCP are most closely temporally associated with symptom production in ketamine-treated schizophrenic subjects (Lahti et al 1994) and are consistent with increased limbic blood flow in patients (Lahti et al 1995). Of course, it is the early effects that are most closely linked with the ketamine-induced psychosis and cognitive impairments, because these effects are largely short-lived (on the order of hours; Krystal et al 1994).…”

“…Psychotomimetic indoleamines, such as lysergic acid diethylamide, can induce profound sensory hallucinations without causing any apparent deficit state in normal subjects (Geyer and Markou 1994) and without precipitating symptomatology in schizophrenic patients (Cohen et al 1962). In contrast, the noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) ր glutamate receptor, including phencyclidine (PCP) and ketamine, seem to be capable of inducing both positive and negative symptoms of schizophrenia, including cognitive dysfunction in normal humans (Snyder 1980; Javitt and Zukin 1991;Tamminga 1998); these drugs also profoundly exacerbate both positive and negative symptoms in schizophrenic patients (Itil et al 1967;Lahti et al 1994;Malhotra et al 1997a).Because of the more comprehensive psychopathology induced by PCP, many researchers have studied the effects of NMDA receptor antagonists in humans and animals to gain insights into the neurobiology of schizophrenia. In this review, the validity of NMDA receptor antagonist-induced models of schizophrenia in humans and animals are considered, and the applicability of acute versus chronic administration of PCP as a more precise model is assessed.…”

“…Nevertheless, scientists have recently utilized a PCP congener, ketamine, to produce a model of psychosis in humans. This drug, which (like PCP) noncompetitively blocks NMDA receptors, also simulates schizophrenic psychopathology in normal humans (Krystal et al 1994;Malhotra et al 1996) and exacerbates symptoms in schizophrenic patients (Lahti et al 1994;Malhotra et al 1997a). Although it seems that ketamine can induce many of the effects of PCP in humans, it should be noted that ketamine is far less potent for inducing psychotomimetic reactions, especially after chronic use (Rainey and Crowder 1974).…”

Glycine Transport Inhibitors for the Treatment of Schizophrenia

“…Moreover, in a double-blind, placebo-controlled study, Lahti et al . [18] reported that ketamine induced a brief (less than 30 minutes), dose-related worsening of positive symptoms in schizophrenic patients maintained on haloperidol. In contrast, Zarate et al .…”