Methylene blue adjuvant therapy of schizophrenia.

There is growing interest in the role of the nitric oxide (NO) pathway in idiopathic psychotic disorders such as schizophrenia. In this preliminary study, we examined the therapeutic efficacy of methylene blue (MB), a "downstream" inhibitor of one of NO's actions, administered orally as an adjuvant to conventional neuroleptic medications. Specifically, MB blocks NO's activation of soluble guanylyl cyclase. MB has previously been reported to have therapeutic effects in the treatment of psychosis and mania. Preclinical data also suggest that MB might possess antipsychotic potential. Participants in the current study were eight patients with schizophrenia who had incomplete responses to conventional antipsychotics (as evidenced by a Brief Psychiatric Rating Scale [BPRS] total score of 35 or more). These patients completed a 4-week open-label study with a 1 week "off", 2 week "on", and one final week "off" design. Measures of treatment efficacy were the BPRS, Schedule for the Assessment of Negative Symptoms, and Clinical Global Improvement Scale administered weekly. Final scores for each outcome measure item were based on the consensus of at least two trained raters present during each rating interview. A statistically significant, albeit modest, decrease in the severity of psychopathology was observed while the subjects were taking MB, and psychopathology significantly worsened when MB was discontinued. The results suggest a need for further study with MB or perhaps other NO-dependent guanylyl cyclase-inhibiting medications.

Effects of nifedipine, a calcium channel antagonist, on cognitive function in schizophrenic patients with tardive dyskinesia.

We examined whether nifedipine, a calcium channel antagonist, added to a stable regimen of neuroleptic medication would affect cognition in patients with chronic schizophrenia or schizoaffective disorder who had tardive dyskinesia. Fifteen patients with tardive dyskinesia were treated with nifedipine (60 mg daily) or matching placebo for 4 weeks and then were crossed over from nifedipine to placebo or from placebo to nifedipine for another 4 weeks. At the end of each 4-week phase of the study, the patients performed a rotary pursuit test of procedural learning and a dementia scale assessing general cognitive abilities. Nifedipine improved performance in the rotary pursuit test and conceptual abilities in the dementia scale compared with placebo, but only for patients who first were exposed to the tests during the placebo condition. These results provide preliminary evidence that calcium channel antagonists might enhance learning and memory in schizophrenic patients with tardive dyskinesia.

D-cycloserine adjuvant therapy to molindone in the treatment of schizophrenia.

This preliminary investigation examined the therapeutic efficacy of two doses of oral D-cycloserine (5 and 15 mg p.o. b.i.d.) administered as an adjuvant to molindone (150 mg p.o. q.d.) in the treatment of schizophrenia. D-Cycloserine is an agonist at the N-methyl-D-aspartate (NMDA) subclass of glutamate receptor complex. An NMDA agonist intervention was studied because of the schizophreniform psychosis precipitated by phencyclidine (PCP), which is a noncompetitive antagonist at the NMDA glutamate receptor. The PCP model of schizophrenia is regarded as the most comprehensive pharmacological model of this disorder. In this preliminary, placebo-controlled, double-blind, parallel-group study, the measures of treatment efficacy were the Brief Psychiatric Rating Scale, Schedule for the Assessment of Negative Symptoms, and Clinical Global Impression Scale. The final scores for each item of the outcome measures employed were based on the consensus of at least two trained raters who were present during each rating interview. In the 13 subjects evaluated, although the D-cycloserine was well tolerated, neither dose seemed to possess adjuvant therapeutic efficacy. However, since another recent report of nine patients with schizophrenia treated for 2 weeks with a slightly higher dose of D-cycloserine (50 mg/day) described significant clinical and neuropsychological improvement, further study of the adjuvant potential of slightly higher doses of D-cycloserine seems warranted. Additionally, there might be a therapeutic window for D-cycloserine dosing, as daily doses of 250 mg have been associated with symptom worsening.

An open-label study of the therapeutic efficacy of high-dose famotidine adjuvant pharmacotherapy in schizophrenia: preliminary evidence for treatment efficacy.

Histaminergic projections innervate brain areas implicated in the pathophysiology of schizophrenia. In a previous open-label study, there was the suggestion that famotidine, and H2 histamine-receptor antagonist, possessed adjuvant therapeutic properties when added to the stable neuroleptic medications regimens of 10 treatment-refractory patients. In that study, the maximal dosage of famotidine was limited to 40 mg/day, the recommended maximal dosage for the treatment of peptic ulcer disease. In this study, we examined 18 patients fulfilling DSM-III-R criteria for schizophrenia and schizoaffective disorder who had famotidine (100 mg/day) added to their stable neuroleptic medication regimen. Patients were rated on baseline, weekly thereafter, and 1 week after famotidine discontinuation, by using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Assessment of Negative Symptoms (SANS), and the Clinical Global Impression (CGI). On all of these outcome measures, statistically significant improvements suggestive of a beneficial adjunctive effect of famotidine were found. Famotidine (100 mg/day) was well tolerated by the study subjects. There was a wide range of famotidine blood levels achieved at the end of 3 weeks of famotidine adjunctive treatment, but these blood levels did not correlate with BPRS or SANS score changes. However, the patients with the greatest improvement in BPRS scores (and without concomitant deterioration in SAND scores) had some of the higher famotidine levels found in the study. Double-blind studies further assessing the potential adjunctive benefit of famotidine in the treatment of schizophrenia are indicated.

Smooth pursuit eye movements in the evaluation of famotidine adjunctive therapy of schizophrenia: a preliminary report.

Smooth pursuit eye movements (SPEM) are often abnormal in schizophrenic patients and have been proposed as a trait marker of the disorder. We explored the use of SPEM as an outcome measure in an open-label clinical trial of famotidine, an H-2 antagonist, in patients with schizophrenia; famotidine has been proposed as an adjunctive medication, particularly for negative symptoms. Prior studies using SPEM as an outcome measure have not found a significant effect with "typical" neuroleptic medication, and one study found greater SPEM dysfunction with clozapine treatment. In this study, 19 schizophrenic subjects were stabilized for at least 1 week on conventional neuroleptic medications and then administered oral famotidine, 100 mg daily, for an additional 3 weeks. SPEM and clinical measures were assessed. Whereas Brief Psychiatric Rating Scale (BPRS) and Schedule for Assessment of Negative Symptoms (SANS) scores decreased significantly with famotidine administration, there was no significant change in SPEM performance over the course of the study. Two subjects (11%) doubled their signal/noise ratio and maintained this increase after famotidine discontinuation, whereas three subjects (17%) approximately halved this ratio and returned to baseline after famotidine discontinuation. SPEM changes were not found to correlate significantly with changes in BPRS or SANS scores. These findings suggest that SPEM dysfunction reflects a "trait" rather than clinical "state" in schizophrenia, and changes in SPEM performance might not be expected always to parallel changes in clinical ratings.

Famotidine adjunctive pharmacotherapy of schizophrenia: a case report.

Recent reports suggest some utility for famotidine, a histamine type 2 (H2) antagonist, in the treatment of schizophrenia. The current report describes a treatment-resistant patient with chronic undifferentiated schizophrenia whose most dramatic symptomatic improvements were temporarily related to the open-label addition of famotidine (40-100 mg/day) to conventional neuroleptic treatment (molindone 150-200 mg/day) over the course of approximately 10 months. During one 2-week interval, his symptoms were controlled with famotidine (40 mg/day) alone. The case suggests that some adjuvant efficacy exists for famotidine in at least some patients with schizophrenia. Placebo-controlled trials are needed to more fully evaluate the utility of famotidine in the treatment of schizophrenia.

The relationship between cocaine-induced paranoia and compulsive foraging: a preliminary report.

Two prominent behavioral syndromes associated with chronic cocaine use that have been described in the literature are cocaine-induced paranoia (CIP) and cocaine-induced compulsive foraging (CICF) for cocaine. To help to clarify the relationship between the two cocaine-induced syndromes, the concordance and sequence of onset of the two cocaine-induced behaviors over the course of the patients' lifetime use of cocaine and during the course of a binge was examined in 62 crack cocaine-dependent men. Thirty-four (54.8%) reported experiencing both CIP and CICF. In 18 (29%) of the patients, only one of these cocaine-induced behavioral syndromes was reported. Ten (16.1%) of the subjects reported neither CIP nor CICF. Patterns of cocaine or other substance use and degrees of tolerance to cocaine were not significantly different between the groups endorsing different patterns of cocaine-induced behaviors. CIP typically preceded the onset of CICF both over the course of the patients' lifetime use of cocaine and over the course of a binge. The study results suggest varying thresholds for the expression of these behaviors in chronic cocaine-abusing individuals.

Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence.

Recent preclinical studies suggest utility for voltage-sensitive calcium channel blockers (VSCCBs) in the treatment of cocaine addiction. The following double-blind placebo-controlled study examined the role of the VSCCB nimodipine in attenuating cocaine craving in 66 recently abstinent cocaine-dependent patients on an inpatient substance abuse treatment unit utilizing an intensive 12-step milieu-oriented psychosocial therapy. While the medication was well tolerated, the dose of nimodipine used in this study (90 mg q.d.) was not superior to placebo in reducing background or cue-induced cocaine craving over the 3 weeks of the study. There was the suggestion that nimodipine might attenuate the severity of some cocaine-induced brain deficits, as detected by evaluation of smooth pursuit eye movement function. A rationale for evaluating higher doses of nimodipine for the treatment of cocaine addiction is presented. As nimodipine might have anticraving and mood-stabilizing properties and cardio- and neuroprotective properties in the face of cocaine intoxication and might possibly even reverse some cocaine-induced brain deficits, further investigation of the role of nimodipine (and other VSCCBs) in cocaine addiction appears an attractive avenue of future medication development.

Phenomenologic comparison of the idiopathic psychosis of schizophrenia and drug-induced cocaine and phencyclidine psychoses: a retrospective study.

Both stimulant-induced and phencyclidine (PCP)-induced psychoses have been proposed as models of the idiopathic psychosis of schizopherenia. In this two-part study, the phenomenology of the psychosis associated with a period of cocaine intoxication was evaluated retrospectively in 34 male crack cocaine-dependent patients without concomitant psychiatric disorder and then was compared with the psychosis of 16 actively psychotic schizophrenic men (without a history of drug or alcohol abuse in the past year). Certain First Rank Schneiderian Symptoms (FRSS) were more commonly observed in the schizophrenic patients (e.g., thought broadcasting, thought withdrawal) than in the cocaine addicts. In the second part of this study, we retrospectively examined the cocaine and PCP experiences of an additional 22 cocaine addicts who had a past history of separate periods of cocaine and PCP use. Overall, the frequency of FRSS recalled during periods of cocaine and PCP intoxication was similar. However, the psychosis related to cocaine intoxication was more associated with an intense suspiciousness and paranoia related to a fear of being discovered or harmed while using cocaine. PCP-induced psychosis was less associated with suspiciousness and more associated with delusions of physical power, altered sensations, and unusual experiences [e.g., out of body experiences, experiencing religious figures or events directly (e.g., being with Noah at the time of the Arc)]. As elements of both cocaine and PCP psychosis can be found in schizophrenia, a model integrating the mechanisms of several psychotogenic drugs may be more informative. Such an integrative model might better capture the heterogeneity of psychotic symptoms that can be seen in schizophrenia. Furthermore, different pharmacologic interventions (e.g., "anti-stimulant" versus "anti-PCP") might address different aspects of the positive symptom picture in schizophrenia.

Famotidine adjunctive pharmacotherapy for schizophrenia: preliminary data.

The usefulness of the histamine-2 (H2) antagonist famotidine as an adjunct to conventional antipsychotic treatments of idiopathic psychotic disorders (i.e., schizophrenia and schizoaffective disorder) was investigated in an open-label study. After stabilization for at least 1 week with their conventional antipsychotic medication regimen, 10 patients completed a 3-week study period in which famotidine (20 mg twice a day) was added as an adjunctive medication. The 10 patients were all somewhat treatment refractory and had spent a mean of 230 days of the previous 2 years in the hospital. Total Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression scores were significantly lower during the 3 weeks with famotidine compared with the week before and after its administration. Nevertheless, review of the scores revealed that the magnitude of the changes were small. Negative symptoms as measured by the Schedule for the Assessment of Negative Symptoms (SANS) were not significantly different during famotidine treatment, although there was the tendency for total SANS scores to be lower during famotidine treatment. When BPRS items were divided into specific versus nonspecific symptom subscales, only the specific-item subscales had significantly improved during famotidine treatment. The results of this study suggest that famotidine might prove a useful adjunctive agent in certain patients with schizophrenia. Future studies using a double-blind placebo-controlled design and higher doses are needed. Additionally, other H2 receptor antagonists with better penetration across the blood-brain barrier should be pursued.

Transient compulsive foraging behavior associated with crack cocaine use.

Compulsive foraging behavior associated with use of crack cocaine involves compulsively searching the environment for possibly misplaced pieces of crack. Of 41 crack cocaine addicts evaluated, 33 (80.5%) reported at least some compulsive foraging associated with use of crack; 21 (51.2%) reported such behavior as always associated with crack use. The mean length of time spent in compulsive foraging was 90 minutes. Cocaine-induced foraging may represent a drug-induced model of a type of compulsive behavior.