[Schizophrenia and addiction: An evaluation of the self-medication hypothesis]. / Schizophrénie et toxicomanie: une relecture du concept d'automédication.

Despite the fact that most researchers acknowledge the high prevalence of comorbid substance abuse among schizophrenic patients, there is no common agreement regarding the etiology of this serious public health problem. At the center of this debate though, Khantzian's self-medication hypothesis has captured most of the attention. In the present literature review, the authors evaluate this hypothesis in the light of our current knowledge. Formulated in a clinical context, in reaction to the psychoanalytic interpretation of addiction as a pleasure seeking pathology, Khantzian's hypothesis holds that schizophrenic patients use psychoactive substances to relieve their symptoms. Properly understood, this conjecture presupposes that, with the relief of certain target symptoms, substance use would no more be a necessity. But in reality, the use of psychoactive substances usually leads to a general deterioration of the patients' condition. Pharmacodependent schizophrenic patients relapse more often, they are more frequently hospitalized, they show more violent behaviors, and they are more frequently homeless. In particular, the positive symptoms of these patients are generally exacerbated by the psychoactive drugs--with the possible exception of opiates. This observation is in lign with the fact that psychostimulants (cocaine, amphetamines), anesthesic dissociatives (PCP, ketamine) as well as hallucinogens (cannabis, LSD) are all known to exert psychotomimetic effects. As for negative symptoms, the reality is more complex. Preliminary results certainly suggest that stimulants (minor or major) relieve these symptoms, but in the case of the other psychoactive substances, empirical evidence remains fragmentary. Still, the properties of psychoactive substances invite to pay close attention, among the negative symptoms, to the cognitive deficits, the social inaptitudes and the hedonic deficits of these patients. Unsatisfied with the self-medication hypothesis, an increasing number of researchers hypothesize that schizophrenic patients abuse drugs in hope to relieve the negative affects (stress, depression) that commonly accompany their symptomatology. Interestingly, increasing data link these negative manifestations and substance abuse among schizophrenic patients. But these same data do not elucidate whether these manifestations are primary or secondary to drug abuse. For the moment, these findings must be replicated. Furthermore, it remains to be clarified what negative affect is involved here. Is it stress, anxiety or, as commonly thought, depression? Other paths aim in the direction of personality traits and dissociation. The first path is suggested by recent studies demonstrating that pharmacodependent schizophrenic patients differ from non-abusing schizophrenics in that their personality is characterized by traits such as sensation seeking and impulsivity. As for the second path, it is suggested by a recurrent observation in addictive medicine practice, that is: alcohol, cannabis, ketamine, LSD, opiates, PCP, all these substances can induce dissociative states (depersonalization, derealization, etc.). Surprisingly, most of the hypotheses advanced so far have been formulated without reference to neuroscience. However, from a biological perspective, substance abuse among schizophrenic patients appears paradoxical: while the positive symptoms of schizophrenia might involve an hyperactivity of the reward system, the drugs of abuse all seem to increase dopamine release in that same system. That very paradox further casts some doubt on the self-medication hypothesis. And it opens an alternative: schizophrenic patients might be biologically vulnerable to the rewarding effects of drugs abuse. On the therapeutic level finally, the authors argue that polypharmacy medications such as clozapine and quetiapine, known to act on the reward system preferentially to the extrapyramidal system and known to dissociate fastly from the dopamine-D2 receptor, could simplify clinical intervention.

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer.

The evolution of alterations on chromosome 9, including the putative tumor suppressor genes mapped to the 9p21-22 region (the MTS genes), was studied in relation to the progression of human urinary bladder neoplasia by using whole organ superimposed histologic and genetic mapping in cystectomy specimens and was verified in urinary bladder tumors of various pathogenetic subsets with longterm follow-up. The applicability of chromosome 9 allelic losses as non-invasive markers of urothelial neoplasia was tested on voided urine and/or bladder washings of patients with urinary bladder cancer. Although sequential multiple hits in the MTS locus were documented in the development of intraurothelial precursor lesions, the MTS genes do not seem to represent a major target for p21-23 deletions in bladder cancer. Two additional tumor suppressor genes involved in bladder neoplasia located distally and proximally to the MTS locus within p22-23 and p11-13 regions respectively were identified. Several distinct putative tumor suppressor gene loci within the q12-13, q21-22, and q34 regions were identified on the q arm. In particular, the pericentromeric q12-13 area may contain the critical tumor suppressor gene or genes for the development of early urothelial neoplasia. Allelic losses of chromosome 9 were associated with expansion of the abnormal urothelial clone which frequently involved large areas of urinary bladder mucosa. These losses could be found in a high proportion of urothelial tumors and in voided urine or bladder washing samples of nearly all patients with urinary bladder carcinoma.

Risperidone and clozapine in the treatment of drug-resistant schizophrenia and neuroleptic-induced supersensitivity psychosis.

1. Supersensitivity psychosis (SSP) has emerged as a potential side effect of long-term neuroleptic therapy similar to tardive dyskinesia (TD). 2. Six schizophrenic patients with SSP, considered to be drug-resistant, were treated with risperidone, while another 5 were treated with clozapine. 3. The 6 risperidone-treated patients (all women) were rated on the Clinical Global Impression Improvement Scale as at least very much improved. Among the 5 clozapine-treated patients, all 4 men were found to have a marked response to clozapine, while the female patient was judged to be minimally improved. 4. It is hypothesized that not only TD but also SSP arise from destruction of cholinergic interneurons in the striatum as a consequence of prolonged neuroleptic administration. Thus, the drug-induced parkinsonism, which was proposed as mediating the antipsychotic effect of dopamine D2 blocking drugs, depends on the integrity of these cholinergic neurons. If these neurons are destroyed, drugs such as haloperidol lose their therapeutic effect. 5. In contrast, atypical neuroleptics like clozapine and risperidone reduce dopamine release in the striatum independently of prior production of extrapyramidal symptoms and, in this way, may be effective in psychotic illnesses unresponsive to classical anti-D2 neuroleptics. 6. In the present sample of patients, it is worth noting that schizophrenic men were good responders to clozapine. In comparison, risperidone was found to be efficacious in schizophrenic women.

Effects of supramaximal exercise on blood glucose levels during a subsequent exercise.

The purpose of the present investigation was to examine the effects of hyperglycemia induced by supramaximal exercise on blood glucose homeostasis during submaximal exercise following immediately after. Six men were subjected to three experimental situations; in two of these situations, 3 min of high-intensity exercise (corresponding to 112, SD 1% VO2max) was immediately followed by either a 60-min period of submaximal exercise (68, SD 2% VO2max) or a 60-min resting period. In the third situation, subjects performed a 63-min period of submaximal exercise only. There were no significant differences between the heart rates, oxygen uptakes, and respiratory exchange ratios during the two submaximal exercise bouts (greater than 15 min) whether or not preceded by supramaximal exercise. The supramaximal exercise was associated within 10 min of the start increases (P less than 0.05) in blood glucose, insulin, and lactate concentrations. This hyperglycemia was more pronounced when subjects continued to exercise submaximally than when they rested (at 7.5 min; P less than 0.05). There was a more rapid return to normal exercise blood glucose and insulin values during submaximal exercise compared with rest. The data show that the hyperinsulinemia following supramaximal exercise is corrected in between 10-30 min during submaximal exercise following immediately, suggesting that this exercise combination does not lead to premature hypoglycemia.

Effects of dietary manipulations on blood glucose and hormonal responses following supramaximal exercise.

The effects of supramaximal exercise on blood glucose, insulin, and catecholamine responses were examined in 7 healthy male physical education students (mean +/- SD: age = 21 +/- 1.2 years; VO2max = 54 +/- 6 ml X kg-1 X min-1) in response to the following three dietary conditions: a normal mixed diet (N); a 24-h low carbohydrate (CHO) diet intended to reduce liver glycogen content (D1); and a 24-h low CHO diet preceded by a leg muscle CHO overloading protocol intended to reduce hepatic glycogen content with increased muscle glycogen store (D2). Exercise was performed on a bicycle ergometer at an exercise intensity of 130% VO2max for 90 s. Irrespective of the dietary manipulation, supramaximal exercise was associated with a similar significant (p less than 0.01) increase in the exercise and recovery plasma glucose values. The increase in blood glucose levels was accompanied by a similar increase in insulin concentrations in all three groups despite lower resting insulin levels in conditions D1 and D2. Lactate concentrations were higher during the early phase of the recovery period in the D2 as compared to the N condition. At cessation of exercise, epinephrine and norepinephrine were greatly elevated in all three conditions. These results indicate that the increase in plasma glucose and insulin associated with very high intensity exercise, persists in spite of dietary manipulations intended to reduce liver glycogen content or increase muscle glycogen store.(ABSTRACT TRUNCATED AT 250 WORDS)