Age of alcoholism onset. I. Relationship to psychopathology.

Numerous attempts have been made to subdivide populations of alcoholics into homogeneous subgroups. Although no consensus has been reached about the characteristics of these subgroups, a number of classification schemes have identified a subgroup of patients with a high genetic loading for alcoholism, an early onset of alcoholism, a severe course, and coexisting psychiatric problems consisting of aggressive tendencies or criminality. In a recent typology proposed by Cloninger on the basis of adoption studies, this subgroup has been classified as type 2. Another group of patients who were found to differ in their mode of inheritance and clinical characteristics was classified as type 1. The identification of etiologically homogeneous subgroups is easier in studies of adoptees than in studies of individuals who were not adopted. In an attempt to divide alcoholics into two groups of individuals presenting type 1 and type 2 characteristics, we used as a criterion the age of alcoholism onset because type 2 alcoholics as well as their fathers had been found to abuse alcohol at a younger age than type 1 patients. Patients with an onset of alcoholism before their 20th birthday were found to have a significantly higher incidence of paternal alcoholism and were twice as likely to have been incarcerated for crimes involving physical violence. We also observed other features not previously described in this patient subgroup. Patients who started abusing alcohol in their teens were three times as likely to be depressed and four times as likely to have attempted suicide as patients with a later onset of alcohol abuse.

Age of alcoholism onset. II. Relationship to susceptibility to serotonin precursor availability.

Alcoholics who start abusing alcohol early in life have been found to exhibit problems with mood and aggression control more frequently than patients with a later onset of alcoholism. Because alcohol preference and consumption, as well as mood and aggression regulation, are believed to be influenced by serotonin, relationships between tryptophan availability and mood and aggression regulation were explored in alcoholics. When studied in the entire population, the ratio of tryptophan over other amino acids competing for brain entry (which influences brain serotonin) was found to be lowest one day after cessation of drinking and to increase progressively over the following two to three weeks. When the population was divided into two groups of patients according to whether subjects started abusing alcohol before or after 20 years of age, associations between a low tryptophan ratio and depressive and aggressive tendencies were significant only in the subgroup of patients with an early onset of alcoholism. They were not significant in the rest of the population. Our data are compatible with the interpretation that patients with an early onset of alcoholism have a preexisting serotonin deficit that could manifest itself by an increased alcohol intake early in life and by an increased vulnerability to fluctuations in precursor availability.

Extrapyramidal side effects in lithium maintenance therapy.

The authors neurologically examined 36 patients who had been maintained on lithium therapy for periods ranging from 6 months to 7 years to determine the presence of parkinson-like side effects. Only a few patients demonstrated rigidity, including cogweel rigidity, and this was at a low level of severity. These results do not support the previously reported frequent occurrence of cogwheel rigidity in patients on lithium maintenance.

Effects of neuroleptic adjustment on clinical condition and tardive dyskinesia in schizophrenic patients.

The authors decreased neuroleptic medication in 21 chronic schizophrenic patients in an attempt to minimize the risks of tardive dyskinesia. Level of psychopathology and severity of dyskinetic symptoms were monitored while the neuroleptic was gradually decreased over 3 months and then discontinued. Only 1 patient relapsed during drug decrease; however, 15 patients relapsed within 6 months after drug withdrawal. After relapse, medication was gradually increased. The doses needed to induce recovery were higher than those which had been sufficient to prevent relapse during gradual drug reduction. Dyskinetic symptoms were not significantly modified during drug reduction but increased significantly after drug discontinuation.

Cortisol in alcoholics with a disordered aggression control.

Considerable evidence exists that the limbic system and the hypothalamus play an important role in the HPA axis disturbances found in depressive disorders. Evidence also exists that the limbic system plays a role in the modulation of aggressive behavior. Yet the HPA function of individuals with a disordered regulation of aggression has received little scrutiny. Because aggressive behavior has been observed to be extensively correlated with heavy alcohol use, we explored the HPA function of alcoholics who had had a life-long history of violence. Basal 0700h cortisol was measured in 4 consecutive wk following cessation of drinking in 19 alcoholics with a history of depression, and 17 alcoholics with a history of violent behavior, eight of whom had been incarcerated because of the severity of their violent acts. When compared with alcoholics with no problem in mood or aggression regulation, significant cortisol increases were found in the group of patients who had been incarcerated for violent acts and not in any other group. This increase persisted for 4 wk after cessation of drinking. A variety of variables, including several measures of alcohol consumption, amounts of benzodiazepines used for detoxification, and liver function tests, failed to show significant associations with cortisol. Data are interpreted as indicating that individuals displaying severe forms of violence could have a dysregulated HPA function revealed by exposure to excessive amounts of alcohol.

Loxapine succinate as a neuroleptic agent: evaluation in two populations of elderly psychiatric patients.

Loxapine succinate, a newly developed neuroleptic drug, was administered to two groups of geropsychiatric patients: (a) 12 with psychosis and organic brain syndrome, and (b) 14 with chronic schizophrenia. After a two-week baseline period, loxapine was given for 12 weeks. The moderate therapeutic effect of loxapine in the "responders" was similar to that of other neuroleptic drugs. The therapeutic dosage range was found to be from 10 to 80 mg daily--about half that used for younger patients. The chief side effects were drowsiness, mild extrapyramidal symptoms, and a slight increase in blood pressure.

Intra-patient variability in the measurement of tardive dyskinesia.

Intra-patient variability in the movements of tardive dyskinesia was examined through the analyses of 8-min frequency counts collected over a period of 11 weeks for six chronic schizophrenic patients. Weekly observation segments of 8 min, 4 min, 2 min, 1 min and 30 s showed considerable variation both across weeks and within sessions. Variations were of sufficient magnitude to contribute to the possibility of false negative tardive dyskinesia assessments and false positive treatment outcome designations. Measurement procedures taking this variability into account are urged for the study of tardive dyskinesia. Additionally, independently obtained rating scale scores showed no association to the collected frequency count data, suggesting fundamental differences between these two assessment procedures.

Effects of loxapine on the sleep of chronic schizophrenics.

The sleep patterns of four male chronic schizophrenic patients were monitored throughout the various phases of a 1-year therapeutic trial with loxapine succinate, a newly developed neuroleptic. Compared with the initial drug-free baseline, the early drug period was characterized by an increase in REM percentage, REM density, and REM activity. During the drug maintenance period, the increase in REM phasic events was accompanied by an increase in total sleep. Severe insomnia was noted during the initial period of drug withdrawal. The absence of time lag between changes in drug administration schedule and the associated alterations in sleep patterns was in contrast with the time latency of the therapeutic response. This neuroleptic on sleep and on psychopathology are mediated by different mechanisms.

Alterations in synaptic membrane molecular order associated with alcoholization and protein deficiency in rats.

The effects of chronic alcoholization and protein deficiency on synaptic membrane characteristics were studied in rats fed the following four liquid diets for 4 weeks: a protein-deficient diet containing alcohol, a protein-deficient diet containing no alcohol, a non-protein-deficient diet containing alcohol and a non-protein-deficient diet containing no alcohol. A fluorescent probe, diphenylhexatriene (DPH), was used to estimate the fluidity of synaptic membranes and their sensitivity to the fluidizing effect of ethanol added in vitro, in concentrations ranging from 50 mM to 800 mM. Prior to in vitro addition of ethanol, the difference between the fluidity of synaptic membranes of alcoholized and non-alcoholized animals was significant for the two groups of protein-deficient animals but not for the two groups of non-protein-deficient animals. After in vitro addition of ethanol, the differences between the fluidity of synaptic membranes of the alcoholized and non-alcoholized animals were larger and more frequently significant for the protein-deficient animals than for the non-protein-deficient animals. In view of previous observations that rats fed a protein-deficient diet experience more severe withdrawal symptoms following alcoholization than rats fed a nutritionally adequate diet, the results of the present experiment lend additional support to the hypothesis that tolerance and dependence may be mediated by alterations in biomembrane characteristics.

Are the effects of chronic ethanol administration on erythrocyte membrane mediated by changes in plasma lipids?

The effect of chronic ethanol consumption on plasma and erythrocyte membrane lipids were studied in rats fed a liquid diet containing ethanol for 4 weeks and intubated with the same diet 90 min prior to killing. Control animals underwent the same treatment, except that their liquid diet did not contain ethanol, but an isocaloric amount of carbohydrates. Plasma total cholesterol, free (unesterified) cholesterol and HDL cholesterol were higher in ethanol-fed animals than in controls. Phospholipids were also higher in the plasma of ethanol-fed animals when compared to controls so that the plasma cholesterol/phospholipid ratio (Ch/PL ratio) of the two groups did not differ significantly, regardless of the cholesterol fraction considered. Experimental and control animals did not differ either in the Ch/PL ratio of their erythrocyte membranes. In view of the fact that it has been suggested that the factor determining the direction of the cholesterol exchanges between plasma and erythrocyte membranes is the equilibrium between their respective Ch/PL ratios, these results are interpreted as being compatible with the hypothesis that the effect of chronic ethanol intake on erythrocyte membrane lipids is mediated through changes in plasma lipids.

P3 in alcoholics with disordered regulation of aggression.

Alcoholics have been found to show deficits in the P3 component of event-related potentials obtained using information-processing paradigms. However, alcoholic patients form a heterogeneous population. In a study of P3 voltages in subgroups of alcoholics with disorders in mood and aggression control, we observed significant decrements in these voltages in patients with lifelong histories of aggressive behavior. Patients with histories of incarceration for crimes involving physical violence had the lowest P3 amplitudes. The same patients also had a rate of paternal alcoholism significantly higher than that observed in the rest of the population. They could thus be classified as type 2 alcoholics, as a tendency to antisocial behavior and a high genetic loading for alcoholism have been described in this alcoholic subtype. These data could indicate that decrements in P3 amplitude characterize a subgroup of alcoholics with a disordered regulation of aggression. Alternatively, P3 deficits could be associated with some psychopathological conditions in individuals who abuse alcohol rather than with alcoholism, per se.

Lithium in tardive dyskinesia.

A single blind trial and a placebo controlled double blind trial of lithium were carried out in elderly patients with tardive dyskinesia. In the pilot study, neuroleptics were continued: in the controlled trial, neuroleptics were discontinued. The results of both studies were essentially negative. Thus, the suppression effect of neuroleptics is much more dramatic than anything seen in the two studies. Several reasons for this were discussed namely, the severity and chronicity of the symptoms.

Morbidity risk for alcoholism and drug abuse in relatives of cocaine addicts.

The morbidity risks for alcoholism in the first-degree relatives of a cohort of male cocaine addicts with or without alcoholism comorbidity were studied. Of the 71 patients who participated in our study, 40 (56.3%) had a history of alcoholism and 37 (59.1%) a history of opioid abuse. Twenty-two patients (30.1%) also met criteria for a lifetime diagnosis of a major psychiatric disorder. Significant increases in morbidity risks for alcoholism were found among male relatives of cocaine addicts with comorbid alcohol dependence when compared with relatives of cocaine addicts with no alcohol comorbidity. Among fathers, risks were .69 vs .32 (z = 2.98, p < .003). Among brothers, risks were .38 vs .15 (z = 2.35, p < .03). Significantly increased risks were also observed in male relatives when probands with a psychiatric diagnosis were excluded from the analyses. Among female relatives, increases in morbidity risks were found but they failed to reach statistical significance. Two interpretations are consistent with these findings. One of these interpretations is that alcoholism is a disorder distinct from other addictions and has its own mode of transmission. The second interpretation is that the transmission of substance use disorders lacks specificity and that the substances selected are influenced by sociocultural or biological factors.

A two year trial of loxapine succinate in chronic psychotic patients.

Thirty-one chronic psychotic patients were treated with loxapine succinate, 20 for two years and eleven for one year, in order to evaluate its long-term efficacy and safety. Results presented here indicate that loxapine succinate is an effective treatment for chronic schizophrenia over a period of at least two years. Improvement, which occurred during the first six months of treatment (mostly during the first month), was maintained over the following year and a half. Unwanted effects were most frequent inthe early months of treatment and decreased as the two year trial progressed. No specifically long-term side effects were observed. The most frequent side effects were mild to moderate extrapyramidal signs. Blood pressure decreased and pulse rate increased, while remaining within normal limits, and returned to normal or near normal levels during the second year of treatment. Weight increased steadily during the two years and dropped markedly during the four week post-drug period. No drug-related abnormal laboratory findings were observed. It may be concluded that loxapine succinate is a safe and effective maintenance treatment for chronic schizophrenia.

High- and low-potency neuroleptics in elderly psychiatric patients.

The efficacy and side effects of a low-potency neuroleptic, thioridazine hydrochloride, and those of a high-potency neuroleptic, fluphenazine hydrochloride, were compared in 30 elderly chronic schizophrenic patients. Through a crossover design, each patient received both drugs with an intervening washout period. Although both drugs produced a similar degree of improvement, their side effects differed. Fluphenazine caused slightly more extrapyramidal effects than thioridazine, though few occurred with use of either drug. Thioridazine caused weight gain, blood pressure decreases, and ECG changes. High-potency neuroleptic agents appear to be the drugs of choice for elderly schizophrenic patients.