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To the Editor.— A recent letter to theArchivesreported some modestly favorable results in treating cocaine dependence in methadone-treated patients with buproprion hydrochloride. 1 Starting from a different theoretical basis, we embarked on a double-blind evaluation of buproprion vs placebo in patients being treated only for cocaine dependence. Buproprion was chosen because, like cocaine, it is a high-affinity dopamine uptake inhibitor but, unlike cocaine, produces no euphoria or dependence. Thus, it might act to mitigate the actions of cocaine. 2 We planned to exploit our 28-day inpatient treatment program to monitor the course of treatment in this study for a period of 21 days. Our limited goal was to determine whether buproprion might reduce craving for cocaine during this period. Our patients were largely young (median age, 27 years), male (38 men and eight women), inner city youth who were of low socioeconomic class and borderline intelligence (mean IQ

• Plasma thyrotropin (TSH) levels varied relatively little over minutes to days in the same individual not subjected to challenge with thyrotropin-releasing hormone (TRH). Thus, the TSH response to stimulation with TRH is not likely to be confounded by spontaneous changes of comparable degree. Variable numbers of depressed patients showed a blunted response to TRH stimulation of the pituitary, but the exact prevalence of this phenomenon remains to be clearly defined. In any case, the pituitary response to TRH stimulation was not correlated with the prevailing level of depression, nor did this response to an initial TRH challenge predict the degree of clinical change during a 15-day treatment during which three intravenous doses of 600 δg of TRH were given. Depressed patients, as do schizophrenics and normal patients, show diminished TSH responses to repeated challenges with TRH. Whether or not these three groups differ in regard to the rate at which the pituitary response can be abolished remains to be determined.

• Criteria for establishing a diagnosis of schizophrenia have been proposed by several different authors. This study compared six different research diagnostic criteria (RDC) in a series of 166 patients who received a clinical diagnosis of schizophrenia in a multicenter study. The alternative criteria differed in the proportion of clinical diagnoses that were confirmed, with the Washington University (Feighner) criteria accepting only 26%. The criteria also disagreed concerning which particular patients qualified for the diagnosis. The Washington University and New York RDC disagreed 50% of the time, and some other disagreement rates were even higher. More evaluative research is needed before arbitrary criteria are permitted to redefine the concept of schizophrenia.

• Fifty-five schizophrenic outpatients with negative symptoms were treated for up to six weeks by the addition of alprazolam (mean dose, 4.2 mg/d), diazepam (mean dose, 40.4 mg/d), or placebo to their ongoing neuroleptic treatment. A repeated-measures analysis of variance with baseline measurements entered as covariates indicated the presence of a significant time × drug interaction effect for the weekly Brief Psychiatric Rating Scale (BPRS) withdrawal/retardation subfactor scores. During the initial weeks of the study, the alprazolam-treated group had lower scores, while the diazepam-treated group had higher scores than the placebo-treated group. However, an end point analysis performed on the final BPRS withdrawal/retardation subfactor scores showed no significant differences among the three groups, nor were beneficial effects observed on any of the BPRS subfactor scores that assess positive symptoms. Plasma alprazolam levels were maintained throughout the study and ranged from 20 to 100 ng/mL. These results suggest that alprazolam had no sustained significant effect on negative schizophrenic symptoms.

IN THE evaluation of psychiatric drug treatments, two types of errors are sometimes present in conclusions based upon statistical analyses of data. It can be concluded that the treatments differ when, in fact, they do not; or it can be concluded that the treatments do not differ when, in fact, they do. In the past, most concern in the analysis of such data has been with the possibility of erroneously concluding that the treatments differ when they do not. Too little attention has been paid to the power of tests in detecting true treatment differences where they exist. When sample sizes are too small, statistical tests will fail to indicate significant differences between drug treatments, even though real and important differences exist. The purpose of this article is to provide estimates of sample size required for doubleblind controlled studies using one, or two independent

Oral doses of extracts of marihuana were found to induce a greater concentration on the present and a foreshortening of the span of awareness into the future. Although there were individual differences in emotional reactions, the greater concentration on the present was associated, in general, with euphoric moods.

A total of 320 newly admitted schizophrenic men were randomly assigned to either an aliphatic, piperidine, or piperazine phenothiazine. Physicians chose drugs within the class assigned and used them to maximal clinical advantage. None of the drug classes was superior to another in total efficacy. Finer differences were that piperazines were more effective in patients who were older and who were categorized as having "core" or "nonparanoid" types of schizophrenia, characterized chiefly by thought disorders. The prevailing belief that these drugs are more specific antipsychotic agents was given some support. Past difficulties in replicating specific indications for antipsychotic drugs, as well as the few differences found in this study, force the clinician still to choose drugs empirically. Differing reactions of individual patients to various drugs are more likely due to differences in drug kinetics than to any important pharmacological differences.

Plasma testosterone levels were determined in 18 young men in Officer Candidate School. Plasma testosterone levels were significantly lower during the early, stressful part of the course as contrasted with levels during the senior phase. This finding represents the first evidence in humans supporting the hypothesis that psychological stress suppresses levels of circulating plasma testosterone.

VARIABILITY in responses to drug treatments plagues the researcher concerned with evaluating therapeutic efficacy of psychotropic drugs as well as the clinician who uses them in practice. Some of this variability is associated with patient characteristics that can be identified empirically. The purpose of this investigation was to define some of the more important extrinsic (nondrug) factors that influence short-term symptom reduction under a variety of different drug treatments. Numerous studies have shown that the nature of presenting psychopathology is related to a variety of historical, social, and cultural factors.1-4Several studies have been concerned with the prediction of treatment outcome and subsequent course of illness.5-7Most of the latter have considered prognosis in a broader sense than considered here, such as the number of days back in the community during an extended period.8Previous research has suggested that the relevance of

WE HAVE recently reported that marihuana extract, calibrated for content of (—)-Δ1-tetrahydrocannabinol (THC), significantly impaired the serial coordination of cognitive operations during a task that required sequential adjustments in reaching a goal.1Our term for this mental incoordination is temporal disintegration. From a cognitive standpoint, temporal disintegration means that the individual has difficulty in retaining, coordinating, and serially indexing those memories, perceptions, and expectations that are relevant to the goal he is pursuing. Subjectively, temporal disintegration is experienced as a confusion of past, present, and future while a person attempts to pursue goals. This paper focuses on the relationship of temporal disintegration to depersonalization (that is, the experience of the self as strange and unreal) during marihuana intoxication. Hypotheses Since the personal past, present, and future constitute a fundamental subjective framework through which an individual views and identifies himself, we postulated that the fragmentation and disorganization of temporal experience

RESEARCH into the nature of depression and its treatment by drugs is hobbled by the fact that depressions do not constitute a single homogeneous entity. The term "depression" is employed to refer to a symptom, a syndrome, or a diagnostic entity.1It has been unclear whether so-called antidepressant drugs are to be regarded as specifically effective for treatment of the symptom, syndrome, or diagnostic entity. Our research has led us to the conclusion that it is important to evaluate the potential usefulness of drug treatments in distinct syndromes of depression. In our series of studies, we began by comparing the therapeutic efficacy of antidepressant drugs among heterogeneous groups of patients whose presenting symptom was predominantly depression of mood. Although it was possible to demonstrate a significant average difference in therapeutic response between a tricyclic antidepressant, imipramine, and placebo, the difference was not striking.2A subsequent study, which

In a double-blind study, time production tasks and clinical tests of memory function were performed by 15 normal subjects given placebo and "social" doses of alcohol (ethyl alcohol) and marihuana, calibrated to (-)-δ 1 -tetrahydrocannabinol. Using subjects as their own controls, it was found that, compared to alcohol and placebo, marihuana induced a significant under production of time intervals suggesting an acceleration of the internal clock. At these dose levels, there were no significant changes in memory function, but during marihuana intoxication some consistent trends toward greater impairment of tracking information over time were noted.

• We investigated the relationship between urinary excretion of MHPG and the clinical response of 17 depressed patients to nortriptyline hydrochloride. Plasma concentrations of nortriptyline were monitored to assure optimal doses. Patients were classified as having "low" or "normal-high" excretion of MHPG based on one to five 24-hour urine specimens. Hamilton Depression Rating Scale scores were not reduced significantly more among the nine low excreters as compared with the eight normal-high excreters. However, when a true bimodal distribution of MHPG excretion was created by comparing only the six lowest excreters with the six highest excreters, the low group improved significantly more than the high group. This differential response to nortriptyline somewhat supports the notion that MHPG excretion may predict response to specific tricyclics. Collecting urine for MHPG determination in depressed patients is not easy; the variability of excretion within patients is considerable, and the range of MHPG excretion closely parallels that in normal persons. The clinical utility of this procedure is still to be determined.

In Reply.— If our article was "troubling", then it probably served its purpose. Unfortunately, the various diagnostic criteria are being widely and uncritically adopted without adequate validation. Our article was not intended as a criticism of any particular approach to operationalizing diagnostic criteria. It was intended merely to emphasize the need for empirical evaluation and validation of whatever approach is ultimately accepted. The rebuttal by Spitzer and colleagues states that the purpose of the Washington University criteria, the New York criteria, and the DSM-III criteria is to improve clinical practice by incorporating into diagnostic criteria distinctions that have been shown "by research study" to have some validity in terms of such variables as course, response to specific therapy, familial pattern, etc. Instead of repeating the oft-stated research claims, would it not be more convincing to document them? Dr Spitzer obviously recognizes the critical difference that specific wording of diagnostic criteria can

Protirelin (formally known as thyrotrophin releasing hormone [TRH]) was evaluated as a treatment in depression in two independent investigations using a similar protocol. The latter was designed so that some patients received three 600μg intravenous injections of protirelin early in their course and others received them toward the end of their course of treatment. Regardless of when protirelin was given in the course of depression, or how the course of the illness was measured, it seemed to be devoid both of therapeutic and of major adverse effects.

To the Editor.— Recently, Sandoz, Ine (East Hanover, NJ) produced an advertisement entitled "Sandoz Answers Common Questions About: Tardive Dyskinesia: Are Some Neuroleptics Less Likely to Cause It?" This advertisement is a prime example of how unscientific assertions and conclusions result in a misleading promotion of a useful drug. From the outset, this advertisement claims that thioridazine (Mellaril) is a site-specific, low-potency antipsychotic that has little effect on extrapyramidal dopamine receptors and therefore is less likely to cause long-term movement disorders, specifically tardive dyskinesia (TD). This alluring categorization of thioridazine is belied by the fact that there are no substantive research data or even supportive clinical data that thioridazine is any less likely to cause TD than any other neuroleptic. On the contrary, there are verified cases of thioridazine-induced TD that indicate that, like all neuroleptics, thioridazine can cause TD. Having carefully reviewed and assessed the statements in each paragraph

Exretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured repeatedly in 17 normal subjects. The amount of MHPG excreted over a 24-hour period was fairly stable over a period of three consecutive 24-hour samplings, but stability was rather poor over subsequent periods of several weeks, suggesting that execretory patterns are not traits. A normal range of MHPG excretion was estimated to be 900 to 3,500 micrograms/24 hr. This range covers the majority of persons with affective disorders whose excretion patterns have been measured, although comparisons of absolute values between laboratories must be made cautiously. Further, substantial changes within this range may occur in normal subjects with no accompanying change in affect. A slight but definite diurnal pattern of excretion was found, with a peak at the period of 1600 to 1800 hours. No clear relationship to MHPG excretion to state of physical activity, recent consumption of foods or beverages, or prevailing affective state was defined in those subjects living under normal conditions. While MHPG excretion may yet prove useful for categorizing depressed patients and predicting response to drugs, any inferences drawn regarding the pathogenesis of affective disorders must be guarded.

We used three different studies involving patients undergoing detoxification to evaluate the worth of propranolol hydrochloride in withdrawal of opiates. If propranolol acts as a narcotic antagonist, the patient's condition should become worse and require increased methadone hydrochloride; if it were to afford symptomatic relief by blocking autonomic responses, methadone requirements might be decreased. None of the studies indicated that propranolol hydrochloride in doses of 160 mg/day or less aggravated withdrawal symptoms. Patients treated with the drug consistently required a somewhat smaller methadone dose for detoxification. Patients who responded favorably had mild withdrawal symptoms. The small benefit from the drug hardly merits its consideration as an adjunct to the treatment of withdrawal from opiates.

Marihuana or placebo cigarettes were smoked by 12 subjects in two environments, one "favorable" and one "neutral." The object was to determine the contribution of setting to the effects reported from the drug. Two quantifiable self-report measurements, the linear euphoriant scale and the card-sort version of the Addiction Research Center Inventory (marihuana and hallucinogen scales), were the major reporting criteria. Analyses of variance consistently demonstrated strong effects for subjects and drug but not for the environmental conditions. Reports of marihuana effects may be assumed to be highly colored by psychological differences in the mental set of subjects, or biological variations in their responses to the drug. The actual environment in which the drug is taken seems to play little, if any, role.

The rationale for the use of vasodilators in the aged has changed from the attempt to increase cerebral blood flow to the attempt to improve cerebral metabolism. Review of 102 studies of eight vasodilators showed that significantly more controlled studies claimed practical clinical benefit from drugs supposed to improve neuronal intermediary metabolism with secondary vasodilatation than from drugs supposed to have only vasodilator action (P less than .005). Studies of both classes of drugs often suffered from poor study design, inappropriate and inconsistent application of outcome measurements, as well as negative bias due to selection of severely demented subjects. Future studies should be placebo-controlled investigations of drugs with primarily metabolic action, address questions of dose and time response, consistently use appropriate outcome measurement, and concentrate on the elderly in whom cognitive improvement is possible.

MARIHUANA, ethanol, and dextroamphetamine are three widely used social drugs with somewhat different actions. Marihuana is a sedative somewhat like ethanol, but also has perceptual effects resembling those of hallucinogens. Ethanol is primarily a sedative, while dextroamphetamine is a stimulant. As it has been seldom possible to compare these three drugs in the same subjects, using quantified doses, we measured their effects on mood and selected mental functions. Methods Twelve normal young volunteers were chosen primarily on the basis of their being in good physical and emotional health and intelligent and cooperative enough to carry out the required procedures. All but one were men. Although most subjects had had prior experience with small doses of marihuana and amphetamines, and all with alcoholic beverages, none were chronic or recent users of any of these drugs, except for mild use of beverage alcohol. Subjects were told that these three drugs were to

Male patients experiencing the symptoms of acute alcohol withdrawal were assigned at ramdom to double-blind treatment with chlordiazepoxide, chlorpromazine, hydroxyzine, thiamine, or placebo for a period of ten days. They were rated three times daily by nursing personnel using a Nurses' Rating Scale and were asked to complete a Mood Scale daily. Patients generally showed a rapid improvement in different symptom areas regardless of the group to which they had been assigned. Treatment comparisons suggested that fewer symptoms were associated with placebo and thiamine treatment than with the three psychoactive drugs. However, the greater incidence of convulsions and delirium occurring in these two groups as compared with the chlordiazeposide group more than offset any advantage that may exist for what is essentially supportive treatment.

Sixty-seven newly admitted depressed patients were classified on the basis of their presenting signs and symptoms as having the syndrome of anxious depression. They were assigned randomly either to treatment with the phenothiazine derivative, acetophenazine, or with the antianxiety drug, diazepam. After four weeks of treatment, both groups were equally improved. Study of the interactions between drugs and demographic variables revealed that patients with less long-term and uncomplicated depressions responded better to diazepam, the converse being true for acetophenazine. Although our previous studies indicated that phenothiazine derivatives were preferable to conventional tricyclic antidepressants in patients with anxious depressions, antianxiety agents are also effective. In fact, because most patients fall into the group which responds best to them, as well as because of their greater safety, drugs such as diazepam might be the first choice for treating the most common depressive syndrome, that of anxious depression.

DIAGNOSTIC classification of psychiatric patients must be based primarily on description of clinical syndromes, since definite etiological bases and the relevance of much historical data are still undetermined. Psychiatric rating scales can be conceived as mechanisms for describing, in form amenable to further quantitative evaluation, the symptoms and signs upon which psychiatric diagnoses have traditionally been based. During the last decade several rating scales have been widely used in psychiatric research, primarily to increase objectivity in evaluating the therapeutic efficacy of drug treatments. 1-4 The consequent availability of large collections of symptom and behavior ratings has made it possible to derive empirically a structural model representing major dimensions of clinical phenomena presented by hospitalized psychiatric patients. The Brief Psychiatric Rating Scale (BPRS) was developed to provide quantitative representation of important symptoms and signs on unitary 7-point scales. 4 Although the

In a double-blind study, the amplitude of the contingent negative variation (CNV) was assessed in 12 normal men given placebo and quantified "social" doses of 1-δ 9 -transtetrahydrocannabinol (THC) and alcohol (ethyl alcohol). Using subjects as their own controls, it was found that THC selectively enhanced the amplitude as compared to placebo while alcohol depressed it.