Jonathan O. Cole

Buprenorphine treatment of refractory depression

Opiates were used to treat major depression until the mid-1950s. The advent of opioids with mixed agonist-antagonist or partial agonist activity, with reduced dependence and abuse liabilities, has made possible the reevaluation of opioids for this indication. This is of potential importance for the population of depressed patients who are unresponsive to or intolerant of conventional antidepressant agents. Ten subjects with treatment-refractory, unipolar, nonpsychotic, major depression were treated with the opioid partial agonist buprenorphine in an open-label study. Three subjects were unable to tolerate more than two doses because of side effects including malaise, nausea, and dysphoria. The remaining seven completed 4 to 6 weeks of treatment and as a group showed clinically striking improvement in both subjective and objective measures of depression. Much of this improvement was observed by the end of 1 week of treatment and persisted throughout the trial. Four subjects achieved complete remission of symptoms by the end of the trial (Hamilton Rating Scale for Depression scores < or = 6), two were moderately improved, and one deteriorated. These findings suggest a possible role for buprenorphine in treating refractory depression.

Venlafaxine for treatment-resistant unipolar depression.

The purpose of this study is to evaluate the novel antidepressant venlafaxine for the management of treatment-resistant unipolar depression. We gave unblinded venlafaxine to 84 consecutive outpatients and inpatients who met DSM-III-R criteria for major depression and who had failed to respond to at least three adequate trials of antidepressants from at least two different antidepressant classes or electroconvulsive therapy, plus at least one attempt at augmentation. Patients were evaluated after a drug free period at baseline and regular intervals with the 21-item Hamilton Rating Scale for Depression (HAM-D-21), Montgomery-Asberg Depression Rating Scale (MADRS), and the Clinical Global Impressions Scale Improvement item (CGI). Full response for each scale was defined as follows: HAM-D-21 score of 8 or lower, a MADRS score of 12 or lower, and CGI score of 1; partial responses was defined as a 50% decrease in the HAM-D and MADRS, with final scores greater than 8 and 12, respectively, and for the CGI, a score equal to 2. About a third of patients were considered to be either full or partial responders (32.9% by HAM-D-21, 30.0% by MADRS, and 40% by CGI) after 12 weeks of venlafaxine treatment. To date, about 46% of responders have sustained their response for at least 3 months after the acute response. Venlafaxine is effective for a significant, but small, minority of patients with rigorously defined triple-resistant depression; the improvement was maintained for about half of the responders for the first 3 months of maintenance therapy.

Toward a biochemical classification of depressive disorders

Pretreatment urinary MHPG levels were examined in 28 depressed patients as a possible predictor of response to treatment with maprotiline, a tetracyclic antidepressant that exerts potent effects on norepinephrine uptake, but has little effect on serotonin uptake. Maprotiline was administered in doses up to 150 mg/day during the first 2 weeks after which time the dose could be increased incrementally up to 300 mg/day if indicated clinically. At 2 weeks, patients with low pretreatment urinary MHPG levels responded more favorably to treatment than did patients with high MHPG levels. At 4 weeks, patients with low MHPG levels continued to show more favorable responses; however, differences between the two groups were less clear-cut than at 2 weeks. The findings suggest that patients with low pretreatment urinary MHPG levels are more sensitive to, and respond more rapidly to, treatment with maprotiline than patients with high pretreatment urinary MHPG levels.Pretreatment urinary MHPG levels were examined in 28 depressed patients as a possible predictor of response to treatment with maprotiline, a tetracyclic antidepressant that exerts potent effects on norepinephrine uptake, but has little effect on serotonin uptake. Maprotiline was administered in doses up to 150 mg/day during the first 2 weeks after which time the dose could be increased incrementally up to 300 mg/day if indicated clinically. At 2 weeks, patients with low pretreatment urinary MHPG levels responded more favorably to treatment than did patients with high MHPG levels. At 4 weeks, patients with low MHPG levels continued to show more favorable responses; however, differences between the two groups were less clear-cut than at 2 weeks. The findings suggest that patients with low pretreatment urinary MHPG levels are more sensitive to, and respond more rapidly to, treatment with maprotiline than patients with high pretreatment urinary MHPG levels.

ACTH 4-10 in the amelioration of neuropsychological symptomatology associated with senile organic brain syndrome

Eighteen male and female volunteers over the age of sixty who exhibited mild senile organic brain syndrome were administered ACTH 4-10 (Org OI 63) (30 mg, s.c.) or saline in a 2×2 Latin square design. Subjects experienced a reduction in depression and confusion and an increase in vigor. This evidence of an increase in vigor was supported behaviorally by a delay in the onset of increased latency in reaction time. Data also indicated that retrieval from memory may be enhanced by this compound. The electroencephalogram evinced a shift to lower frequencies under ACTH 4-10, but this effect was primarily noted in the females who received drug followed by placebo. These effects of ACTH 4-10 are intriguing and suggest that further work in this area should be encouraged.

B Complex Vitamin Patterns in Geriatric and Young Adult Inpatients with Major Depression

This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non‐alcoholic inpatients with major depression. Twenty‐eight percent of all subjects were deficient in B2 (riboflavin), B6 (pyridoxine), and/or B12 (cobalamin), but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non‐psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini‐Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression, but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study.

The natural history of tardive dyskinesia.

Follow-up data from the first 100 patients with early dyskinesia are presented. After an average of 40.9 months, the cohort showed statistically significant decreases in tardive dyskinesia (TD) ratings. After TD onset, ratings decreased for 4 years, then plateaued and rose during the 7th year. Age was not a negative prognostic factor in this cohort. Improvement in TD correlated significantly with fewer neuroleptic-free periods before and more neuroleptic-free periods after TD onset. Neuroleptic dosage correlated negatively with improvement in trunk and dystonia ratings. Improvement in TD is the usual finding in longitudinal studies of TD cohorts. Follow-up studies of neuroleptic-treated groups with varying proportions of patients showing TD, by contrast, tend to show increased TD because new TD cases more than offset improvement. A naturalistic study with pharmacotherapy tailored to the underlying psychiatric disorder and conducted long-term from TD onset is the ideal design for investigating the natural history of TD.

Psychotic and nonpsychotic depressions: I. Comparison of plasma catecholamines and cortisol measures.

Unconjugated plasma catecholamines and cortisol were measured before and after a 1 mg dose of dexamethasone in 22 medication-free depressed patients and 6 healthy, medication-free control subjects. Plasma dopamine (DA) levels in the psychotically depressed subgroup (n = 4) were significantly higher both before and after dexamethasone than those in the nonpsychotic depressed group and higher before dexamethasone than in the control group. Similarly, the psychotically depressed group exhibited significantly higher cortisol levels both before and after dexamethasone than the nonpsychotic depressed group or the control group. In contrast, the psychotically depressed group had significantly lower postdexamethasone plasma norepinephrine levels compared to the nonpsychotic depressed group. In both patients and controls, plasma DA was significantly higher after dexamethasone administration than before, but the magnitude of the increase was 10 times greater in controls than in patients.

Sensitivity of the impact of geological uncertainty on production from faulted and unfaulted shallow-marine oil reservoirs: objectives and methods

Estimates of recovery from oil fields are often found to be significantly in error, and the multidisciplinary SAIGUP modelling project has focused on the problem by assessing the influence of geological factors on production in a large suite of synthetic shallow-marine reservoir models. Over 400 progradational shallow-marine reservoirs, ranging from comparatively simple, parallel, wave-dominated shorelines through to laterally heterogeneous, lobate, river-dominated systems with abundant low-angle clinoforms, were generated as a function of sedimentological input conditioned to natural data. These sedimentological models were combined with structural models sharing a common overall form but consisting of three different fault systems with variable fault density and fault permeability characteristics and a common unfaulted end-member. Different sets of relative permeability functions applied on a facies-by-facies basis were calculated as a function of different lamina-scale properties and upscaling algorithms to establish the uncertainty in production introduced through the upscaling process. Different fault-related upscaling assumptions were also included in some models. A waterflood production mechanism was simulated using up to five different sets of well locations, resulting in simulated production behaviour for over 35 000 full-field reservoir models. The model reservoirs are typical of many North Sea examples, with total production ranging from c. 15×106 m3 to 35×106 m3, and recovery factors of between 30% and 55%. A variety of analytical methods were applied. Formal statistical methods quantified the relative influences of individual input parameters and parameter combinations on production measures. Various measures of reservoir heterogeneity were tested for their ability to discriminate reservoir performance. This paper gives a summary of the modelling and analyses described in more detail in the remainder of this thematic set of papers.

Recall and recognition as diagnostic indices of Malignant Memory loss in senile dementia: A bayesian analysis

The Benign Senescent Forgetfulness of normal aging and the Malignant Memory Loss of Senile Dementia of the Alzheimer Type (SDAT) each have a distinct symptomatology, course, and prognosis. The purpose of this study was to evaluate the discriminative validity and relative predictive values of recall and recognition as diagnostic screening tests for the Malignant Memory Loss of SDAT. Thirty-six patients with mild to moderate SDAT and 40 normal aged controls were studied. Both recall and recognition showed good discriminative validity. However, analysis of recall and recognition by Bayess Theorem revealed the relative predictive values as diagnostic screening instruments were 11% and 100% respectively. Thus, it was concluded that while both recall and recognition have discriminative validity under experimental conditions, a test of recognition is the preferred diagnostic instrument when screening for the Malignant Memory Loss of SDAT.

Psychophysiologic responses of schizophrenics to drugs

Studies of psychophysiologic responses of schizophrenics to drugs have involved cardiovascular measures (heart rate, blood pressure, and finger pulse volume), electrical skin activity, digital temperature, pupillary response, muscle activity, and respiration. Drugs included phenothiazines and both sympathetic and parasympathetic agents. Effects of drugs were varied and complex and no simple conclusions are possible. Phenothiazines reduced generally elevated basal levels of psychophysiological activity of schizophrenics (except for heart rate) as well as their reactivity to stimuli. These changes were often accompanied by behavioral improvement, suggesting that schizophrenics can be characterized by excessive levels of arousal which are decreased by phenothiazines to more moderate levels. In contrast, Russian work indicated that the basal levels of schizophrenics are initially low and are generally elevated by drugs, including phenothiazines, with accompanying improvement in psychological functions. These diverse findings were interpreted as showing that the psychological functioning of schizophrenics is a nonmonotonic (inverted-U) function of psychophysiological arousal. A second hypothesis was proposed to account for nonphysiological (cognitive) deficits of schizophrenics, namely, that performance is a positive, monotonic function of attention. Consequently, a two-process theoretical model involving attention and arousal processes was proposed to account for schizophrenic behavior. Several methodological questions prevented clear interpretation of many drug findings. One particular problem involved possible effects from homeostatic restraint mechanisms (law of initial values or LIV effect). A technique for removal of LIV effects was described.