Biomedical subjects
Publications and source records attributed to D F Klein.
Sixteen panic patients and fifteen normal controls performed submaximal exercise testing on a bicycle ergometer. Only one patient subject panicked. Biochemical, physiological, and psychological data showed similar exercise tolerance in both patients and controls. Exercise-induced distress and lactate increment do not appear to cause panic attacks.
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To assess the role of noradrenergic stimulation during lactate-induced panic, ten patients with panic disorder who panicked during a standard sodium-lactate infusion underwent a repeat infusion following intravenous clonidine pretreatment. Although clonidine significantly lowered prelactate systolic blood pressure, the drug did not significantly lower prelactate anxiety levels, as reflected by the Acute Panic Inventory (API). Clonidine blocked lactate-induced panic in four of ten subjects, a significant effect. Clonidine treatment also significantly attenuated lactate-panic symptoms, as reflected by time to panic and API comparison between trials. Nevertheless, over half the subjects still panicked in response to lactate despite clonidine. This preliminary study suggests that reduction of central noradrenergic activity by clonidine, at least at the dosage levels employed in the current study, only partially attenuates panic response to lactate. Noradrenergic theories of panic may not therefore fully account for lactate panicogenesis.
To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.
The acquaintanceship procedure is a method for obtaining a control group matched to relatives of probands on demographic variables. Relatives are asked to name six acquaintances who are the same gender, and who are about the same age and social class as themselves. An acquaintance is randomly selected from this list and contacted for recruitment. Rates of mental disorder in this group are assumed to approximate general population rates in a group with these demographic characteristics. This report focuses on an extension of the acquaintanceship procedure in which "super-normal" controls are used in a family study design. Two questions were addressed: (1) Does the acquaintance group (n = 166), as a whole, show a higher rate of illness than the relatives of acquaintances with no mental disorder (n = 129)? (2) Is there a relationship between mental disorder in acquaintances and in providers of acquaintance names? The prevalence of mental illness was significantly greater among acquaintances compared to relatives of "never ill" acquaintances. There was no evidence of assortative selection. We concluded that using the relatives of well acquaintances is a cost-effective control selection methodology which maximizes the detection of intergenerational transmission in family studies of mental disorder.
Childhood panic attacks and panic disorder were assessed retrospectively in adult anxiety clinic patients (N = 343) and their adult relatives (N = 560). Only nine (1%) of the 903 subjects were judged to have experienced spontaneous panic attacks before age 13 by clinically trained interviewers. The narrative summaries of these cases were reviewed, and only three of nine provided convincing descriptions of spontaneous panic attacks in childhood. The authors conclude that prepubertal spontaneous panic attacks are rare, and that retrospective assessments of panic phenomena are difficult, even among adequately trained mental health professionals.
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Although the literature appears to demonstrate the efficacy of standard antidepressant medications for the short-term treatment of patients with minor depression, they are not widely prescribed. In comparison, psychotherapy is generally recommended, but without convincing data to support this conviction. We, therefore, advocate successive trials with antidepressants in any depressed patient, particularly if they have failed to benefit from psychotherapy or other supportive measures for three months.
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BACKGROUND: Paraphilias and related disorders have recently been thought of as sexual addictions. However, it has also been argued that these disorders are sexual compulsions. The question arises as to whether these disorders and obsessive compulsive disorder respond in the same way to pharmacotherapy. METHOD: We retrospectively reviewed outcome in 13 patients who presented with sexual symptoms and were treated with serotonin reuptake blockers. Symptoms were divided into paraphilias, nonparaphilic sexual addictions, and sexual obsessions. RESULTS: Paraphilias had the least improvement, while sexual obsessions had the best response to medication. CONCLUSION: Paraphilias and related disorders may be less responsive than sexual obsessions or compulsions to serotonin reuptake blockers. Perhaps paraphilias and related disorders are on the impulsive rather than the compulsive end of the spectrum of obsessive compulsive disorders. Controlled trials are, however, necessary to replicate these preliminary findings.
The antipanic utility of imipramine and monoamine oxidase inhibitors has led to hypotheses of noradrenergic and/or serotonin (5-HT)-related abnormalities underlying panic disorder (PD) and its agoraphobic complications. Further data support significant antipanic effects for agents with acute 5-HT reuptake blockade effects. It is unlikely that ameliorative effects observed following chronic administration of 5-HT drugs remain 5-HT specific. Despite a range of recently discovered 5-HT receptor subtypes, evidence for a specific receptor abnormality in PD is lacking. Preclinical studies suggest an important role for 5-HT effects in several animal models of anxiety, including separation-induced infant protest responses and respiratory modulation. Induction of anxiety with putative 5-HT agents such as meth-chloro-phenylpiperazine and fenfluramine lend further support to 5-HT involvement in anxiety states. Critical behavioral, physiologic, and neuroendocrine differences between putative 5-HT anxiogens and "classic" panicogens, such as lactate and carbon dioxide are discussed. We propose that 5-HT agents mediate antipanic effects through amelioration of a deranged internal evaluative mechanism along cybernetic lines, rather than simple augmentation or reduction of 5-HT function.
Data for 401 depressed outpatients with mood reactivity who participated in a randomized trial comparing placebo, imipramine, and phenelzine were analyzed for predictors of differential response by stepwise multiple regression techniques. Features of the Columbia criteria for atypical depression including oversleeping, overeating, severe anergy, and pathologic rejection sensitivity were each predictive of a poorer response to imipramine than to phenelzine only when compared to those patients with none of the features. These features were not additive in their contribution to differential outcome. Lack of endogenous features was not predictive of a differential drug treatment response. Compared with patients who have no symptoms of atypical depression, patients with any of the four features had an inferior imipramine response rather than a superior phenelzine response. These analyses indicate that the clear differential responsivity to medication treatment in atypical depression is not simply related to any one defining symptom and that further correlates of this apparent biological heterogeneity need to be explored.
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We employed a study design that permitted a double-blind 12-week contrast of imipramine hydrochloride and phenelzine sulfate therapies in patients who met Columbia University criteria for atypical depression and were unresponsive to 7 weeks of treatment with placebo. These patients were found to benefit selectively from therapy with monoamine oxidase inhibitors compared with tricyclic drug therapy. This supports our observation about treatment response in depressed patients with reversed vegetative features. The design we utilized in this study has not previously been reported, to our knowledge. It was hypothesized that it would offer the advantage of the removal of a portion of placebo responders and serve to replicate our original findings. Treatment response to therapy with both imipramine and pheneizine in placebo nonresponders was uniformly lower (roughly 20% less than corresponding rates for patients who did not participate in the initial 6-week placebo trial). This is consistent with the view that the lower response rates were a result of the removal of some "placebo" responders in the drug groups. We think this is a useful design that should be considered in all studies of placebo and two active treatment regimens.
To evaluate noradrenergic (NE) function in obsessive-compulsive disorder (OCD), behavioral, physiological, and neuroendocrine responses to the alpha 2-adrenergic agonist clonidine were examined in 18 patients with OCD and 10 healthy subjects. Subjects received single i.v. doses of 2 micrograms/kg of clonidine administered under double-blind, placebo-controlled, random-assignment conditions. Following clonidine, but not following placebo, patients transiently experienced a significant reduction of obsessions and compulsions. Significant drowsiness and a reduction in anxiety were also noted, but the antiobsessional effect appeared independent of the soporific and antianxiety effects. Growth hormone (GH), cortisol, and 3-methoxy-4-hydroxyphenylglycol responses to clonidine did not differentiate patients from healthy controls. Blood pressure and pulse in response to clonidine did not differ between groups. Improvement in OCD symptoms after clonidine significantly correlated with GH response to clonidine, suggesting specific noradrenergic mediation. This finding lends only partial support for a primary defect of noradrenergic function in OCD.
To investigate the effect of fluoxetine on serotonergic sensitivity in obsessive-compulsive disorder (OCD), the partial serotonin agonist metachlorophenylpiperazine (mCPP) was compared to placebo under double-blind conditions in six patients with OCD before and during treatment with fluoxetine. Readministration of oral mCPP (0.5 mg/kg) after at least 12 weeks of fluoxetine treatment did not increase obsessive-compulsive (OC) symptoms, in contrast to exacerbation of OC symptoms produced by mCPP before treatment. Chronic fluoxetine treatment resulted in a significant increase in prolactin and cortisol response to mCPP. This may be accounted for, however, by substantially increased plasma mCPP levels during fluoxetine treatment. Chronic fluoxetine treatment diminished the behavioral sensitivity to mCPP and did not diminish, but may have partially normalized, the neuroendocrine response to mCPP in patients with OCD. These adaptive homeostatic effects may reflect fluoxetine's antiobsessional mechanism.
OBJECTIVE: The authors attempted to identify different patterns of improvement among patients receiving placebo during clinical trials. It was hypothesized that patients who improved abruptly would differ from patients whose improvement was gradual in that they would tend to improve earlier and would tend to have less persistent improvement. METHOD: The subjects were 144 patients who met the DSM-III criteria for depressive illness and were randomly assigned to placebo medication in four double-blind antidepressant drug trials. All studies lasted 6 weeks. Mood change was rated each week on a 7-point scale; a rating of 1 or 2 was considered an indication of improvement. Improvement was judged to be abrupt if the first score of 1 or 2 was immediately preceded by a score of 4 or worse, and it was classified as gradual if the first score of 1 or 2 was preceded by a score of 3 in at least 1 week. Improvement was considered persistent if a score of 1 or 2 was not followed by a score of 3 or worse in any subsequent week. RESULTS: Of the 144 patients, 72 showed clinical improvement during at least one weekly visit; 33 improved abruptly and 39 improved gradually. The abrupt improvements occurred significantly earlier in the trial and were less likely to persist than the gradual improvements regardless of when they occurred. CONCLUSIONS: These data suggest that among patients receiving placebo abrupt improvements are a form of placebo response and gradual responses may be the result of spontaneous remission. These preliminary observations require validation.
OBJECTIVE: The authors studied the responses of drug-treated patients in an attempt to validate observations about abrupt and gradual improvements in patients receiving placebo. Since previous data suggested that in the first 2 weeks of antidepressant treatment specific drug effects are unlikely, the authors hypothesized that this improvement is a placebo effect. Therefore, in the first 2 weeks of antidepressant treatment abrupt and gradual improvements should have the characteristics of their placebo counterparts. METHOD: The subjects were 263 patients in controlled antidepressant trials lasting 6 weeks. RESULTS: The percentage of abrupt improvements that occurred in the first 2 weeks was higher than that for gradual improvements. Abrupt improvements during the first 2 weeks of drug treatment were also less persistent than gradual improvements with drug and no more persistent than improvements with placebo during the same period. However, in weeks 3, 4, and 5, abrupt and gradual improvements with drug were equally persistent and both were more persistent than abrupt improvements with placebo. CONCLUSIONS: These data support the authors' findings about placebo. Abrupt improvements during treatment with both drug and placebo are more likely during the first 2 weeks of treatment and are less likely to persist than gradual improvements. The fact that persistence of abrupt improvements with drug in weeks 1 and 2 appears different from that of gradual improvements but appears no different after week 3 suggests that the mechanism of action of abrupt improvement with drug changes after week 2.