Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss.

BACKGROUND: The expanded suffocation false alarm theory (SFA) hypothesizes that dysfunction in endogenous opioidergic regulation increases sensitivity to CO2, separation distress and panic attacks. In panic disorder (PD) patients, both spontaneous clinical panics and lactate-induced panics markedly increase tidal volume (TV), whereas normals have a lesser effect, possibly due to their intact endogenous opioid system. We hypothesized that impairing the opioidergic system by naloxone could make normal controls parallel PD patients' response when lactate challenged. Whether actual separations and losses during childhood (childhood parental loss, CPL) affected naloxone-induced respiratory contrasts was explored. Subjective panic-like symptoms were analyzed although pilot work indicated that the subjective aspect of anxious panic was not well modeled by this specific protocol. METHOD: Randomized cross-over sequences of intravenous naloxone (2 mg/kg) followed by lactate (10 mg/kg), or saline followed by lactate, were given to 25 volunteers. Respiratory physiology was objectively recorded by the LifeShirt. Subjective symptomatology was also recorded. RESULTS: Impairment of the endogenous opioid system by naloxone accentuates TV and symptomatic response to lactate. This interaction is substantially lessened by CPL. CONCLUSIONS: Opioidergic dysregulation may underlie respiratory pathophysiology and suffocation sensitivity in PD. Comparing specific anti-panic medications with ineffective anti-panic agents (e.g. propranolol) can test the specificity of the naloxone+lactate model. A screen for putative anti-panic agents and a new pharmacotherapeutic approach are suggested. Heuristically, the experimental unveiling of the endogenous opioid system impairing effects of CPL and separation in normal adults opens a new experimental, investigatory area.

False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis.

A carbon dioxide hypersensitivity theory of panic has been posited. We hypothesize more broadly that a physiologic misinterpretation by a suffocation monitor misfires an evolved suffocation alarm system. This produces sudden respiratory distress followed swiftly by a brief hyperventilation, panic, and the urge to flee. Carbon dioxide hypersensitivity is seen as due to the deranged suffocation alarm monitor. If other indicators of potential suffocation provoke panic this theoretical extension is supported. We broadly pursue this theory by examining Ondine's curse as the physiologic and pharmacologic converse of panic disorder, splitting panic in terms of symptomatology and challenge studies, reevaluating the role of hyperventilation, and reinterpreting the contagiousness of sighing and yawning, as well as mass hysteria. Further, the phenomena of panic during relaxation and sleep, late luteal phase dysphoric disorder, pregnancy, childbirth, pulmonary disease, separation anxiety, and treatment are used to test and illuminate the suffocation false alarm theory.

Clinical psychopharmacologic practice. The need for developing a research base.

The advent of psychotropic drugs has enormously improved psychiatric care. Nonetheless, our practice is not optimum. Current knowledge is not regularly applied. It has been repeatedly shown that the majority of patients with psychiatric illness go undiagnosed, and even if diagnosed, they are inappropriately or ineffectively treated, both by clinical psychiatrists and by primary care practitioners. Improved care depends on practitioner education, often referred to as "technology transfer."

Methylphenidate effects in learning disabilities. Psychometric changes.

Sixty-one children of average intelligence with appreciable learning lags, but no behaviour disorders, received placedo or methylphenidate hydrochloride for a 12-week period. Methylphenidate was instrumental in improving performance on many psychological tests, but did not affect performance on standardized achievement tests. None of the patient characteristics investigated was stringly predictive of drug effect. Methylphenidate seems to have a specific effect on visualmotor processes, which in turn positively affect performance tasks, but not verbal tasks. Under the conditions of this study, methylphenidate treatment alone did not emerge as a useful agent for the amelioration of reading performance, although the data provide evidence for stimulation effects on children's cognitive functions.

Smoking and panic attacks: an epidemiologic investigation.

BACKGROUND: Epidemiologic studies have reported a lifetime association between smoking and panic disorder. In this study, we examine potential explanations for this association. METHODS: Analysis was conducted on data from 2 epidemiologic studies, the Epidemiologic Study of Young Adults in southeast Michigan (N = 1007) and the National Comorbidity Survey Tobacco Supplement (n = 4411). Cox proportional hazards models with time-dependent covariates were used to estimate the risk for onset of panic attacks associated with prior smoking and vice versa, controlling for history of major depression. The role of lung disease in the smoking-panic attacks association was explored. RESULTS: Daily smoking signaled an increased risk for first occurrence of panic attack and disorder; the risk was higher in active than past smokers. No significant risk was detected for onset of daily smoking in persons with prior panic attacks or disorder. Exploratory analyses suggest that lung disease might be one of the mechanisms linking smoking to panic attacks. CONCLUSIONS: The evidence that the association between smoking and panic disorder might result primarily from an influence in one direction (i.e., from prior smoking to first panic attack) and the possibility of a higher risk in active than past smokers suggest a causal hypothesis for the smoking-panic attacks relationship.

Neurologic soft signs in schizophrenia and character disorders. Organicity in schizophrenia with premorbid asociality and emotionally unstable character disorders.

Previous studies indicated that for two subgroups of patients, schizophrenics with premorbid asociality (SPA) and individuals with emotionally unstable character disorders (EUCD), central nervous system damage may have etiologic significance. It was hypothesized that these two patient groups would also have an increased number of neurologic soft signs. The relationship of neurologic examination, tests of auditory-visual integration, and intelligence quotient, and diagnoses was studied for 350 patients. Tests of reliability and persistence for all observed signs were performed. The EUCD and SPA groups had increased evidence of neurologic soft signs. Differences in patterns of IQ scores also suggest that different forms of brain damage may be present in these two groups. When the two groups were removed from the larger patient sample, those patients with other types of schizophrenia and character disorder did not exhibit evidence of neurologic impairment. This study of neurologic soft signs adds to the validity of considering SPA and EUCD as separate diagnostic entities.

Prophylaxis of affective disorders. Current status of knowledge.

A review of all properly controlled studies clearly indicates that lithium carbonate is prophylactic for mania in bipolar patients; it is suggestive of prophylaxis for depression in both bipolar and unipolar patients. Studies are outlined that would clarify lithium carbonate's prophylactic effect for depression in these two patient groups. Continuation therapy with antidepressants reduces incidences of recurrence in unipolar depressives. The only controlled study indicates that tricyclic antidepressants may have prophylactic effect in unipolar patients. This finding needs confirmation. Data are insufficient for conclusions on prophylactic treatment for schizoaffective disorders.

Very high dosage vs standard dosage fluphenazine in schizophrenia. A double-blind study of nonchronic treatment-refractory patients.

Previous work with chronic schizophrenic patients and a pilot study with nonchronic treatment-refractory schizophrenic patients indicated that very high doses of fluphenazine hydrochloride (1,200 mg/day) have a greater antipsychotic effect than do standard doses. Increased side-effects were not reported. In a double-blind six-week random assignment study, 18 nonchronic treatment-refractory patients received the very high dose and 13 the standard dose. The standard-dose treated patients had greater improvement on a variety of measures. Analysis of Inpatient Multidimensional Psychiatric Scale scores indicate that some patients taking very high doses had akinesia, and extrapyramidal side-effect that in part accounted for their inferior response.

Monoamine oxidase inhibitors. A review of antidepressant effectiveness.

Data from double-blind, placebo-controlled trials of the monoamine oxidase (MAO) inhibitors show that phenelzine is clearly effective in neurotic or atypical depressives, but the findings concerning its effect in endogenous depressives are inconclusive. Although few controlled studies have been done with tranylcypromine, similar conclusions are warranted. Studies have contrasted MAO inhibitors and tricyclic antidepressants (TCAs) to gain further information about the type of patients likely to respond to MAO inhibitors. We believe that simply contrasting the relative efficacy of TCAs and MAO inhibitors is outdated. Neurotic or atypical depression is probably a heterogeneous syndrome, and delineation of subtypes responsive to specific antidepressants is needed. The implications of fast acetylation, selective MAO inhibitors, types MAOA and MAOB, and measures of platelet MAO inhibition are discussed in this article.

Fluphenazine decanoate, oral fluphenazine, and placebo in treatment of remitted schizophrenics. II. Rating scale data.

This study of patients with remitted chronic schizophrenia in an aftercare clinic was designed to test whether such patients require maintenance antipsychotic medication. A previous report showed that the group receiving active medication, fluphenazine decanoate and oral fluphenazine, had far fewer relapses; but the former group had a high incidence of akinesia. This present report presents rating scale data substantiating these two findings: (1) patients terminated on clinical grounds because of a schizophrenic relapse showed rating scale changes consistent with that diagnosis; and (2) the patients removed due to severe akinesia showed a worsening on items selected a priori to measure akinesia, and when compared to survivors on the same items, showed significant differences--thus confirming our clinical judgments.

Panic and avoidance in agoraphobia. Application of path analysis to treatment studies.

We explored a causal sequence between panic and avoidance to provide recommendations for psychotherapy, pharmacotherapy, and their combination in treating agoraphobia. We produced a two-way [( imipramine hydrochloride vs placebo] by [office-based behavioral therapy vs in vivo exposure]) design by amalgamating two studies. We assessed agoraphobic patients for panic and avoidance at these time points: baseline (week 0), midcourse (week 13), and termination (week 26). The causal sequence model was tested by path analysis. Imipramine was superior to placebo in lowering panic and avoidance at both postbaseline time points. Exposure was superior to office-based treatment in lowering avoidance only at week 13. Exposure appeared to produce quicker improvement of avoidance than office-based therapy, but relapse occurred if this improvement was not supported by medication. Exposure did not benefit panic. We believe patients should be informed that imipramine is superior to exposure in inducing a panic-free state. Exposure without imipramine is of benefit only in reducing avoidance, but adding imipramine to exposure is necessary for panic control and substantially improves exposure and exposure maintenance.

Discordance between the SCL-90 and therapists' psychopathology ratings.

This study examines the symptom checklist 90 (SCL-90), a patient self-report rating scale, as a screening and baseline psychopathology measure in an outpatient clinic. A low correlation (r = .17) was found between the SCL-90 and the SCL analogue, a matched psychopathology instrument rated by clinicians. The most common causes of discordance in ratings were patients' underreporting of symptoms due to patients' paranoia or fearfulness, overreporting of symptoms consistent with patients' "demonstrative" style, and false-positive items related to patients' physical illness. We conclude that the SCL-90 has limited validity as a clinical measure in the study of patients seen in evaluation in our setting.

Fluphenazine decanoate, fluphenazine hydrochloride given orally, and placebo in remitted schizophrenics. I. Relapse rates after one year.

In a simple remitted, nonpsychotic schizophrenics, the relapse rate within one year was significantly higher for those patients taking placebo as opposed to those taking fluphenazine hydrochloride orally or fluphenazine decanoate. There were no differences in relapse rates between the two active drugs, but there were significantly more terminations due to toxicity from fluphenazine decanoate than from pluphenazine given orally, entirely due to the fact that in 35% of patients receiving fluphenazine decanoate, severe akinesia developed.

Are prophylactic antiparkinson drugs necessary? A controlled study of procyclidine withdrawal.

Of 55 aftercare patients receiving long-term treatment with antipsychotic and antiparkinson (AP) drugs, 37 were switched to being given placebo, and 18 remained on a regimen of procyclidine hydrochloride. The dose of antipsychotic was kept constant. After three weeks extrapyramidal side effects (EPS) developed in 54% of those patients receiving placebo and in none of those receiving procyclidine (P less than .002): Twenty-seven percent of the placebo group had EPS without akinesia, and in the same percentage akinesia developed (P = .003). We believe the risk-benefit ratio favors the routine use of AP drugs for prophylaxis and maintenance so as to avoid misdiagnosing as psychopathology, unspontaneity due to akinesia, and to reduce unreliable pill-taking due to EPS.

Clinical effectiveness of "short" vs "long" psychiatric hospitalization. I. Inpatient results.

To evaluate the clinical effectiveness of short-term (three month maximum length of stay) and long-term (discharge based on clinical judgement) hospitalization, the inhospital course of 68 "short-" and 58 "long-term" psychiatric patients was studied. The results indicate that patients assigned without bias to short-term patterns, however, indicated that these results could be entirely accounted for by the significantly greater use of group therapy as an additional treatment modality in the short-term units. The need for a more systematic exploration of the effect of restricted hospital stay on the treatment patterns of the clinician and the effect of these differential treatment patterns on inhospital improvement is emphasized. The necessity for follow-up data to gain a complete picture of these treatment contrasts is clear.

Behavior therapy, supportive psychotherapy, imipramine, and phobias.

In a controlled outcome study of phobias, 111 adult patients (69% women, 31% men) received a course of 26 weekly treatment sessions consisting of (1) behavior therapy and imipramine hydrochloride (2) behavior therapy and placebo, or (3) supportive psychotherapy and imipramine. Patients were classified as agoraphobic, mixed phobic, or simple phobic. The great majority of patients in all groups showed moderate to marked global improvement (70% to 86%, depending on rater). In agoraphobics and mixed phobics (both groups experiencing spontaneous panic attacks), imipramine was significantly superior to placebo. There was no difference between behavior therapy and supportive therapy, both resulting in high improvement rates (76% to 100%, depending on rater). In simple phobic patients, there was a high rate of improvement with all treatment regimens (72% to 93%, depending on rater), with no significant difference between imipramine and placebo or between behavior therapy and supportive therapy. Of 88 moderately to markedly improved patients followed up for one year after completing treatment, 83% maintained their gains and 17% relapsed. No patients showed symptom substitution. Eighteen percent of the patients receiving imipramine hydrochloride showed marked stimulant side effects on from 5 to 75 mg/day.

Treatment of agoraphobia with group exposure in vivo and imipramine.

Seventy-six white agoraphobic women, 21 to 45 years old, were treated with combined group exposure in vivo and imipramine or placebo in a randomized double-blind study. A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement. However, imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement: primary phobia, spontaneous panic, and global improvement. There was a negative correlation between depression and outcome; ie, the more depressed patients fared worse on several outcome measures than those who were less depressed. A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment, but no significant difference between the two groups at the completion of therapy.

Methylphenidate and growth in hyperactive children. A controlled withdrawal study.

The effect of stimulants on growth has been controversial. Among hyperactive children receiving long-term methylphenidate hydrochloride treatment, we examined the effects of methylphenidate withdrawal on the growth of hyperactive children randomly assigned to be taken off, or remain on, the medication regimen over two consecutive summers. After one summer, no group difference in height was found, but weight was higher in the group that had been taken off methylphenidate therapy. In contrast, two summers of being off methylphenidate treatment had a significant positive effect on height but not on weight. The results document a linkage between exposure to methylphenidate and reduction in growth velocity. However, they do not address whether the medication has long-term effects on height.

Cortisol and sodium lactate-induced panic.

Sodium lactate infusions induce panic attacks in patients with panic disorder, but not in normal controls, by an unknown mechanism. We studied the plasma cortisol response to infusion of 0.5 mol/L of sodium lactate in 103 patients with panic disorder or agoraphobia with panic attacks, and 32 normal controls. Baseline cortisol levels did not distinguish early panickers from non-panickers and controls, but late panickers had significantly elevated baseline cortisol levels. In addition, a higher percentage of late panickers manifested an increase in cortisol during the baseline period compared with the other groups. Despite the fact that late panickers manifested elevated baseline cortisol levels, early panickers had significantly greater somatic distress as measured by the Acute Panic inventory. There was no increase in cortisol with lactate-induced panic, and cortisol levels fell significantly during the lactate infusion in all groups. Cortisol elevation occurred with moderate anxiety but not with severe panic anxiety. These results suggest different pathophysiologic mechanisms of early and late panic, and differences between anticipatory anxiety and panic anxiety.