Sleep Disorders Center, Baptist Memorial Hospital and "Department of Psychiatry, University of Tennessee, Memphis, Tennessee, 38163
Patients with fear or depression of long standing are subject to melancholia. Hippocrates, Aphorisms V (10) A woman at Thasos became morose as the result of a justifiable grief, and . . . she suffered from insomnia, loss of appetite . . . she complained of fears and talked much; she showed despondency and . . . many intense and continuous pains. Hippocrates, Epidemics HI (10) (more…)

San Diego Neuropsychiatric Medical Clinic and Human Relations Center, Inc., San Diego, California 92103
In 1955, Goodman and Gilman in their textbook, The Pharmacologic Basis of Therapeutics, devoted only two chapters to psychopharmacology. The first chapter focused on barbiturates and the second on bromides, chloral hydrate, paraldehyde, and cannabis. Since then, the field of psychopharmacology has become much more sophisticated and, to be accepted, new pharmacologic treat­ments have had to conform to increasingly stringent scientific criteria, namely, prospective, double-blind, placebo-controlled studies. The understanding of anxiety and depression has grown considerably during this time, although it is still often difficult to separate the two in clinical practice. In addition, options for the management of these disorders have become more complex. Neuroleptics and antidepressants, including monoamine oxidase (MAO) in­hibitors and tricyclics, were introduced in the late 1950s, as were the antianxiety agents, benzodiazepines. However, chlordiazepoxide was viewed with skepticism, and in 1965, diazepam was endorsed in a lukewarm fashion. As newer anxiolytic and antidepressant treatments were investigated, some (e.g., subcoma insulin, atropine coma therapy, and hypnotherapy) were never incorporated as standards because of lack of efficacy or because of failure to compare favorably with more acceptable modes of therapy. Others (e.g., electroconvulsive therapy) were used only for the treatment of the most severe complications of these disorders, such as depression unresponsive to pharmacotherapy. In some cases, treatments have withstood the test of time. These include thioridazine for the treatment of anxiety associated with allergic bronchial asthma and combined neuroleptic-antide­pressant therapy for some phobic disorders associated with paranoid ideation and depression that preceded or were associated with anxiety. (more…)

There exist a group of patients commonly seen in primary care as well as psychiatric settings that exhibit admixtures of depressive and anxiety symptoms that fluctuate over time on a subacute or chronic basis. They are variously referred to as anxious depressives, mixed anxiety depressives, and atypical depressives. A longitudinal perspective is necessary to determine the temporal relationship between the depressive and anxiety symptoms. When anxiety symptoms antedate depressive manifestations —and this is often the case in young individuals—then the likelihood is that this is a neurotic illness complicated by depression. Patients who have suffered from many years of generalized anxiety or full-blown panic attacks gradually get demoralized and disgusted with themselves; insomnia in the first half of the night leads to a tendency to feel fatigued and hypersomnolent in the morning, hence the origin of several of the symptoms that are considered to be atypical depressive manifestations. Even in the original British reports (13,17), these atypical depressive patients with neurasthenic symptoms were ba­sically considered anxiety neurotics. In these patients studied in our sleep lab­oratory, polysomnographic findings have failed to reveal REM sleep findings characteristic of primary depressive illness, and instead have shown features observed in anxiety disorders (i.e., multiple awakenings in the first half of the night). Hence our contention that a subgroup of atypical depressives is more appropriately described as atypical anxiety disorder, and would therefore benefit from monoamine oxidase inhibitors or alprazolam. Other depressives with atyp­ical features conform to the subaffective dysthymic pattern and are more likely to respond to noradrenergic tricyclics and lithium carbonate (1); these patients represent genuine forms of primary mood disorder and are unrelated to anxiety disorders. In other words, there seem to be at least two types of atypical depression (7), of which one with anxious depressive features is more accurately classified as an anxiety disorder. When anxiety symptoms occur in the setting of depressive manifestations — and this is often the case in older individuals—one must give preference to the diagnosis of a primary depressive illness. As emphasized in DSM-III (6), an anxiety disorder rarely, if ever, begins after the age of 40. Unfortunately, this fact is sometimes forgotten and manifestations indicative of autonomic nervous system hyperactivity are automatically ascribed to a neurotic illness. Indeed, once physical illness is excluded, the diagnosis of an anxiety state, rather than primary depressive illness, is initially entertained by many primary care physi­cians. What complicates differential diagnosis is the fact that some of these pa­tients completely deny the subjective psychological symptoms of mood disorder, e.g., depression, anhedonia, lowering of self-esteem, guilt, suicidal ideation, etc. Among the masked depressives studied in our sleep laboratory, about a dozen were middle aged or elderly patients (in their late 40s or older) who presented with such symptoms as sudden awakening with intense autonomic arousal and the fear of dying in their sleep. None of these patients had experienced panic attacks in their younger years or had premorbidly exhibited neurotic patterns. Elderly individuals with no psychiatric illness showed modest shortening of their REM latency. But even after taking this fact into consideration, the patients we studied with fear of dying in their sleep and other autonomic manifestations of anxiety had sleep EEG findings characteristic of primary depression. It would appear that the mere presence of anxiety attacks is not diagnostic of anxiety neurosis in that such attacks appearing for the first time after age 40 may represent affective equivalents. Melancholic patients presenting in this way are typically agitated and experience intense apprehension; they may even harbor delusions regarding calamities to themselves and their loved ones, which confirms the diagnosis. These agitated melancholias should be treated like other primary depressives. The use of benzodiazepines, if needed, should be purely on a symp­tomatic basis and limited to short periods of time to supplement standard an­tidepressant therapy.

This report is based on a group of patients who presented seeking relief from a primary complaint of anxiety in two ambulatory settings for the treatment of anxiety. They represent a convenience sample gathered from sequential admissions,
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*Department of Psychiatry, University of Milan Medical School, 20161 Milan, Italy; **Department of Pharmacology, University of Milan Medical School, 20129 Milan, Italy; + Ravizza Clinical Research Laboratories, 20053 Muggio, Italy
The administration of long- and intermediate-acting benzodiazepines for the symptomatic relief of anxiety and mixed anxious-depressive syndromes is gen­erally viewed as safe and effective. Among the most widely prescribed anxiolytics in this country are chlordesmethyldiazepam (CDDZ), a derivative of diazepam’s major active metabolite with a half-life of about 83 hr in young adults (4), and alprazolam (APZ), a triazolobenzodiazepine with a half-life ranging from 11 hr in young males to 19 hr in elderly ones (10). Both drugs show the full spectrum of clinical and side effects of the classical minor tranquilizers and have been consistently shown to be more effective than placebo in the short- and long-term treatment of anxiety (1,8). The efficacy of the two compounds, however, has never been tested by direct comparison in a psychiatric population. As interest for newer and more selective anxiolytics grows, clinicians have shifted their attention from effectiveness against so-called target symptoms to a more solid concern for the short- and long-term sequelae of benzodiazepine administration (12). One of the most debated consequences regarding benzodiazepine hypnotics is the increase in daytime sleepiness above baseline levels. This has been both subjectively reported by patients receiving intermediate- and long-acting com­pounds in clinical doses, and objectively demonstrated for at least several days after the initial dose (5). Nonetheless, many anxious and anxious-depressed subjects appear to adapt quickly to the hypnogenic effect of anxiolytics, especially if the dose is slowly increased and well titrated against the more unpleasant symptoms. The intro­duction of standardized EEG laboratory techniques for the objective assessment of sleepiness, such as the multiple sleep latency test (MSLT) (6), however, has seriously challenged the reliability and accuracy of self-rated vigilance estimates (7). Some individuals seem to grossly over- or underestimate their capacity to maintain steady vigilance levels throughout the day. The inaccuracy seems par­ticularly evident in neurotic and anxious people who claim to be hyperalert even when taking sedative anxiolytics. In fact, subgroups of chronic insomniacs have been shown to have MSLT profiles similar to those of age-matched con­trols (14). Acute administration of hypnotic benzodiazepines produces daytime carryover effects that are dependent on the dose taken at night and on the pharmacokinetic characteristics of the compounds. Thus, the MSLT has been employed partic­ularly for the quantification of daytime residual effects on vigilance (9). It has been shown, for example, that short-acting hypnotics tend to produce less daytime somnolence than long-acting drugs (5). In fact, the MSLT can also be profitably applied for assessing the daytime somnolence of anxious patients who receive benzodiazepines exclusively during the daytime for the control of anxiety. This approach may be even more informative and clinically useful than the study of carryover effects since most anxious and anxious-depressed subjects need the anxiolytic effect, but not the excessive daytime sedation that causes a dramatic drop in their already reduced mental efficiency. In order to obtain a profile of daytime sleepiness in a target population, we have adopted the MSLT procedure in two groups of anxious middle-aged patients who were undergoing anxiolytic treatment with CDDZ and APZ. (more…)

Further support for the view that the therapeutic effect of tricyclic antide­pressants extends well outside the classical spectrum of severe endogenous depressions comes from a study that we have recently undertaken and that is currently being analyzed. This is a placebo-controlled trial of amitriptyline in depressions presenting in general practice. We were interested in this problem because the majority of depression in Britain are treated by general practitioners, only about one in ten being referred to psychiatrists. We had undertaken earlier a study (35,36) that confirmed the general impression that such depressions are relatively mild, differing markedly in severity and quality from psychiatrically treated depressions. Even in com­parison with outpatient depressives, general practice depressives were less severely ill, less often primary, endogenous, or retarded. Most of the evidence for the efficacy of tricyclic antidepressants depends on controlled trials carried out in psychiatric outpatients or inpatients. We have, therefore, undertaken a controlled trial in general practice laying considerable emphasis on classificatory data to enable a search for those subgroups who show or fail to show drug/placebo differences. One hundred and forty-one depressives identified in general practice and sat­isfying the Research Diagnostic Criteria for major or minor depression were treated for at least 4 weeks and in most cases 6 weeks with amitriptyline or placebo double-blind. The mean doses in the fourth week and sixth week were approximately 120 mg daily. Mean initial total scores on the 17-item Hamilton Rating Scale for Depression were closely identical and were a little below 15, confirming the relative mildness of the sample. Differences started to appear surprisingly early and at 2 weeks had reached significance on this scale, although not on some others. By 6 weeks, highly significant differences had appeared on a wide variety of outcome measures with amitriptyline very impressively superior to placebo. It has sometimes been argued that the effects of tricyclic antidepressants in mildly depressed patients in general practice are largely owing to sedation and effects on sleep. We, therefore, examined a wide set of symptom ratings, partic­ularly from the Hamilton Rating Scale and the Clinical Interview for Depression (21). Individual symptom ratings showing drug/placebo differences by compar­ison of change scores using /-tests at the end of the study included, in addition to insomnia, a variety of core symptoms of depression, particularly depressed mood, guilt, pessimism, hopelessness, and depressed appearance. The effect was clearly a true antidepressant one, and it was also shown on a number of global measures. In order to examine for responsive subgroups we carried out a series of two-way analyses of covariance with initial level as covariate and using as the second factor a variety of classifications from the literature. We sought interactions that would indicate differential drug placebo differences. We analyzed six rel­atively global outcome measures and since this involved a comparatively large number of analyses, we have only accepted them for further examination when at least two of the six outcome measures in a subgroup showed significant interactions at the 5% level or better. The analyses are still in progress. So far, significant interactions have been relatively few, indicating fairly strong and consistent drug effects across most subgroups. Initial subgroups examined reflect demographic variables, history of chronicity, severity of depression, and endogenous versus neurotic depression in terms of symptoms or precipitant stress. Only in one area, severity, were there interactions, and even here they were relatively weak, only reaching 5% significance in two of the six analyses, although there were consistent effects at around the 10% level on the other out­come measures. These two subgroups, based on RDC major versus minor depression and on severity on the Hamilton Scale do show an illuminating pattern. The distinction between RDC major and minor depression depends mainly on the number of concomitant symptoms of depression that are present. For minor depressions of less severity, drug and placebo groups both improved but remained closely similar. For major depressions, starting with more severity, the amitriptyline group improved considerably more than the placebo group to reach levels at the end of the study similar to those of the minor depressives. Active drug was beneficial to major depressives but not to minor. On initial Hamilton Score, we divided the sample into three groups: the most mild, with Hamilton scores below 13; intermediate, with initial scores 13 to 15; and relatively more severe, with scores over 16. Even these patients were not very severely ill, only comparable with psychiatric outpatients. We found a very similar pattern in outcome to that based on major and minor depression. Here, however, it was only the very mildly ill patients who showed no benefit from the active drug: there were considerable drug/placebo differences for the two other patient groups, and again the effect was to produce final scores from ami­triptyline close to those of the mildly ill. There appears to be a level that the milder patients reach spontaneously, which represents improvement rather than no change and which is as much as can be achieved in 6 weeks. The effect of the active drug is to move the patients in the higher ranges of what is still a relatively mild disorder down to this level. A similar analysis has been carried out to compare patients scoring higher and lower on anxiety. So far only a single grouping has been examined, depending on total scores from the Clinical Interview for Depression, for depression and for anxiety. Using initial scores we sought to define two groups, high on anxiety but low on depression and high on depression but low on anxiety. There was, as might be expected, considerable overlap. We have carried out a similar analysis with these two groups. There were no significant interactions between this group­ing and drug effects at the end of 6 weeks.

In addition to ratings on these items, the scales in Table 3 were completed by the interviewer or patient as appropriate; the listing refers to the individual scales applied to consecutive patients. The numbers completing the self-rating scales
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