Decreased intracranial self-stimulation in a new animal model of endogenous depression

Neonatal treatment of rats with clomipramine may produce adult animals which model endogenous depression. We report here that a major factor of depression in humans, the diminished capacity for pleasure, appears present in these rats. At age 7 months, bar-press responding for rewarding hypothalamic stimulation is reduced across a range of intensities. At age 4 or 5 months this effect is not seen, although other behavioral abnormalities are present at the younger age. The delayed onset of diminished intracranial self-stimulation may relate to the gradual insidious onset of endogenous depression in humans.     

Diminished sexual activity in a new animal model of endogenous depression

Our laboratory has proposed a new animal model of endogenous depression. The proposal is that in rats neonatal clomipramine (CLI) produces adult animals that model endogenous depression. Diminished sexual activity is a salient behavioral abnormality found in endogenous depression. This suggests that an animal model of endogenous depression should show diminished sexual activity. We report here a test of the prediction that after neonatal treatment with CLI, adult male rats show decreased sexual activity. We found that after neonatal CLI, adult male Long-Evans rats had a pervasive diminution of sexual activities including decreased mounts, intromissions, ejaculations, and increased mount latencies and postejaculatory pause. Sprague-Dawley and Wistar strains also tended to show decreased intromissions and ejaculations, but their baseline sexual activity was too low to give interpretable data. The results with the sexually active Long-Evans strain are consistent with the hypothesis that neonatal CLI produces adult rats that model human endogenous depression.     

Drug effects on REM sleep and on endogenous depression

In earlier work REM sleep deprivation (RSD) by arousals improved endogenous depression. This suggested that drugs producing a similar RSD would have antidepressant activity. The arousal RSD was large, persisted for weeks, and was followed by a REM rebound. We call RSD with these properties arousal-type RSD. The present study reviewed literature from 1962 to 1989 on drug REM sleep effects to examine the hypothesis that drugs producing arousal-type RSD improve endogenous depression. The literature reviewed concerned the REM sleep effects of amine precursors, antidepressants, antihistamines, antipsychotics, barbiturates, benzodiazepines, other hypnotics, drugs affecting cholinergic and noradrenergic neurotransmission, ethanol, lithium and narcotics. Four hundred and sixty-eight relevant papers were read and 215 contributed information that could be used in the review. The findings indicated that all drugs producing arousal-type RSD improved endogenous depression. Four drugs that improved endogenous depression did not produce arousal-type RSD.     

Procedure- and age-dependent hyperactivity in a new animal model of endogenous depression

We have replicated the findings of Mirmiran and colleagues that neonatal administration of the antidepressant clomipramine (CLI) to male rats results in hyperactivity in open-field tests in adulthood. We report that this effect does not reliably occur in a "Digiscan" activity device. The difference in effect between the two activity measuring devices may be due to more stress being present in the open-field test, and we propose that the CLI-treated rats may be more reactive to stress. This hypothesized enhanced reactivity to stress may be similar to the proposed vulnerability of depressed humans to stress. In addition, we have found that the open-field effect does not occur until the rats are at least 4 months old; this delayed effect may be analogous to the progressive onset of endogenous depression in humans.     

抑郁症患者REM睡眠研究

目的：探讨抑郁症患者快眼动睡眠的异常改变以及与临床的相关性。方法：对１８例抑郁症患者和１９名正常对照者进行睡眠脑电图检查,并予以比较。结果;抑郁症患者出现明显的ＲＥＭ潜零碎 期缩短和ＲＥＭ密度增加,且与抑郁严重程度显著相关。结论：ＲＥＭ睡眠的潜伏期缩短和密度增加可作为抑郁症诊断中具有参考价值的生物学指标。     

A new animal model of endogenous depression: a summary of present findings

In 1982 our laboratory proposed a new animal model of endogenous depression. The proposal was that in rats, neonatally administered clomipramine (CLI) will produce adult animals that model endogenous depression. We summarize here several tests of the validity of the model. Results were that after neonatal CLI, adult male rats showed behavioral abnormalities of the human disorder: decreased sexual, aggressive, and intracranial self-stimulation activities, as well as motor hyperactivity in a stressful situation. Preliminary evidence suggested that behavioral abnormalities in rats (sexual, aggressive, and motor) briefly treated with antidepressant treatments (imipramine, REM sleep deprivation) begin to normalize. Lastly, after neonatal CLI, the adult rats showed REM sleep abnormalities of endogenous depression, viz, low REM latency, frequent sleep onset REM periods, and abnormal temporal course of REM rebound after REM sleep deprivation. These results supported the hypothesis that in rats neonatal CLI produced adult animals that modelled endogenous depression.     

REM sleep abnormalities and psychiatry.

Since the 1950s, with the discovery of REM sleep and its relationship to dreaming, psychiatric sleep researchers have been interested in uncovering the complex relationship between disturbed sleep and psychiatric disorders. This paper reviews the alterations in REM sleep of relevance to psychiatry and indicates that continued developments in sleep research may assist in further understanding the neuropathophysiology of affective and other psychiatric illnesses.     

REM sleep latency and contingent negative variation in endogenous depression suggestion for a common cholinergic mechanism

In a sample of 13 endogenous depressive inpatients, REM (rapid eye movement) latency (recorded over 4 consecutive nights after 2 habituation nights) and contingent negative variation amplitude showed significant relationship, suggesting that both parameters may depend on the same mechanisms, possibly cholinergic.     

Cholinergic REM sleep induction in atypical depression

The arecoline REM induction test, a measurement of central cholinergic sensitivity, was performed in 10 patients with atypical depression. Arecoline induced REM sleep significantly more rapidly than placebo. Atypical depressives without evidence of anxiety, in particular those without panic attacks, had a more rapid REM induction response to arecoline than atypicals with anxiety symptoms. We compared our atypical depressives with normal controls and affectively ill patients studied in other laboratories. The rapid REM induction response observed in atypical depressives without anxiety was comparable to that seen in endogenous depressives and euthymic bipolars. Previous studies have demonstrated the presence of cholinergic supersensitivity in the latter two groups of patients. Our results suggest that atypical depressives may be distinguished in their response to arecoline based on their anxiety history, and that cholinergic supersensitivity is present in atypical depressives without anxiety. Additional studies with larger samples and simultaneously studied control groups are necessary to test these preliminary findings.     

REM sleep abnormalities in severe athetoid cerebral palsy

Various abnormalities of sleep have been reported in extrapyramidal diseases in adults. We have investigated the disturbances of REM sleep (SREM) in severe athetoid cerebral palsy (ACP) originating perinatally. Ten ACP patients, 5 males and 5 females ranging from 15 to 30 years old, were studied by means of all-night polygraphic examination. Three cases showed a marked decrease in rapid eye movements in SREM. Moreover, the tone of submental muscle in SREM was also disturbed in three. Regarding body movements during sleep, gross movements and twitch movements of the submental muscle were analyzed. In most of the patients, an abnormal distribution of body movements according to sleep stages was observed, the rate being significantly reduced in SREM. REMs, atonia and body movements are considered to be related to the brainstem function in animals. The results of the present study suggest that perinatal extrapyramidal diseases could also coincide with brainstem dysfunctions.     

REM sleep in primary depression: a computerized analysis.

REM sleep in 35 inpatients with primary depression was automatically analyzed for 7 consecutive nights during placebo administration. For the total night of sleep, as well as each individual REM period, the number of REMs, their total voltage integral over time, the sum of their durations and the average REM size were automatically calculated. Validity of these automated REM measures was established by significant correlations with manually scored REM measures. Changes in REM sleep across the night were also investigated. Similar to findings in normal subjects, REM time did not change from REM period to REM period. Average REM size increased significantly from REM period 2-3 and 3-4. Contrary to what is seen in normal subjects, REM frequency was high during the first REM period, significantly decreased from the first to second REM period and then remained constant. Finally, a significant inverse correlation between REM frequency for the first REM period and REM latency was noted. This pattern of REM sleep is interpreted as indicating a high pressure for phasic REM at the beginning of the night which is dissipated by the first REM period.     

REM sleep in depression is influenced by ethnicity

The influence of ethnicity on the manifestation of EEG sleep changes in depression was studied in 95 patients (21 African-Americans [AA], 17 Asians [AS], 37 Caucasians [C] and 20 Hispanics [H]) with unipolar major depression. Subjects were studied twice for 2 consecutive nights. On the second night of each 2-night session, placebo or scopolamine (1.5 microg/kg, IM, at 23.00 h) was administered. On the baseline (placebo) night, sleep architecture, sleep continuity and rapid eye movement (REM) sleep variables were generally comparable among the groups. However, REM sleep was less in AA and AS subjects than in C and H subjects. Furthermore, the distribution of REM sleep over the course of the night in AA and AS subjects differed significantly from that in the C and H groups. Although scopolamine significantly affected sleep continuity and REM sleep measures, no significant differential effects of scopolamine were observed. Because many antidepressants suppress REM sleep, the differences in baseline REM sleep observed might be related to the greater sensitivity of some ethnic-minority depressed patients to pharmacotherapy.     

REM sleep,naps, and depression

Continued interest in rapid eye movement (REM) sleep abnormalities in depression stimulated comparative studies on daytime naps versus nighttime sleep. In a group of 15 depressed patients, REM latencies in morning and afternoon naps were similar to the shortened REM onset at night. Although REM latency did not vary across the three times, the propensity for REM sleep appeared to be greater in the morning nap than in the afternoon nap and the early portion of nocturnal sleep. Finally, the data suggest that responders to tricyclic treatment tend to be poor sleepers during daytime naps.     

REM latency in neurotic and endogenous depression and the cholinergic REM induction test

Latency of rapid eye movement (REM) sleep was measured in eight healthy volunteers under baseline conditions and after administration of physostigmine. An infusion of 0.5 mg of physostigmine 5 minutes after sleep onset caused a significant shortening of REM latency in comparison with baseline conditions. In 45 patients with major depression, REM latency during baseline nights was significantly shorter than in control subjects. This shortening of the REM latency was found to be similar in endogenous, neurotic, and unclassified depressed patients. In contrast to findings in the controls, the physostigmine infusion provoked no further significant reduction of REM latency in depressed patients, but awakened the majority of patients. The data concerning spontaneous REM latency and REM latency after physostigmine do not allow a differentiation among the endogenous, neurotic, and unclassified depressed subgroups. The results of the cholinergic REM induction test do not conclusively support the hypothesis of a cholinergic hypersensitivity in depression.     

Bimodal distribution of REM sleep latencies in depression.

The REM sleep latency of endogenously depressed patients was investigated by analyzing 90 polysomnograms of six patients during depression and 58 polysomnograms of four of these patients after remission. During depression the REM sleep latencies are distributed bimodally with peaks at sleep onset (sleep onset REM phases, SOREMPs) and 60 min later. During the follow-up examinations some time after remission, the occurrence of SOREMPs is very rare. A model is proposed according to which the occurrence of SOREMPs in the sleep of these patients is caused by a reduced amplitude of the circadian rhythm of the arousal system.     

Minute-by-minute analysis of REM sleep timing in major depression

Sleep changes described in depressed patients may represent alterations in the timing of rapid-eye-movement (REM) sleep or sleep onset. We examined these variables in groups of healthy control subjects (n = 47), depressed outpatients (n = 98), and depressed inpatients (n = 41). Outpatient depressives had greater severity of clinical symptoms than inpatients using the Hamilton Rating Scale for Depression. The depressed inpatient group had a later mean sleep onset time than the other groups, and the depressed outpatient group had a wider range of good night times than control subjects. REM timing in each group was examined as a relative frequency distribution of REM sleep (FDRS) for each minute across the night. The FDRSs for the three groups were statistically compared using the parameters from a two-component model, which includes a deterministic sinusoidal function and a time series process for errors. The slope of the linear trend in the FDRS rhythm was smaller (less positive) for both depressed groups than for controls. The ultradian FDRS rhythm occurred at an earlier phase, relative to sleep onset, in the inpatient depressed group compared to the control group. The ultradian FDRS rhythm had a longer period in the outpatient group compared to the control and inpatient groups. When referenced to 24-hr clock time in an exploratory analysis, the depressed groups appeared to have less robust FDRS ultradian rhythms than controls, but they did not appear to have a systematic phase alteration compared to controls. Abnormalities of REM sleep timing in groups of depressed patients may reflect a disturbance of sleep initiation and generation, or difficulty in entrainment of REM, rather than a systematic phase alteration in REM sleep propensity.     

REM sleep reduction effects on depression syndromes.

Thirty-four endogenous and 18 reactive, depressed patients (hospitalized and nonschizophrenic) were treated in a double-blind, crossover study of the hypothesis that rapid eye movement (REM) sleep reduction (by awakenings) relieves depression. In the endogenous group-but not in the reactive group-subjects deprived of REM sleep for three weeks improved significantly more than control subjects awakened from non-REM sleep. Therapeutic efficacy of REM sleep reduction appeared similar to reported efficacy of imipramine hydrochloride treatment of depression. Eight of nine endogenous patients, unimproved by REM sleep deprivation, did not improve with imipramine. Results suggested (1) that substantial REM sleep reduction has antidepressant activity, and (2) since imipramine and other drug antidepressants reduce REM sleep much more so than nonantidepressant drugs, that an antidepressant "mechanism" of drugs resides in their capacity to substantially reduce REM sleep.