Effects of clomipramine infusion on sleep in depressed patients

Sleep structure of 10 endogenous depressed patients was investigated before and after clomipramine treatment. Clomipramine significantly reduced REM time, increased REM latency and induced dissociation between the tonic and phasic events of REM sleep, without affecting any of the other sleep parameters. The REM suppressing effect was most prominent on the third night after beginning treatment.     

Clomipramine and EEG sleep in depression

Recent studies with clomipramine (CMI) have demonstrated that a pulse-loading approach is associated with a rapid improvement in symptomatology in the absence of continuous treatment. In the present study, sleep changes were evaluated to ascertain the rapidity of clomipramine's effect on electroencephalographic sleep, especially rapid eye movement (REM) and delta wave sleep measures. Clomipramine produced rapid changes in sleep with reduced sleep continuity and almost complete suppression of REM sleep as well as a redistribution of slow wave sleep. Delta waves during sleep were also found to be shifted to the earlier part of the night and increased in intensity. Spectral analysis revealed an increase in power in the delta frequency range that was correlated with clinical responsiveness. These studies point toward a role for clomipramine in the rapid treatment of depression and confirm that sleep physiology may be a good predictor of antidepressant action.     

Cortical reactivity in REM sleep with tonic mentalis EMG activity induced by clomipramine: an evaluation by slow vertex response

Slow vertex response (SVR) to sound stimuli was used as an index to assess whether cortical reactivity in REM sleep with tonic mentalis EMG activity (stage 1-REM) corresponds to that in REM sleep or rather to that in stage 1 of NREM sleep. In 11 young adult subjects 3 night polygraphic records were made after administration of 25 or 50 mg of clomipramine or non-active placebo. Stage 1-REM was observed in the drug night in 8 of the 11 subjects. N₁-P₂ and P₂-N₂ amplitudes of SVR were markedly smaller in stage 1-REM than in stage 1, but were virtually of the same height in stage 1-REM and in stage REM. This indicates that cortical reactivity in stage 1-REM closely resembles the counterpart in stage REM. This findings corresponds well with the frequent emergence of vivid dreams in stage 1-REM, indicating that stage 1-REM observed in the present subjects probably represents REM sleep without muscle atonia.     

The effects of total sleep deprivation and subsequent treatment with clomipramine on depressive symptoms and sleep electroencephalography in patients with a major depressive disorder

In the present study patients with a major depressive disorder were first subjected to total sleep deprivation (TSD) and then treated with clomipramine. Sleep electroencephalography (EEG) was registered prior to and after TSD, during the 2 initial nights of antidepressive treatment and after 19 days. A negative correlation between response to TSD and clomipramine was found. TSD did not differentially influence the sleep EEG (responders vs nonresponders): responders tended, however, to show a more classical depressive sleep pattern prior to TSD. Clomipramine profoundly suppressed rapid eye movement (REM) sleep; the amount of initial REM sleep reduction, however, did not correlate significantly with therapy response after 3 weeks of treatment.     

REM sleep abnormalities in a new animal model of endogenous depression

Endogenous depression has reliable REM sleep abnormalities. These include a short REM latency, frequent sleep onset REM periods, and after REM sleep deprivation (RSD), an abnormal temporal course of REM rebound in the presence of a normal total REM rebound. The reliability of these abnormalities suggests that they ought to be present in an animal model of endogenous depression. In 1982, we proposed a new animal model of endogenous depression. Our hypothesis is that in rats neonatal clomipramine (CLI) will produce adult animals that model endogenous depression. In this study we tested the prediction that after neonatal treatment with CLI, adult rats will show the above three REM sleep abnormalities of human endogenous depression. We found that neonatal treatment with CLI produced rats that at age 6 months had shorter REM latency, more sleep onset REM periods than control rats, and after RSD, had an abnormal temporal course of REM rebound in the presence of a normal total REM rebound. The finding of these REM sleep abnormalities supported the validity of the animal model of endogenous depression.     

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.     

Differential effects of chlorpromazine, imipramine, nitrazepam and amobarbital on REM sleep and REM density in man.

The effect of chlorpromazine (CPZ), imipramine (IMP), nitrazepam (NZP) and amobarbital sodium (AMOB) on the REM period of sleep (REMP) was investigated on four subjects by means of all-night sleep polygraphy with the schedule PPPDDDPP where P is placebo and D active drug. CPZ 25 mg resulted in a slight increase in %REMP, and no significant change in REM density (1 second fraction method) and total REM activity during the drug and withdrawal nights. IMP 25 mg produced moderate decrease in %REMP in the three drug nights, whereas REM density decreased only in the first drug night. NZP 5 mg resulted in a slight parallel suppression of %REMP, REM density and total REM activity during the drug nights. AMOB 200 mg produced a slight decrease in %REMP and marked decrease in REM density during the drug nights. Rebound increase of %REMP and a tendency of carry over decrease of REM density were observed in the withdrawal nights. Decrease in the REM density was more marked in AMOB than in NZP drug night. The importance of the simultaneous analysis of %REMP and REM density for the study of effects of psychotrophic drugs on sleep was emphasized.     

The effects of clomethiazole on polysomnographically recorded sleep in healthy subjects

Clomethiazole is widely used in European countries to treat alcohol withdrawal symptoms including delirium tremens. The current study aimed to explore the effects of clomethiazole on the sleep of healthy volunteers. We postulated both a hypnotic and a REM suppressive effect as well as the occurrence of a rebound phenomenon following three days of treatment with clomethiazole. The study group was composed of five men and five women. The probands were examined in the sleep laboratory throughout a course of seven nights. The first night was considered as the adaptation night and the second as the baseline night. Prior to nights 3 to 5, probands took 384 mg clomethiazole at 22 hours. The 6^th and 7^th nights served to record potential effects of medication discontinuation.The current study confirms the indication in the scientific literature with regard to hypnotic and REM–suppressive effects of clomethiazole, as well as a rebound phenomenon following discontinuation of the medication. The effect of clomethiazole on the sleep EEG was most obvious in the first half of the night. The analysis of the polysomnogram in terms of each half of the night gave no indication of a rebound phenomenon during the second half.The REM sleep–suppressing component of clomethiazole is of great interest in connection with its use in treating delirium tremens. The rebound phenomenon in healthy controls after only three days of medication at a relatively low dosage of clomethiazole underscores the need to administer it in doses individually tailored to the extent of the alcohol withdrawal syndrome in the individual patient.     

Studies of nocturnal penile tumescence and sleep electroencephalogram in patients with major depression and in normal controls

Nocturnal penile tumescence (NPT), sleep electroencephalogram and testosterone secretion were investigated in 25 nonmedicated male patients with an acute episode of major depression. Twelve patients were reassessed after a stable remission and withdrawal of antidepressants. Four of the 25 patients had no NPT activity during acute depression, but this was reversed after recovery. The area under the NPT curve increased after remission, whereas all other NPT variables remained unchanged. Nocturnal testosterone secretion was enhanced after recovery, whereas the sleep structure remained unchanged. The NPT findings for the depressed patients did not differ from those for a control group, even though the latter group was younger. Hence, there are no general NPT changes that could be used to separate depressed patients and normal controls. However, a lack of NPT seems to be a possible, reversible symptom of depression in men.     

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.     

Mood alterations and sleep

We have reviewed literatures about neurobiological aspect of mood disorders in the light of abnormalities of REM sleep. A shortened REM latency is a consistent finding in depressed patients and may be considered a biological marker for depression. Most depressed patients with shortened REM latency also show non-suppression on dexamethasone-suppression test (DST). The commonly used antidepressant drugs cause a significant reduction in REM sleep. Patients with abnormal DST show a better response to sleep deprivation than those with normal DST. Recent studies indicated that borderline patients, primary dysthymic patients and obsessive-compulsive patients (OCD) have shortened REM latency. Farthermore, patients with OCD have a fairly good response to antidepressant clomipramine. Diagnostic and therapeutic strategies can conceivably be related on the examination of sleep patterns of psychiatric patients.     

Mood Alterations and Sleep

Abstract: We have reviewed literatures about neurobiological aspect of mood disorders in the light of abnormalities of REM sleep. A shortened REM latency is a consistent finding in depressed patients and may be considered a biological marker for depression. Most depressed patients with shortened REM latency also show non-suppression on dexamethasone-suppression test (DST). The commonly used antidepressant drugs cause a significant reduction in REM sleep. Patients with abnormal DST show a better response to sleep deprivation than those with normal DST. Recent studies indicated that borderline patients, primary dysthymic patients and obsessive-compulsive patients (OCD) have shortened REM latency. Farthermore, patients with OCD have a fairly good response to antidepressant clomipramine. Diagnostic and therapeutic strategies can conceivably be related on the examination of sleep patterns of psychiatric patients.     

EVALUATION of SHORT-TERM and LONG-TERM TREATMENT of the NARCOLEPSY SYNDROME WITH CLOMIPRAMINE HYDROCHLORIDE

Clinical examinations, questionnaires, and 24- or 36-hour polygraphic recordings were performed on 21 adult patients with the narcolepsy syndrome to investigate the short- and long-term effects of clomipramine HCL. Cataplexy was improved by the medication, but tolerance was observed after 4 1/2 months of treatment. Clomipramine HCL induced significant changes in the sleep EEG, chin EMG, and EOG. In two patients, clomipramine HCL caused a nocturnal myoclonia that produced insomnia. Sexual side effects were seen with clomipramine HCL, particularly in males. A combination of clomipramine HCL and L-Dopa apparently prevented this difficulty in one patient. A rebound of cataplexy was seen during the 15 days following withdrawal of the drug. Methysergide maleate was found to be ineffective on cataplexy in four patients.     

Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression

Complex neurobiological models based on animal research have been formulated in an attempt to explain the cyclic pattern of nonREM and REM sleep. The "reciprocal interaction model" of nonREM and REM sleep regulation, which has been updated to incorporate new evidence is still the most convincing. Therefore it is reasonable to apply this model also to REM sleep abnormalities such as shortened REM latency and increased REM density, observed in patients with depression and alcohol dependency. In a retrospective analysis baseline data from 40 subjects with primary alcohol dependency are compared with a group of 40 patients diagnosed with major depression (diagnoses according to DSM-III-R) and healthy subjects. All alcohol dependent patients were examined in the sleep laboratory during subacute withdrawal at least 7 days off medication and after at least 14 days of abstinence. The patients with major depression (at least 7 days off psychoactive medication) and the healthy subjects had been examined previously by polysomnography during the last few years in the context of various studies and were assembled from our database to match the group of alcohol dependent patients with respect to age and sex.Alcohol dependent patients exhibited similar disturbances in sleep continuity and REM sleep as depressed patients in comparison to healthy controls while parameters of sleep architecture were even more strongly disturbed in alcohol dependence.While enhanced sensitivity of cholinergic receptors is the most likely explanation for the increase in "REM pressure" in depressives, this appears not to apply to alcoholics, who rather exhibit a decreased response to cholinergic stimulation. Thus, according to the reciprocal interaction model of nonREM- and REM sleep regulation and in contrast to the interpretation of the findings in depressed patients, an impaired aminergic rather than an increased cholinergic neurotransmission might be responsible for the increased REM sleep pressure in alcohol dependent patients. Alternatively or in addition the REM anomalies in alcoholic patients could also be due to adaptive regulatory processes during chronic alcohol consumption that lead to downregulation of GABA(A)- and upregulation of NMDA-receptors or their intracellular signalling and become apparent with alcohol withdrawal. Such adaptive counterregulation might also explain the alterations in slow wave sleep found in alcoholics that are even more pronounced in these patients than in patients with major depression.     

Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers

AIMS: To evaluate the potential interaction of 20 mg paroxetine and 1 mg alprazolam (early morning once-daily administration) on polysomnographic (PSG) sleep and subjective sleep and awakening quality, both after a single intake and after reaching a steady-state concentration. METHODS: Twenty-two (11 for the PSG) healthy young volunteers of both sexes with no history of sleep disturbances (Pittsburgh Sleep Quality Index <5) participated in a double-blind, double-dummy, placebo-controlled, repeated-dose, 4-period, cross-over study. All volunteers received all 4 treatment sequences: paroxetine-alprazolam placebo (PAP); paroxetine placebo-alprazolam (PPA); paroxetine-alprazolam (PA), and paroxetine placebo-alprazolam placebo (PLA), in a randomized order. Each treatment was administered over 15 consecutive days, with a treatment-free interval of 7 days prior to the subsequent study period. In each experimental period, one PSG sleep study was performed on the 1st night (single-dose effects) and another study was performed on the 15th night (repeated-dose effects). Additionally, two other PSG studies were assessed: an adaptation recording, and a control night recording. All-night PSG recordings were obtained following standard procedures. Each 30-second period was scored according to the criteria of Rechtschaffen and Kales by means of an automatic sleep analysis system: Somnolyzer 24x7. A self-rating scale for sleep and awakening quality and early morning behavior was completed no later than 15 min after awakening over the 15 days of each experimental intervention. General lineal models (treatment/time) were applied separately to each variable. RESULTS: (1) No significant effects were observed in any sleep variables when control nights were compared with the 1st night with PLA. (2) Sleep continuity: After PAP a clear awakening effect was seen both in the first and second evaluations, mainly in wake time, movement time, number of awakenings and stage-1 duration. After PPA an evident hypnotic effect was observed on night 1. This effect was mainly observed in maintenance variables and slightly in sleep initiation variables; it had decreased by night 15. After PA an intermediate behavior in the variables related to sleep continuity was seen, highlighting the absence of the tolerance phenomenon observed when PPA was administered alone. (3) Sleep architecture: The most important effects in REM sleep were observed after PAP; an increase in REM latency and decreases in REM sleep. PAP also induced decreases in the number of non-REM and REM periods and increases in the average duration of non-REM periods and sleep cycles. PA presented a similar pattern to PAP, and PPA similar to PLA. In relation to non-REM sleep, PA showed more stage-2 and less slow-wave sleep (SWS). (4) Subjective perception: No significant differences were observed between treatments while they were being taken, but impairments in subjective sleep quality, awaking quality, latency and efficiency were seen, mainly after PA but also after PPA discontinuations. CONCLUSION: The combination of PAP and PPA presented an intermediate pattern in relation to sleep continuity, with less awaking effect than PAP alone and less hypnotic effect than PPA alone, and without developing tolerance. The PAP and PPA combination also showed a similar effect to PAP on REM sleep and was the treatment with the longest stage 2 and shortest SWS. No subjective sleep and awakening effects were seen during drug intake but subjective withdrawal reports were seen after abrupt interruption. The high agreement rate for the epoch-by-epoch comparison between automatic and human scoring confirms the validity of the Somnolyzer 24x7 and thus facilitates sleep studies in neuropsychopharmacological research.     

Why low-dose benzodiazepine-dependent insomniacs can't escape their sleeping pills

Psychobiological aspects of low-dose benzodiazepine dependence (LBD) and drug withdrawal were investigated in 76 middle-aged and elderly chronic insomniacs in a sleep laboratory. Comparison with drug-free insomniacs showed that LBD leads to a complete loss of hypnotic activity and substantial suppression of delta and REM sleep. Only small differences were found between benzodiazepines with different half-life time. Upon withdrawal, recovery from this suppression, especially in REM sleep, occurred, while insomnia did not increase. The patients, however, reported sleeping longer while taking the drug compared with withdrawal. This misperception seems to be a specific effect of benzodiazepines, and contrasts with the full awareness of insomnia upon withdrawal. It is concluded that these effects play a leading role in the patients' inability to escape their sleeping pills. The response of REM sleep to withdrawal should make this a useful measure to objectively confirm low-dose benzodiazepine dependence.     

Effects of the GABAB antagonist CGP 35348 on sleep-wake states, behaviour, and spike-wave discharges in old rats

The GABA_B antagonist CGP 35348 was intraperitoneally given in doses of 100, 300, and 900 mg/kg to old rats. These rats were earlier chronically provided with EEG and EMG electrodes. Sleep recordings based on visual inspection of EEG and EMG recordings were made for 3 h post injection, and spontaneous behaviour in the recording cage was additionally observed. With 100 and 300 mg/kg, the drug produced an increase in the duration of REM sleep compared to the saline-injected control group. The REM sleep latency was correspondingly reduced. Non-REM sleep and total sleep duration increased and an s-shaped dose-response relationship was found. Explorative behaviour was diminished after injections with 100 and 300 mg/kg CGP 35348. The number and duration of spike-wave discharges were reduced after all doses of CGP 35348 and during all 3 recording hours. The latter outcomes confirm the strong suppressive action of this drug on spike-wave discharges; these effects have also been reported in models of absence epilepsy. The hypnotic properties and especially the increase in REM sleep after the administration of CGP 35348 deserve attention considering the paucity of drugs which facilitate REM sleep. The discovery of drugs promoting REM sleep might have theoretical as well as clinical consequences.     

REM latency: a psychobiologic marker for primary depressive disease.

Previous investigations have indicated that one of the most consistent EEG sleep findings in depressive patients has been a shortened REM latency. On the basis of these studies, we have concluded that with the exception of drug withdrawal states (such as CNS depressant or amphetamine withdrawal and narcolepsy) shortened REM latency points to a strong affective component in the patient's illness. Short REM latency has also been observed in patients suffering from schizo-affective illness as well as in certain schizophrenic patients who require tricyclic antidepressants in their management. Furthermore, this psychobiologic marker is a persistent, rather than a transient phenomenon, and can be observed over a period of several weeks unless a patient's condition becomes more favorable through clinical intervention. This present report indicates that short REM latency is found in virtually all primary depressive illness and is absent in secondary depression. Thus, REM latency appears to be a dependable, measurable marker for diagnosing primary depression, and we argue that the phenomenon is independent of age, drug effect and changes in other sleep parameters. It is expected that EEG sleep and motor measurements can yield further significant data and improve differential diagnosis in psychiatry, in much the same way that laboratory data support other medical specialities.     

Neuropsychological function and REM sleep in schizophrenic patients.

To test the hypothesis that rapid eye movement (REM) sleep in schizophrenic patients is associated with cognitive function, we studied 18 schizophrenic inpatients by means of electroencephalograms taken during sleep in their own hospital beds after a minimum 2-wk medication withdrawal period. Patients underwent neuropsychological tests to measure memory function and other aspects of cognitive performance. REM sleep measures demonstrated positive and negative correlations with cognition and memory measures, depending on when REM occurred after sleep onset. Minutes of REM sleep and REM density in the first period correlated negatively with performance, while REM minutes occurring after the first REM period correlated positively with neuropsychological performance. Further work should test whether phasic REM sleep regulation at the beginning of the night plays a compensatory role for neuropsychological dysfunction in schizophrenics.