Sustained Antidepressant Effect of Sleep Deprivation Combined with Pindolol in Bipolar Depression A Placebo-Controlled Trial

Abstract

Total sleep deprivation (TSD) shows powerful but transient clinical effects in patients affected by bipolar depression. Pindolol blocks the serotonergic 5-HT KEY WORDS : Sleep deprivation; Pindolol; Bipolar disorder; LithiumTotal sleep deprivation (TSD) causes a marked but transient improvement of depressive symptomatology in bipolar depressed patients: it acts rapidly and with a response rate of about 60%, but the dramatic mood improvement is usually followed by an early relapse (i.e., within the first days after TSD) which lessens the clinical usefulness of this treatment (Wu and Bunney 1990). Several studies, indeed, showed better clinical responses with the combination of sleep deprivation and antidepressant drugs (Leibenluft and Wehr 1992). In particular, positive interactions were reported with lithium, fluoxetine, nortryptiline, clomipramine, desipramine, and amitriptyline (e.g., Elsenga and Van den Hoofdakker 1982/1983Baxter et al. 1986;Shelton and Loosen 1993;Szuba et al. 1994;Kuhs et al. 1996;Benedetti et al. 1997), while negative interactions were observed with trimipramine and amineptine (HolsboerTrachsler et al. 1994;Benedetti et al. 1996).Though several hypotheses have been proposed, the mechanism of action of TSD is still unclear. From a neurochemical point of view, sleep deprivation enhances the functioning of several neurotransmitter systems including brain serotonin (5-HT) pathways, which physiologically show the highest activity during behavioral arousal and the lowest during sleep (Fornal and Jacobs 1988). In particular, preclinical research showed that From the Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, University of Milan, School of Medicine, Milan, Italy.Address correspondence to: Prof. Enrico Smeraldi, Istituto Scientifico Ospedale San Raffaele, Department of Neuropsychiatric Sciences, Via Prinetti 29, 20127 Milano, Italy. Received October 20, 1997; revised March 4, 1998; accepted April 13, 1998. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 20 , NO . 4 Sustained Antidepressant Effect of Sleep Deprivation 381 changes in the activity of brain 5-HT pathways after sleep deprivation included an increase in the serotonergic neuronal activity in the dorsal raphe nucleus (DRN) of cats (Gardner et al. 1997), an increase in brain 5-HT turnover in rats and hamsters (Hery et al. 1970;Cramer et al. 1973;Asikainen et al. 1995), and an increase in behavioral responsiveness to 5-HT precursors (Santos and Carlini 1983). In agreement with these findings, a clinical study showed that in human depressed females sleep deprivation led to an enhanced prolactine response to tryptophan, an effect mediated by serotonergic pathways (Salomon et al. 1994).Preclinical studies showed that changes in 5-HT function due to TSD involve a reduction in sensitivity of 5-HT 1A autoreceptors. In rats, Maudhuit et al. (1996) showed that REM sleep deprivation reduced the inhibitory response of serotonergic DRN neurons to citalopram, an effect mediated by 5-HT 1A autoreceptors stimulatio...

Circadian genes, rhythms and the biology of mood disorders

“…Several circadian phase setting and sleep-phase hypotheses have been put forth in an attempt to explain its therapeutic action (Wirz-Justice and Van den Hoofdakker, 1999). Interestingly, pindolol, a drug that blocks the serotonergic 5-HT 1A autoreceptor and is used to augment the antidepressant effects of serotonin reuptake inhibitors, was shown to potentiate the effects of TSD (Smeraldi et al, 1999). In contrast, pretreatment with the dopamine agonist, amineptine, prevents the antidepressant effects of TSD (Benedetti et al, 1996).…”

Sleep Deprivation in Mood Disorders

“…Our group developed a treatment schedule based on repeated total SD, three times a week, resulting in a lengthening of the sleep-wake period from the usual 24 to 48 h [1, [45][46][47][48][49][50][51][52] . Each SD cycle is composed of a period of 36 h awake, and on the 1st, 3rd and 5th day, patients are totally sleep deprived from 07: 00 h until 19.00 h of the following day.…”

“…The trend toward amelioration due to incomplete relapses, when present, is expected to reverse within a few weeks after a regular restoring of the usual 24-hour sleep-wake cycle, and in the absence of combined treatments only a 5-10% of bipolar depressed responders achieve sustained remission from their depressive episode [46,48] .…”

Contribution of Sleep Physiology to Depressive Pathophysiology

“…Whereas sleep deprivation modifies some measures of central 5-HT activity (Benedetti et al 1997;Seifritz et al 1997a) in healthy humans, the prolactin secretion upon 5-HT stimulation is enhanced after sleep deprivation (Salomon et al 1994) and may predict clinical response to sleep deprivation (Kasper et al 1988) in depressed patients. Sleep deprivation's efficacy may be amplified by 5-HT enhancing drugs (Wirz-Justice et al 1976;Benedetti et al 1997;Smeraldi et al 1999) and appears to be related with a functional polymorphism within the promoter of the serotonin transporter gene (Benedetti et al 1999). Interestingly, tryptophan depletion does not reverse sleep deprivation's antidepressant effects but rather prevents depressive relapse after one night of recovery sleep (Neumeister et al 1998).…”