Clinical Management of Sleep and Sleep Disorders With Cannabis and Cannabinoids: Implications to Practicing Psychiatrists.

ABSTRACT: Phytocannabinoid derivatives are among the several compounds found in the cannabis plant. The phytocannabinoid chemicals Δ9-tetrahydrocannabinol (THC) and cannabidiol are mostly responsible for the drug's behavioral effects. Chronic cannabis administration has been shown to disrupt circadian rhythms and reduce the duration of the deepest phase (stage N3) of nonrapid eye movement sleep. Cannabidiol is thought to be responsible for the disruption of the circadian rhythm, whereas THC is thought to be accountable for the changes in sleep architecture. The quality of one's sleep has a significant impact on cannabis abstinence or relapse. As a result, the diminished sleep-promoting efficiency of cannabis in chronic users, as well as the resulting sleep difficulties once cannabis use is stopped, may sabotage attempts to quit and raise the risk of relapse. In individuals with obstructive sleep apnea who do not complain about the treatment process known as continuous positive airway pressure, cannabinoids are one of the treatments being considered. In this regard, preclinical investigations have demonstrated that combining the agent oleamide and THC aids in the stabilization of respiration in all stages of sleep as well as the maintenance of autonomic stability during sleep. The synthetic THC dronabinol was found to lower the apnea-hypopnea index in a clinical investigation and is regarded safe for the short-term treatment of obstructive sleep apnea. Patients experiencing nightmares who had been diagnosed with posttraumatic stress disorder were given the synthetic endocannabinoid receptor agonist nabilone. When compared with a placebo, the chemical proved helpful in reducing the frequency of nightmares. It is worth noting that a single study that looked at the effects of cannabidiol on REM behavior disorder found that symptoms improved. Based on the available findings, cannabinoids can be used as an alternate treatment for various sleep disorders. However, additional research is needed to corroborate the conclusions of these investigations.

Clarifying the role of sleep in depression: A narrative review.

It has been established that 4.4 to 20% of the general population suffers from a major depressive disorder (MDD), which is frequently associated with a dysregulation of normal sleep-wake mechanisms. Disturbances of circadian rhythms are a cardinal feature of psychiatric dysfunctions, including MDD, which tends to indicate that biological clocks may play a role in their pathophysiology. Thus, episodes of depression and mania or hypomania can arise as a consequence of the disruption of zeitgebers (time cues). In addition, the habit of sleeping at a time that is out of phase with the body's other biological rhythms is a common finding in depressed patients. In this review, we have covered a vast area, emerging from human and animal studies, which supports the link between sleep and depression. In doing so, this paper covers a broad range of distinct mechanisms that may underlie the link between sleep and depression. This review further highlights the mechanisms that may underlie such link (e.g. circadian rhythm alterations, melatonin, and neuroinflammatory dysregulation), as well as evidence for a link between sleep and depression (e.g. objective findings of sleep during depressive episodes, effects of pharmacotherapy, chronotherapy, comorbidity of obstructive sleep apnea and depression), are presented.

Pharmacotherapy of Insomnia.

Insomnia remains a common clinical concern that is associated with negative daytime consequences for patients and represents a significant public health problem for our society. Although a variety of therapies may be employed to treat insomnia, the use of medications has been a dominant approach. Regulatory agencies have now classified insomnia medications into 4 distinct pharmacodynamics classes. Medications with indications approved for insomnia treatment include benzodiazepine receptor agonists, a melatonin receptor agonist, a selective histamine receptor antagonist, and a dual orexin/hypocretin receptor antagonist. Both pharmacodynamic and pharmacokinetic advances with hypnotic medications in recent years have expanded the pharmacopoeia to allow personalized treatment approaches for different patient populations and individual sleep disturbance patterns.

The effects of local microinjection of selective dopamine D1 and D2 receptor agonists and antagonists into the dorsal raphe nucleus on sleep and wakefulness in the rat.

The effects of the dopamine (DA) D1 and D2 receptor agonists SKF38393, bromocriptine and quinpirole, respectively, on spontaneous sleep were analyzed in adult rats prepared for chronic sleep recordings. Local administration of the DAergic agonists into the dorsal raphe nucleus (DRN) during the light phase of the light-dark cycle induced a significant reduction of rapid-eye movement sleep (REMS) and the number of REM periods. Additionally, bromocriptine and quinpirole significantly increased wakefulness (W). Opposite, the microinjection into the DRN of the DA D1 and D2 receptor antagonists SCH23390 and sulpiride, respectively, significantly augmented REMS and the number of REM periods. Pretreatment with SCH23390 and sulpiride prevented the effects of SKF38393 and bromocriptine, respectively, on sleep variables. Our results tend to indicate that DAergic neurons located in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) contribute to the regulation of predominantly W and REMS by DRN serotonergic neurons.

Zolpidem's use for insomnia.

Zolpidem is a short-acting non-benzodiazepine hypnotic drug that belongs to the imidazopyridine class. In addition to immediate-release (IR) and extended-release (ER) formulations, the new delivery forms including two sublingual tablets [standard dose (SD) and low dose (LD)], and an oral spray form have been recently developed which bypass the gastrointestinal tract. So far, Zolpidem has been studied in several clinical populations: cases poor sleepers, transient insomnia, elderly and non-elderly patients with chronic primary insomnia, and in comorbid insomnia. Peak plasma concentration (Tmax) of zolpidem-IR occurs in 45 to 60min, with the terminal elimination half-life (t½) equating to 2.4h. The extended-release formulation results in a higher concentration over a period of more than 6h. Peak plasma concentration is somewhat shorter for the sublingual forms and the oral spray, while their t½ is comparable to that of zolpidem-IR. Zolpidem-IR reduces sleep latency (SL) at recommended doses of 5mg and 10mg in elderly and non-elderly patients, respectively. Zolpidem-ER at doses of 6.25mg and 12.5mg, improves sleep maintenance in elderly and non-elderly patients, respectively, 4h after its administration. Sublingual zolpidem-LD (5mg) and zolpidem oral spray are indicated for middle-of-the-night (MOTN) wakefulness and difficulty returning to sleep, while sublingual zolpidem-SD (10mg) is marketed for difficulty falling asleep. With their array of therapeutic uses and their popularity among physicians and patients; this review describes the clinical pharmacology, indications and uses, identifying withdrawal symptoms, abuse and dependence potentials, and adverse drug reactions are discussed.

The effects of second generation antipsychotic drugs on sleep variables in healthy subjects and patients with schizophrenia.

Insomnia is a common feature in schizophrenia, and is characterized by an increase of sleep latency (SL), as well as reductions in total sleep time (TST) and sleep efficiency (SE). Regarding sleep architecture, non-rapid-eye-movement (NREM) sleep, slow wave sleep (SWS) and rapid-eye-movement (REM) sleep latency are decreased, whereas REM sleep tends to remain unchanged. According to polysomnographic studies, clozapine, olanzapine, quetiapine and ziprasidone administration increased TST and/or SE in healthy subjects. Additionally, olanzapine and ziprasidone augmented SWS, while changes corresponding to REM sleep were inconsistent. Furthermore, administration of clozapine, olanzapine and paliperidone to patients with schizophrenia was followed in most instances by a significant reduction of SL and an increase of TST and SE. In addition, olanzapine and paliperidone augmented SWS and REM sleep. By contrast, quetiapine administration further disrupted sleep as judged by the increase of SL, wake time after sleep onset (WASO) and REM sleep latency, and the reduction of SWS and REM sleep. No consistent effects on sleep variables were obtained during treatment with risperidone. To date, no polysomnographic studies have been published on the effects of aripiprazole, asenapine, iloperidone and lurasidone on sleep in either healthy subjects or patients with schizophrenia. Taken together, this evidence supports the conclusion that second generation antipsychotics (SGAs) including clozapine, olanzapine and paliperidone may ameliorate insomnia in patients with schizophrenia.

The effect of second-generation antipsychotic drugs on sleep parameters in patients with unipolar or bipolar disorder.

Sleep disturbances predominantly take the form of insomnia in patients with unipolar disorder, while patients with bipolar disorder show a decreased need for sleep. Sleep impairment in these patients is a risk factor for the development of a major depressive episode and suicidal behavior. Administration of second-generation antipsychotics (SGAs) olanzapine, quetiapine, and ziprasidone as augmentation therapy or monotherapy to unipolar and bipolar disorder patients, respectively, has been shown to improve sleep continuity and sleep architecture. Thus, their use by these patients could ameliorate their sleep disorder.

Microinjection of the melanin-concentrating hormone into the sublaterodorsal tegmental nucleus inhibits REM sleep in the rat.

A study was performed on the effects of local microinjection of melanin-concentrating hormone (MCH) into the right sublaterodorsal tegmental nucleus (SLD) on sleep and wakefulness in rats prepared for chronic sleep recordings. MCH 200ng significantly decreased rapid-eye-movement sleep (REMS) time during the first and second 2-h of the recording period which was related to the reduction of the number of REMS periods and the increase of REMS latency. It is proposed that REMS inhibition was related to the direct deactivation of SLD glutamatergic neurons by the peptide.

The effects of systemic administration and local microinjection into the central nervous system of the selective serotonin 5-HT2C receptor agonist RO-600175 on sleep and wakefulness in the rat.

The effects of RO-600175, a selective 5-HT2C receptor agonist, were studied in adult rats implanted for chronic sleep recordings. Intraperitoneal administration of RO-600175 (4 mg/kg) during the light phase of the light-dark cycle significantly increased wakefulness and reduced slow wave sleep and rapid-eye-movement sleep during the first 2 h of the recording period. Direct infusion of RO-600175 into the dorsal raphe nucleus (4 mmol/l), laterodorsal tegmental nucleus (4 mmol/l), or horizontal limb of the diagonal band of Broca (4 mmol/l) also decreased rapid-eye-movement sleep. It is proposed that the activation of γ-aminobutyric acid-ergic cells located in the dorsal raphe nucleus, laterodorsal tegmental nucleus, and horizontal limb of the diagonal band of Broca is responsible, at least in part, for the effects of RO-600175 on rapid-eye-movement sleep. It is suggested that the increased wakefulness observed after systemic injection of the 5-HT2C receptor ligand could be partly related to the increased release of acetylcholine in the frontal cortex and hippocampus. However, additional studies are required to characterize the neurotransmitter systems responsible for the increase in wakefulness.

Melanin-Concentrating Hormone (MCH): Role in REM Sleep and Depression.

The melanin-concentrating hormone (MCH) is a peptidergic neuromodulator synthesized by neurons of the lateral sector of the posterior hypothalamus and zona incerta. MCHergic neurons project throughout the central nervous system, including areas such as the dorsal (DR) and median (MR) raphe nuclei, which are involved in the control of sleep and mood. Major Depression (MD) is a prevalent psychiatric disease diagnosed on the basis of symptomatic criteria such as sadness or melancholia, guilt, irritability, and anhedonia. A short REM sleep latency (i.e., the interval between sleep onset and the first REM sleep period), as well as an increase in the duration of REM sleep and the density of rapid-eye movements during this state, are considered important biological markers of depression. The fact that the greatest firing rate of MCHergic neurons occurs during REM sleep and that optogenetic stimulation of these neurons induces sleep, tends to indicate that MCH plays a critical role in the generation and maintenance of sleep, especially REM sleep. In addition, the acute microinjection of MCH into the DR promotes REM sleep, while immunoneutralization of this peptide within the DR decreases the time spent in this state. Moreover, microinjections of MCH into either the DR or MR promote a depressive-like behavior. In the DR, this effect is prevented by the systemic administration of antidepressant drugs (either fluoxetine or nortriptyline) and blocked by the intra-DR microinjection of a specific MCH receptor antagonist. Using electrophysiological and microdialysis techniques we demonstrated also that MCH decreases the activity of serotonergic DR neurons. Therefore, there are substantive experimental data suggesting that the MCHergic system plays a role in the control of REM sleep and, in addition, in the pathophysiology of depression. Consequently, in the present report, we summarize and evaluate the current data and hypotheses related to the role of MCH in REM sleep and MD.

Increased REM sleep after intra-locus coeruleus nucleus microinjection of melanin-concentrating hormone (MCH) in the rat.

A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep-wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

When insomnia is not just insomnia: the deeper correlates of disturbed sleep with reference to DSM-5.

Recent scientific evidences have brought a paradigm shift in our approach towards the concepts of insomnia and its management. The differentiation between primary and secondary insomnia was proved more hypothetical than actual and based upon the current evidences insomnia subtypes described in earlier system have been lumped into one-insomnia disorder. Research in this field suggests that insomnia occurring during psychiatric or medical disorders has a bidirectional and interactive relationship with and coexisting medical and psychiatric illnesses. The new approach looks to coexist psychiatric or medical disorders as comorbid conditions and hence specifies two coexisting conditions. Therefore, the management and treatment plans should address both the conditions. A number of sleep disorders may present with insomnia like symptoms and these disorders should be treated efficiently in order to alleviate insomnia symptoms. In such cases, a thorough history from the patient and his/her bed-partner is warranted. Moreover, some patients may need polysomnography or other diagnostic tests like actigraphy to confirm the diagnosis of the underlying sleep disorder. DSM-5 classification system of sleep­wake disorders has several advantages, e.g., it has seen insomnia across different dimensions to make it clinically more useful; it focuses on the assessment of severity and guides the mental health professional when to refer a patient of insomnia to a sleep specialist; lastly, it may encourage the psychiatrists to opt for sleep medicine as a career.

The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness.

Different approaches have been followed to characterize the role of 5-hydroxytryptamine (serotonin) receptor 7 (5-HT7) in the regulation of sleep-wake behavior: (1) 5-HT7 receptor knockout mice spend less time in rapid eye movement sleep than their wild-type counterparts, mainly during the light period. In contrast, there is no difference between the genotypes in time spent in wakefulness or slow-wave sleep. (2) Systemic administration of the selective 5-HT7 receptor agonist LP-211 significantly increased wakefulness (time spent awake) and reduced rapid eye movement sleep in the rat. Direct infusion of LP-211 into the dorsal raphe nucleus, locus coeruleus nucleus, basal forebrain (horizontal limb of the diagonal band of Broca), or laterodorsal tegmental nucleus also produced a decrease in rapid eye movement sleep. Additionally, microinjection of the 5-HT7 receptor agonist into the basal forebrain augmented the time animals remained awake. Local injection of the 5-HT7 receptor agonist LP-44 into the dorsal raphe nucleus also suppressed rapid eye movement sleep in the rat. (3) A similar reduction of rapid eye movement sleep has been described following intraperitoneal injection of the selective 5-HT7 receptor antagonists SB-269970 and SB-656104 in the rat and oral administration of the 5-HT7 receptor antagonist NJ-18038683 to rat and man. Local microinjection of SB-269970 into the dorsal raphe nucleus and basal forebrain also induced a decrease in rapid eye movement sleep in the rat. This tends to suggest that the on-off (activation/blockade), two-state ligand-receptor interaction model is not tenable for the 5-HT7 receptor.

Systemic administration and local microinjection into the central nervous system of the 5-HT(7) receptor agonist LP-211 modify the sleep-wake cycle in the rat.

The effects of LP-211, a selective serotonin 5-HT7 receptor agonist were studied in adult rats implanted for chronic sleep recordings. Intraperitoneal administration of LP-211 (2.5-10mg/kg) during the light phase of the light-dark cycle significantly increased wakefulness (W) and reduced rapid-eye-movement sleep (REMS) and the number of REM periods during the 6-h recording period. Direct infusion of LP-211 into the dorsal raphe nucleus (DRN) (2-6 mM), locus coeruleus nucleus (LC) (4 mM), basal forebrain (horizontal limb of the diagonal band of Broca) (HDB) (2 mM) or laterodorsal tegmental nucleus (LDT) (4 mM) induced also a decrease of REMS. Additionally, microinjection of the 5-HT7 receptor ligand into the HDB (2 mM) augmented W. Presently, there is no satisfactory explanation for the effect of 5-HT7 receptor activation on W and REMS occurrence. Additional studies are required to characterize the neurotransmitter systems responsible for the actions of LP-211 on the behavioral states.

The effects of systemic and local microinjection into the central nervous system of the selective serotonin 5-HT6 receptor agonist WAY-208466 on sleep and wakefulness in the rat.

The effects of WAY-208466, a selective 5-HT6 receptor agonist on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. Systemic administration of WAY-208466 during the light phase of the light-dark cycle significantly increased wakefulness (W) and reduced slow wave sleep (SWS), REM sleep (REMS) and the number of REMS periods. Pretreatment with the selective 5-HT6 receptor antagonist RO-399885 prevented the effects of the 5-HT6 receptor agonist on W, SWS and REMS. Direct infusion of WAY-208466 into the dorsal raphe nucleus, locus coeruleus, basal forebrain (horizontal limb of the diagonal band of Broca) or laterodorsal tegmental nucleus specifically decreased REMS without significantly altering W or SWS. In all instances the REMS suppression was dependent upon the reduction of REMS periods. The finding that WAY-208466 increases extracellular γ-aminobutyric acid (GABA) levels in the rat frontal cortex tends to suggest that the neurotransmitter could be involved in the 5-HT6 receptor agonist-induced disruption of the sleep-wake cycle. However, further studies are needed to resolve this issue.

Melanin-concentrating hormone control of sleep-wake behavior.

The melanin-concentrating hormone (MCH) is a 19 aminoacid peptide found in mammals predominantly in neurons located in the lateral hypothalamus and incerto-hypothalamic area. The biological function of MCH is mediated by two G-protein-coupled receptors known as MCHR1 and MCHR2, although the latter is expressed only in carnivores, primates and man. The MCHR1 couples to Gi, Gq and Go proteins, with Gi leading to the inhibition of both excitatory and inhibitory synaptic events. Within the central nervous system (CNS) MCH participates in a number of functions including sleep-wake behavior. In this respect, MCHergic neurons project widely throughout the CNS to brain regions involved in the regulation of behavioral states. MCHergic neurons are silent during wakefulness (W), increase their firing during slow wave sleep (SWS) and still more during REM sleep (REMS). Studies in knockout mice for MCH (MCH(-/-)) have shown a reduction in SWS and an increase of W during the light and the dark phase of the light-dark cycle. Moreover, in response to food deprivation a marked reduction in REMS time was observed in these animals. Conflicting effects on sleep variables have been reported in MCHR1(-/-) mice by different authors. The i.c.v. administration of MCH increases REMS and SWS in the rat. In addition, an enhancement of REMS has been described following the microinjection of the neuropeptide into the nucleus pontis oralis of the cat, while its infusion into the dorsal raphe nucleus (DR) and the basal forebrain (horizontal limb of the diagonal band of Broca) is followed by an increase of REMS and a reduction of W in the rat. Immunoneutralization of MCH in the DR augmented W and suppressed REMS in the rat, as did the s.c. injection of selective MCHR1 antagonists. The robust REMS-inducing effect of MCH is likely related to the deactivation of monoaminergic, orexinergic, glutamatergic, cholinergic (W-on) and GABAergic (REM-off) neurons involved in the generation of W and the inhibition of REMS. On the basis of preclinical studies, it can be proposed that selective MCHR1 receptor agonists could constitute potential therapeutic modalities in the arsenal of insomnia pharmacotherapy. Due to the lack of adequate animal models, the role of the MCHR2 on sleep is still unknown.

Sleep and circadian rhythm dysregulation in schizophrenia.

Sleep-onset and maintenance insomnia is a common symptom in schizophrenic patients regardless of either their medication status (drug-naive or previously treated) or the phase of the clinical course (acute or chronic). Regarding sleep architecture, the majority of studies indicate that non-rapid eye movement (NREM), N3 sleep and REM sleep onset latency are reduced in schizophrenia, whereas REM sleep duration tends to remain unchanged. Many of these sleep disturbances in schizophrenia appear to be caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep-wake cycle. Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep in schizophrenic patients could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system, both associated with core features of schizophrenia and with signaling in sleep and wake promoting brain regions. Since multiple neurotransmitter systems within the CNS can be implicated in sleep disturbances in schizophrenia, the characterization of the neurotransmitter systems involved remains a challenging dilemma.

Microinjection of melanin concentrating hormone into the lateral preoptic area promotes non-REM sleep in the rat.

The ventrolateral preoptic area (VLPO) has been recognized as one of the key structures responsible for the generation of non-REM (NREM) sleep. The melanin-concentrating hormone (MCH)-containing neurons, which are located in the lateral hypothalamus and incerto-hypothalamic area, project widely throughout the central nervous system and include projections to the VLPO. The MCH has been associated with the central regulation of feeding and energy homeostasis. In addition, recent findings strongly suggest that the MCHergic system promotes sleep. The aim of the present study was to determine if MCH generates sleep by regulating VLPO neuronal activity. To this purpose, we characterized the effect of unilateral and bilateral microinjections of MCH into the VLPO on sleep and wakefulness in the rat. Unilateral administration of MCH into the VLPO and adjacent dorsal preoptic area did not modify sleep. On the contrary, bilateral microinjections of MCH (100 ng) into these areas significantly increased light sleep (LS, 39.2±4.8 vs. 21.6±2.5 min, P<0.05) and total NREM sleep (142.4±23.2 vs. 86.5±10.5 min, P<0.05) compared to control (saline) microinjections. No effect was observed on REM sleep. We conclude that MCH administration into the VLPO and adjacent dorsal lateral preoptic area promotes the generation of NREM sleep.