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1 Introduction

This chapter provides an overview of psychotropic drugs encountered in psychiatry and includes the effects on sleep of those frequently prescribed for depression, anxiety, psychosis, dementia and ADHD, with a small section about recreational drugs. Drugs which treat, exacerbate or provoke sleep disorders are covered in the last section.

Most drugs which affect the brain do so by affecting neurotransmitter function in the brain, which they can do by:

  • Simulating the action of a brain neurotransmitter on the receptor (agonists, partial agonists)

  • Blocking its action on postsynaptic receptors (antagonists)

  • Changing the receptor’s sensitivity (allosteric modulators)

  • Increasing the amount of neurotransmitter present in the synapse, either by increasing the release of it into the synaptic cleft, blocking its transportation out of the cleft or preventing the action of enzymes which break it down

The brain’s arousal is maintained by parallel neurotransmitter systems whose cell bodies are located in brainstem or midbrain centres, with projections to the thalamus and forebrain. These activating neurotransmitters are noradrenaline, serotonin, acetylcholine, dopamine, histamine as well as the orexin system with cell bodies in the hypothalamus which promotes wakefulness through regulating arousal pathways (and inhibiting sedating ones). For all these arousing neurotransmitters, waking can be promoted by increasing their function, and sleep or sedation by decreasing their function in the brain.

The promotion of sleep is regulated by a number of other neurotransmitters; primary amongst these is gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. The majority of brain cells are inhibited by GABA, so increasing its function reduces arousal and produces sleep and eventually anaesthesia. There are many subsets of GABA neurons distributed throughout the brain, but a particular cluster in the hypothalamus (ventrolateral preoptic nucleus) can be considered to be the sleep ‘switch’ (Saper et al. 2005). These neurons switch off brain arousal systems at the level of the cell bodies and therefore promote sleep. GABA receptors in the cortex can also promote sedation and sleep by inhibiting the target neurons of the arousal system. Most drugs used in insomnia, and benzodiazepines used in anxiety, act by increasing the effects of GABA at the GABA-A receptor (allosteric modulation).

2 Drugs for Depression

Many of these drugs are used not only to treat depression but also anxiety disorders, and most have profound effects on sleep architecture, particularly on rapid eye movement (REM) sleep; some also affect daytime sleepiness. Both REM effects and daytime sedation effects appear to be similar in depressed patients and healthy volunteers and therefore can be thought of as markers of brain pharmacological action, but there are also effects on non-REM (NREM) sleep and subjective sleep, which are different in the patient population and appear to relate to therapeutic action (Wilson and Argyropoulos 2005).

These effects on sleep are strongly associated with their effects on neurotransmitter systems in the brain, particularly their property of increasing synaptic levels of monoamines. The mechanism common to the most widely used antidepressants is that of inhibition of reuptake of serotonin (serotonin reuptake inhibitors (SRIs), e.g. fluoxetine), noradrenaline (noradrenaline reuptake inhibitors, e.g. reboxetine) and drugs which inhibit reuptake of both (dual reuptake inhibitors, e.g. amitriptyline, venlafaxine) into the presynaptic neuron. Monoamine oxidase inhibitors (MAOIs) also increase the level of synaptic serotonin and noradrenaline (and to a lesser extent dopamine) by preventing breakdown by the enzyme. Other drugs like mirtazapine act on the autoreceptors responsible for homeostatic maintenance of monoamine levels, blocking their negative feedback action and so increasing synaptic levels of noradrenaline and serotonin.

As well as their main action to increase monoamine levels, many antidepressants have (usually antagonist) effects on a variety of brain neurotransmitters including acetylcholine via cholinergic muscarinic receptors, noradrenaline via alpha-1 and alpha-2 adrenoceptors, histamine via H1 receptors and serotonin via 5-HT1A and 5-HT2 receptors.

3 Serotonin Reuptake Inhibitors and Dual Reuptake Inhibitors

There are two major REM sleep effects described with all SRIs and dual reuptake inhibitors such as venlafaxine. These effects are dose related and common to patients and healthy volunteers. They consist of:

  • Reduction in the overall amount of REM sleep over the night

  • Delay of the first entry into REM sleep (increased REM onset latency, ROL)

which together can be called REM suppression (Wilson and Argyropoulos 2005). This is usually within the first few days of treatment, (i.e. before therapeutic effects are manifest), and the size of the effect is similar with all SRIs except fluoxetine, where the changes are generally smaller and do not reach a maximum so quickly (Feige et al. 2002). The decrease in REM amount becomes less evident after chronic treatment, but REM onset latency remains long throughout treatment. This REM suppression after SRIs and venlafaxine is probably caused by increased levels of synaptic serotonin, and it is probable that this stimulates serotonin receptors of the 5-HT1A type in the brainstem REM-initiating areas, which in turn inhibits the initiation of REM sleep (Monaca et al. 2003).

Acute changes in NREM sleep and sleep maintenance following SRI or venlafaxine administration are also similar in volunteers and depressed patients and consist of:

  • Increased light (stage 1) sleep

  • Increased waking during the night

In general, this arousing effect is larger in normal volunteers, but depressed patients start out with very disrupted sleep, and further deterioration is therefore less obvious. These sleep disturbances diminish over time, with most studies in depressed patients showing no difference from baseline after a few days of treatment. The exception to this is fluoxetine, which tends to continue disrupting sleep continuity, and many doctors use a hypnotic to minimise the insomnia and distress that these drugs can induce. Recently, a study has compared the therapeutic response to fluoxetine with and without cotreatment with the new hypnotic eszopiclone. They found that depression scores improved significantly more in the group given the hypnotic and that this effect was not simply due to their having better scores on the sleep items on the depression scales (Fava et al. 2006).

The dual serotonin/noradrenaline reuptake inhibitor duloxetine has smaller effects on REM and sleep continuity than venlafaxine, which may reflect its lower selectivity for serotonin transporters.

4 Older Dual Reuptake Inhibitors

These are usually of tricyclic structure, and, as well as being reuptake inhibitors, they have many other, usually unwanted, properties such as antihistaminergic, anticholinergic and antiadrenergic effects, all of which may impact on arousal and sleep. Their REM effects in general are similar to those of SRIs; clomipramine and imipramine target the serotonin transporter preferentially and are the most REM-suppressing.

They also differ from each other in their effects on sleep initiation and maintenance:

  • Clomipramine, desipramine (a selective noradrenaline uptake blocker) and imipramine tend to disrupt sleep on the first night, with increased amounts of waking during sleep. After a few days, this effect is no longer present in patients but continues in normal volunteers who were good sleepers at baseline.

  • Amitriptyline and dothiepin improve sleep acutely in normal volunteers, but not in depressed patients. After a few days of treatment, most studies show no difference in sleep continuity from baseline.

These differences are probably explained by the fact that as well as inhibiting reuptake, the latter drugs are also potent antihistamines and antagonists at the serotonin 5-HT2 receptor—other 5-HT2 receptor antagonists have effects on sleep—see below. These sleep-promoting effects are occasionally useful in the depressed patient with insomnia.

There is no evidence for the widespread use of low-dose amitriptyline for non-depression-related insomnia, particularly in primary care. At doses below 50 mg per day, amitriptyline is primarily an antihistamine. There are no controlled studies of hypnotic efficacy of low-dose amitriptyline in insomnia. Drugs with tricyclic structure are more likely to be lethal than licensed hypnotics in overdose (Nutt 2005), and sometimes their side effects can be troublesome; therefore it has been recommended that these only be used in insomnia when there is coexistent mood disorder and at antidepressant doses (Wilson et al. 2010).

5 Monoamine Oxidase Inhibitors (MAOIs)

Suppression of REM sleep by the older, irreversible MAOIs is the most marked of all the antidepressants. Total suppression of REM sleep has been described in at least two studies of depressed patients after about a week of treatment at doses from 45 to 75 mg/day of the most popular MAOI, phenelzine. An important research finding is that the REM suppression by phenelzine is reversed by rapid tryptophan depletion, implying that its REM effects are via increased serotonin function (Landolt et al. 2003).

In addition to these actions on REM, phenelzine and tranylcypromine decrease total sleep time and fragment sleep both acutely and chronically, presumably because they increase serotonin and noradrenaline availability (Landolt et al. 2001).

5.1 Rebound Effects of REM-Suppressing Antidepressants

REM sleep rebound (i.e. shortened REM onset latency and increased total REM sleep) occurs after stopping drugs which suppress REM. For most SRIs and dual reuptake inhibitors, this will usually occur within 3–5 days (fluoxetine 10 days), and for MAOIs up to 2–3 weeks. This is important for diagnostic tests for sleep disorders like narcolepsy where early onset of REM sleep is key; if the patient is taking drugs for depression, or has recently stopped them, this is likely to invalidate these tests.

6 Other Antidepressants

  • Vortioxetine has similar effects to SRIs.

  • Trazodone is an antagonist at 5-HT2 receptors. It increases deep non-REM sleep and reduces intra-sleep waking in depression, insomnia and healthy volunteers (Mouret et al. 1988; Paterson et al. 2007, 2009) but has little impact on REM sleep. Sleep-disturbing effects of SRIs are thought to be mediated by increased impact of serotonin on this receptor, and some psychiatrists use a small dose of trazodone to alleviate troubling SRI-induced insomnia (Kaynak et al. 2004).

  • Mirtazapine is also a 5-HT2 antagonist and also increases noradrenergic and serotonergic transmission—it improved subjective sleep in depression compared with venlafaxine (Benkert et al. 2006) and clinically seems to ameliorate insomnia-related problems in depression. It has no effect on REM sleep.

  • Agomelatine is a melatonin agonist and 5-HT2 antagonist. It is reported to improve subjective sleep in depressed patients, although it has very little effect on sleep architecture (Sharpley et al. 2011).

  • Trimipramine (which has tricyclic structure but is not a reuptake inhibitor) is a potent blocker of the 5-HT2 receptor and is strongly sleep promoting, with decreased sleep onset latency, higher sleep efficiency and longer sleep times reported in acute studies of normal volunteers, depression and insomnia (Riemann et al. 2002), and clinical experience suggests the subjective improvement in sleep continuity may be sustained into chronic treatment in depression. Its dopamine receptor blocking actions however mean it is not widely used because of D2 receptor-related risks such as tardive dyskinesia. There are no effects on REM sleep.

  • Reboxetine is a noradrenaline uptake blocker with no direct action on serotonergic transport. It is very selective and has little action at other brain receptors. It suppresses REM sleep with the same pattern as dual reuptake inhibitors but less markedly. It seems to have no significant effect on sleep continuity. It is sometimes used in narcolepsy, with both anticataplectic and arousing actions due to increased noradrenergic function (Larrosa et al. 2001).

6.1 Daytime Sedation

Many antidepressants have effects on vigilance levels or psychomotor function that lead to impairment of performance on daytime functioning such as driving. It is mainly the older drugs such as tricyclic antidepressants that affect central muscarinic acetylcholine or H1 histamine receptors which produce these effects. However, sedative side effects have been reported with nearly all antidepressants, and a wise precaution would be to warn patients at the time of first prescription not to drive until an adequate period has elapsed in which they can assess its sedative action (i.e. 1–2 weeks).

7 Drugs for Psychosis

Most of these drugs, as well as blocking dopamine D2 receptors, can affect a variety of other brain receptors to different degrees. In addition to blocking dopamine D2 receptors, they also have receptor actions on serotonin (5-HT1A partial agonism, 5-HT2A antagonism), noradrenaline (alpha-1 antagonism), histamine (H1 antagonism) and muscarinic (ACh antagonism). Therefore, their effects on sleep are also varied.

In the few studies in healthy volunteers, drugs with D2 and 5-HT2A antagonism decrease waking during sleep and prolong sleep. Olanzapine and ziprasidone also increase slow-wave sleep.

The typical antipsychotics haloperidol and flupentixol and the atypical antipsychotics olanzapine, risperidone and clozapine tend to decrease sleep onset latency and improve sleep maintenance in schizophrenia patients (Monti and Monti 2004).

Subjective sleep improvements have been reported after most antipsychotics, particularly chlorpromazine, risperidone, olanzapine and quetiapine.

8 Wake-Promoting Drugs

Amphetamine-like stimulants used in ADHD and narcolepsy (e.g. methylphenidate, lisdexamfetamine) increase wakefulness by blocking dopamine and noradrenaline reuptake, by stimulating dopamine release or by both mechanisms. Modafinil probably increases wakefulness through activation of dopaminergic systems by dopamine reuptake inhibition. Caffeine inhibits adenosine receptors, which in turn can produce activation via interaction with GABAergic and dopaminergic neurotransmission. These drugs are detrimental to sleep, increasing sleep onset latency and waking during sleep; patients who take them, and their doctors, should take care to time the dosing so that stimulant effects do not impinge on desired sleep.

9 Drugs for Bipolar Disorder

The mechanism of action of these drugs is not well worked out, but they appear to have their actions either by affecting cell signalling via enzyme interactions (lithium) or by modulation of glutamate by blocking sodium and calcium ion channels (valproate and carbamazepine).

  • Lithium and carbamazepine have a fairly neutral or a slightly positive impact on sleep continuity, and both of these tend to increase slow-wave sleep (Friston et al. 1989; Gann et al. 1994).

  • Valproate and levetiracetam do not appear to change sleep but may cause daytime sleepiness in higher doses (Harding et al. 1985; Bell et al. 2002);

  • There have only been a few studies with lamotrigine, but so far there is no indication that it changes sleep (Jain and Glauser 2014).

10 Drugs for Anxiety Disorders

Some of these which also treat depression have been covered above.

Short-term treatment of anxiety often includes benzodiazepine receptor agonist drugs, which modulate the GABA-A receptor to increase the effects of GABA in the brain (positive allosteric modulators). GABA is the major inhibitory neurotransmitter in the CNS and increasing its function has anticonvulsant, sedative, anxiolytic and muscle-relaxant effects, the duration of which depends on half-life of the agent used. For daytime anxiety, longer-acting benzodiazepines are used, such as diazepam, lorazepam, clonazepam and oxazepam. These are likely to cause sleepiness, unsteadiness and difficulties with memory—they mainly affect the acquiring of memorable information. All will increase beta activity in the EEG at night, and they also increase sleep spindles. At higher doses they may decrease slow-wave sleep.

Gabapentin and pregabalin are very similar drugs, but pregabalin is more readily absorbed. In spite of their name, they have their action not through the GABA receptor but via an ion channel and probably affect glutamate signalling. They both tend to increase slow-wave sleep and have been shown to improve sleep continuity and subjective sleep (Garcia-Borreguero et al. 2014).

Buspirone is a serotonin 1A receptor partial agonist which improves sleep continuity modestly, and delays and suppresses REM sleep like the serotonin reuptake inhibitors (Wilson et al. 2005), probably because these receptors are situated in some of the REM-controlling brainstem nuclei.

11 Drugs for Dementia

Most of these (donepezil, rivastigmine, galantamine) act by inhibiting the cholinesterase enzymes and thus increasing cholinergic function in the brain. Because REM sleep is highly regulated by cholinergic neurons in the pons, these drugs tend to bring REM sleep forward in the night and increase it (Schredl et al. 2006, 2000; Riemann et al. 1994), although this effect would appear to be short-lived. Patients taking these drugs, and also those taking the nicotinic receptor partial agonist varenicline for smoking cessation, report vivid dreaming and sometimes nightmares.

There are no reports of the effects on sleep structure by the NMDA antagonist memantine; however there has been a report that symptoms of REM behaviour disorder in dementia with Lewy bodies are ameliorated by this drug (Larsson et al. 2010).

12 Other Drugs

12.1 Sodium Oxybate

The agent for treatment of cataplexy in narcolepsy, sodium oxybate, has marked interesting effects on subjective sleep and sleep architecture. It is the sodium salt of gamma-hydroxybutyric acid (GHB), which probably acts mainly through GABA-B receptors in the brain but may have a neurotransmitter system of its own (GHB receptors). It may also be metabolised to GABA, so it may directly affect GABA-A receptors. This drug is abused for its euphoriant, intoxicating and growth-hormone-promoting effects. Its half-life in plasma is very short, but its central effects are somewhat longer lasting.

Its effects on sleep are to shorten sleep latency, reduce waking and markedly increase slow-wave sleep (Moldofsky et al. 2010). In narcolepsy, it appears to reduce the fragmented occurrence of REM sleep, decreasing the number of REM episodes and lengthening them (Plazzi et al. 2014).

12.2 Alcohol

In healthy good sleepers who are light social drinkers, the effects of going to bed with a blood alcohol concentration (BAC) of about 0.03% (e.g. after about two drinks) on sleep architecture are small. If the BAC is 0.1% (e.g. after five or six drinks), there is a larger effect, with sleep onset latency, light stage 1 sleep and awakenings reduced and slow-wave sleep increased in the first half of the night and decreased in the second half (Feige et al. 2006). In this same study, subjects were recorded with alcohol for three consecutive nights and then for the next two nights without alcohol. There was no rebound effect on withdrawal, and the authors remarked that this was probably because the rebound happens later on the drinking night.

Chronic alcoholics have decreased slow-wave sleep and increased intra-sleep waking during sleep in early abstinence.

12.3 Opiates

Sleep after oral morphine in normal subjects has decreased slow-wave sleep, and, when it is given intravenously, there is also REM suppression. Methadone, although it has similar effects to oral morphine on opiate receptors, seems to improve sleep. During withdrawal from heroin, there is major sleep disruption with reduced total sleep and increased sleep onset latency. This resolves within 3–7 days. However, in studies after methadone withdrawal, insomnia appears to last for much longer and can be present 6–8 weeks after the last methadone dose (Gossop and Bradley 1984).

12.4 Ecstasy (3,4-Methylenedioxy-N-methylamphetamine, MDMA)

There is no acute study of sleep after MDMA use. It is used in situations where people want to be awake, but surveys have shown that sleep may be more fragmented in MDMA-only users: however the effects of disrupted circadian rhythm due to being awake all night were not controlled for (Carhart-Harris et al. 2009). There has been a PSG study after another drug with similar effects called Eve (3, 4 methylenedioxyethamphetamine) (Gouzoulis et al. 1992). In this study, subjects were dosed at 11 p.m. and went to sleep normally. They woke after 1–2 h and stayed awake for about 3 h. Subsequent sleep showed total REM suppression—this would be expected, as it releases serotonin and increased serotonin function suppresses REM sleep.

12.5 Cannabis

Many people say they use cannabis in the evening to help them sleep. This effect may be mediated through enhanced relaxation at bedtime, as there are few objective effects on sleep. Cannabis contains many chemical compounds, but the main two psychoactive ones are tetrahydrocannabinol (THC) and cannabidiol (CBD). THC appears to have no objectively measured effects on sleep in healthy volunteers but increases sleepiness on awakening in the morning after high doses. On the other hand, CBD produces more wakefulness during sleep after high doses and less morning sleepiness (Nicholson et al. 2004). These effects may counteract each other, but relative THC/CBD proportions in cannabis preparations vary as do individuals’ reactions to the drug. There is some evidence that cannabis receptors are involved in pain perception, and in clinical trials of a nasal spray containing THC and cannabidiol for the relief of chronic pain in various long-term illnesses, there was a preliminary improvement in sleep reported by the patients (Russo et al. 2007).

13 Impact of These Psychotropic Medications on Sleep Disorders

Some of these powerful medications may improve sleep disorders, but some may cause or exacerbate them. Table 5.1 summarises these effects.

Table 5.1 Sleep disorders and the drugs which may trigger or exacerbate them
Full size table

All drugs which affect neurotransmitters in the brain are likely to affect sleep, be it just an alteration in sleep structure not perceived by the patient, subjective sleep disturbance or improvement or provocation or exacerbation of a sleep disorder. We need to be aware of these effects even if not working in psychiatry, as a large proportion of the population are taking these drugs and their sleep effects may impact on other disorders.