CLINICAL PHARMACOLOGY 2003 (PART 21C)

Chia sẻ: Big Big | Ngày: | Loại File: PDF | Số trang:15

0
50
lượt xem
9
download

CLINICAL PHARMACOLOGY 2003 (PART 21C)

Mô tả tài liệu
  Download Vui lòng tải xuống để xem tài liệu đầy đủ

Treatment is justified if it has significantly improved their wellbeing and function. A combination of medication with psychological techniques is likely to be most beneficial, especially for resistant cases. Sleep disorders NORMAL SLEEP Humans spend about a third of the time asleep but why we sleep is not yet fully understood. Sleep is a state of inactivity accompanied by loss of awareness and a markedly reduced responsiveness to environmental stimuli. When a recording is made of the electroencephalogram (EEG) and other physiological variables such as muscle activity and eye movements during sleep (a technique called polysomnography), a pattern of sleep emerges, consisting of...

Chủ đề:
Lưu

Nội dung Text: CLINICAL PHARMACOLOGY 2003 (PART 21C)

  1. SLEEP DISORDERS 19 treatment is justified if it has significantly improved Quiet sleep is further divided into four stages, their wellbeing and function. A combination of each with a characteristic EEG appearance, during medication with psychological techniques is likely which there is progressive relaxation of the muscles to be most beneficial, especially for resistant cases. and slower, more regular breathing as the deeper stages are reached. Most sleep in these deeper stages occurs in the first half of the night. During paradoxical sleep, the EEG appearance is Sleep disorders similar to that of waking or drowsiness. There is irregular breathing, complete loss of tone of the skeletal muscles, and frequent phasic movements NORMAL SLEEP particularly of the eyes, consisting of conjugate Humans spend about a third of the time asleep but movements which are mostly lateral but can also be why we sleep is not yet fully understood. Sleep is a vertical (hence the term rapid eye movement sleep); state of inactivity accompanied by loss of awareness most dreaming takes place in this stage. and a markedly reduced responsiveness to environ- The length of total sleep in a day varies between mental stimuli. When a recording is made of the 3 and 10 hours in normal subjects with an average electroencephalogram (EEG) and other physiolo- in the 20-45 year age group of 7-8 h. Sleep time is gical variables such as muscle activity and eye decreased in older subjects, to about 6 h in the over movements during sleep (a technique called poly- 70 year age group, with increased daytime napping somnography), a pattern of sleep emerges, consisting reducing the actual night time sleep even more. The of five different stages. This pattern varies from amount of time spent in each of the five stages person to person, but usually consists of four or five varies between subjects and particularly with age, cycles of quiet sleep alternating with paradoxical, with much less slow wave sleep in older people. or active, rapid eye movement (REM) sleep, with The number of awakenings after the onset of sleep longer periods of paradoxical sleep in the latter half also increases with advancing age. A normal subject of the night. A representation of these stages and has several short awakenings during the night, most cycles over time is known as a hypnogram, and one of which are not perceived as awakenings unless derived from a normal subject appears in Figure they last more than about 2 minutes. Probably there 19.6, with paradoxical sleep depicted as the shaded will not be clear consciousness but subject may areas. have occasional brief thoughts of how comfortable Fig. 19.6 Normal hypnogram 397
  2. 19 PSYCHOTROPIC DRUGS they feel or how pleased that it's not time to get up • other yet, with an immediate return to sleep. If during the sleep scheduling disorders (circadian rhythm short period of waking some factor causes anxiety disorder) or anger, e.g. aircraft noise, partner's snores or restless legs syndrome dread of being awake, progress to full awakening periodic leg movements of sleep. and being remembered is much more likely. The more times this happens the more subjects complain of an unrefreshing sleep. The time spent asleep as a percentage of the time in bed is used as a measure of sleep efficiency (96% in the case shown in Insomnia Figure 19.6). One of the most common ways in which Insomnia is characterised by the complaint of poor insomnia develops is by 'clock watching'; subjects sleep, with difficulty either in initiating sleep or check the time on awakening, remember it and maintaining sleep throughout the night. It can repeat this cycle many times during the night. occur exclusively in the course of another physical Remembering the time of a transient awakening disorder such as pain, mental disorder, e.g. depres- reinforces the subject's perception of sleeping sion, or sleep disorder, e.g. sleep apnoea. In a large poorly (periods of sleep in between are neglected) proportion of patients it is a primary sleep disorder and also produces anger and frustration which in and causes significant impairment in social, occu- turn delay their return to sleep and may promote pational or other important areas of functioning. subsequent awakenings. One survey showed similar deficits in quality of life in insomniacs as in patients with long-term disorders such as diabetes. TYPES OF SLEEP DISORDER About 60% of patients with insomnia have Several types of sleep disorder are recognised and abnormal sleep when measured objectively but the their differentiation is important; a simplified rest have no sleep abnormality which can be measured summary is given below but reference to DSM, ICD at present, yet are as disabled by their perceived or ICD4 will clarify the exact diagnostic criteria symptoms as those with measurable sleep. Insomnia may or may not be accompanied by • insomnia: not enough sleep or sleep of poor daytime fatigue but is not usually accompanied by quality; problems of falling asleep (initial subjective sleepiness during the day. When sleep insomnia) or staying asleep (maintenance propensity in the daytime is measured by objective insomnia), or waking too early means (time to EEG sleep) these patients are in fact • hypersomnia: excessive daytime sleepiness less sleepy than normal subjects. • parasomnia: unusual happenings in the night The time of falling asleep is determined by three nightmares factors, which in normal sleepers occur at bedtime. night terrors These are (a) circadian rhythm, i.e. the body's sleep walking natural clock in the hypothalamus triggers the rest/ REM behaviour disorder sleep part of the sleep-wake cycle, (b) 'tiredness', i.e. time since last sleep, usually about 16 hours and (c) lowered mental and physical arousal. If one 4 DSM-IV American Psychiatric Association (1994) of these processes is disrupted then sleep initiation Diagnostic and statistical manual of mental disorders (DSM is difficult, and it is these three factors that are IV), 1st edition. American Psychiatric Association, addressed by a standard sleep hygiene program Washington DC. (see below). Early in the course of insomnia rigo- ICSD American Sleep Disorders Association (1992) rous adherence to sleep hygiene principles alone International Classification of Sleep Disorders: Diagnostic and Coding Manual. may restore the premorbid sleep pattern but in ICD-10 WHO (1994) Classification of Mental and some patients the circadian process is less stable Behavioural Disorders. and they are less susceptible to these measures. 398
  3. INSOMNIA 19 A summary of precipitating factors for insomnia Sleep hygiene is shown in Table 19.7. • keep regular bedtimes and rising times • reduce daytime napping • daytime (but not evening) exercise and exposure TREATMENT OF INSOMNIA to daylight Timely treatment of short-term insomnia is valu- • avoid stimulants, alcohol and cigarettes in able, as it may prevent progression to a chronic evening condition, which is much harder to alleviate. Psy- • establish bedtime routine — 'wind down' — chological treatments are effective and pharmaco- milk drink may be helpful therapy may be either unnecessary or used as a • avoid dwelling on problems in bed short-term adjunct. The approaches are to: • bed should be comfortable and not too warm or too cold. • treat any precipitating cause (above) • educate about trigger factors for sleep and In the treatment of long-term insomnia the most reassure that sleep will improve important factor is anxiety about sleep, arising from • establish good sleep hygiene conditioning behaviours that predispose to heigh- • consider hypnotic medication. tened arousal and tension at bedtime. Thus the TABLE 19.7 Precipitating factors for insomnia Pharmacological • nonprescription drugs such as caffeine or alcohol. Alcohol reduces the time to onset of sleep but disrupts sleep later in the night. Regular and excessive consumption disrupts sleep continuity; insomnia is a key feature of alcohol withdrawal. Excessive intake of caffeine and theophylline, either in tea, coffee or cola drinks, also contributes to sleeplessness. • starting treatment with certain antidepressants, especially seroton in reuptake inhibitors (e.g. fluoxetine.fluvoxamine), or monoamine uptake inhibitors; sleep disruption is likely to resolve after 3—4 weeks. • other drugs which increase central noradrenergic and serotonergic activity include stimulants such as amphetamine, cocaine and methylphenidate and sympathomimetics such as the 3-adrenergic agonist salbutamol and associated compounds. • withdrawal from hypnotic drugs: this is usually short-lived. • treatment with 3-adrenoceptor blockers may disrupt sleep, perhaps because of their serotonergic action; a 3-blocking drug which crosses blood-brain barrier less readily is preferred, e.g. atenolol. Psychological: hyperarousal due to • stress • the need to be vigilant at night e.g. because of sick relatives or young children • being 'on-call'. Physical • pain, in which case adequate analgesia will improve sleep • pregnancy • coughing or wheezing: adequate control of asthma with stimulating drugs as above, may paradoxically improve sleep by reducing waking due to breathlessness • respiratory and cardiovascular disorders • need to urinate; this may be affected by timing of diuretic medication • neurological disorders, e.g. stroke, movement disorders • periodic leg movements of sleep (frequent jerks or twitches during the descent into deeper sleep), rarely reduce subjective sleep quality but are more likely to cause them in the subject's sleeping partner. Psychiatric • Patients with depressive illnesses often have difficulty falling asleep at night and complain of restless, disturbed and unrefreshing sleep, and early morning waking. When their sleep is analysed by polysomnography.time to sleep onset is indeed prolonged, and there is a tendency for more REM sleep to occur in the first part of the night, with reduced deep quiet sleep in the first hour or so after sleep onset and increased awakenings during the night.They may wake early in the morning and fail to get back to sleep again. • Anxiety disorders may cause patients to complain about their sleep, either because there is a reduction in sleep continuity or because normal periods of nocturnal waking are somehow less well tolerated. Nocturnal panic attacks can make patients fearful of going off to sleep. • Bipolar patients in the hypomanic or manic phase will sleep less than usual and sometimes changes in sleep pattern can be an early warning that an episode is imminent. Disruption of circadian rhythm Shift work, jet lag and irregular routine can cause insomnia, in that patients cannot sleep when they wish to. 399
  4. 19 PSYCHOTROPIC DRUGS bedroom is associated with not sleeping and auto- co-morbid sleep-related breathing disorders such matic negative thoughts about the sleeping process as obstructive sleep apnoea syndrome (see below) occur in the evening. Cognitive behavioural therapy which is exacerbated by benzodiazepines. Objective is helpful in dealing with 'psychophysiological' measures of sleep show that benzodiazepines insomnia and together with education and sleep decrease time to sleep onset and waking during hygiene measures as above is the treatment of the night; subjective effects of improved sleep are choice for long-term primary insomnia. Cognitive usually greater than the objective changes, probably behavioural therapists are specially trained in because of their anxiolytic effects (selectivity between changing behaviour and thoughts about sleep, parti- anxiolytic and sedative effect is low). Other changes cularly concentrating on learned sleep-incompatible in sleep architecture are to some extent dependent behaviours and automatic negative thoughts at on duration of action, with the very short-acting bedtime. The availability of these therapies is often compounds having the least effect. Most commonly limited and some patients are unwilling or unable very light (stage 1) sleep is decreased, and stage 2 to engage with them. sleep is increased. Higher doses of longer-acting Drug therapy may: drugs partially suppress slow wave sleep. Occasionally the agonist (sedative) compounds • relieve short-term insomnia when precipitating in current use cause paradoxical effects, e.g. excite- causes cannot be improved ment, aggression and antisocial acts. Alteration of • prevent progression to a long-term problem by dose, up or down, may eliminate these (as may establishing a sleep habit chlorpromazine in an acute severe situation). • interrupt the vicious cycle of anxiety about sleep itself. Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circula- DRUGS FOR INSOMNIA tion at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, Most drugs used in insomnia act as agonists (see oxazepam is slow (Table 19.8). The liver metabolises GABA receptor above) at the GABAA-benzodiazepine them, usually to inactive metabolites but some receptor and have effects other than their direct compounds produce active metabolites, some with sedating action, including muscle relaxation, long tl/2 which greatly extends drug action, e.g. memory impairment, and ataxia, which can impair chlordiazepoxide, clorazepate and diazepam all performance of skills such as driving. Clearly those form desmethyldiazepam (t l / 2 80 h). drugs with onset and duration of action confined to the night period will be most effective in insomnia Uses. Benzodiazepines are used for: insomnia, and less prone to unwanted effects during the day. anxiety, alcohol withdrawal states, muscle spasm Those with longer duration of action are likely to due to a variety of causes, including tetanus and affect psychomotor performance, memory and con- cerebral spasticity, epilepsy (clonazepam, see centration; they will also have enduring anxiolytic p. 421), anaesthesia and sedation for endoscopies and muscle-relaxing effects. and cardioversion. The choice of drug as hypnotic and anxiolytic Benzodiazepines is determined by pharmacokinetic properties (see before, and Table 19.8). A general account of the benzodiazepines is appropriate here, although their indications clearly Doses. Oral doses as anxiolytics are given with extend beyond use as hypnotics. their indications (see before) and those for hypno- All benzodiazepines and newer benzodiazepine- tics appear in Table 19.8. Injectable preparations: like drugs are safe and effective for insomnia, if the compound with the right timing of onset of action • Intravenous formulations, e.g. diazepam and elimination is chosen. However, care should 10-20 mg, given at 5 mg/min into a large vein be taken in prescribing them to patients with (antecubital fossa) to minimise thrombosis: the 400
  5. INSOMNIA 19 TABLE 19.8 Properties of drugs used for insomnia Works selectively Rapid 1/2t Usual dose Daytime Safety to enhance onset (hours) (P.o.) (hangover) GABA effects Zopiclone / + 3.5-6 7.5 mg ?Yes / Zolpidem / ++ 1.5-3 10mg No / Zaleplon* / ++ 1-2 10mg No / Temazepam / 5-12 20 mg ?Yes / Loprazolam / 5-13 1 mg ?Yes / Lormetazepam / + 8-10 1 mg ?Yes / Nitrazepam / + 20-48 5-10 mg Yes / Lorazepam / + 10-20 0.5-1 mg Yes / Diazepam / + 20-60 5-10 mg Yes / Oxazepam / 5-20 15-30 mg Yes / Alprazolam / + 9-20 0.5 mg Yes / Clonazepam / + 18-50 0.5-1 mg Yes / Chloral hydrate/chloral betaine X + 8-12 0.7-1 g ?Yes X Clomethiazole X + 4-8 192mg ?Yes X Barbiturates X + Yes X Promethazine X 7-14 25 mg ?Yes x// * Can be taken during the night, up to 5 h before vehicle driving. dose may be repeated once in 10 min for status reduce patients' anxiety or sleep disturbance and epilepticus or in 4 h for severe acute anxiety or therefore they are unwilling to stop. If they do stop, agitation: midazolam is a shorter-acting there can be relapse, where original symptoms return. alternative, e.g. for endoscopies. The dose should There can be a rebound of symptoms, particularly be titrated according to response, e.g. drooping after stopping hypnotics, where there is a worsen- eyelids, speech, response to commands. ing of sleep disturbance for one or two nights, with • Intramuscular injection of diazepam is absorbed longer sleep onset latency and increased waking erratically and may be slower in acting than an during sleep—this is common. In anxiety disorders oral dose: lorazepam and midazolam i.m. are there may be a few days of increased anxiety and absorbed rapidly. edginess which then resolves, probably in 10-20% of patients. More rarely, there is a longer withdrawal Tolerance to the anxiolytic effects does not seem syndrome characterised by the emergence of symp- to be a problem. In sleep disorders the situation is not toms not previously experienced, e.g. agitation, so clear; studies of subjective sleep quality show headache, dizziness, dysphoria, irritability, fatigue, enduring efficacy but about half of the objective depersonalisation, hypersensitivity to noise and (EEG) studies indicate decreased effects after 4-8 visual stimuli. Physical symptoms include nausea, weeks, implying that some tolerance develops. vomiting, muscle cramps, sweating, weakness, That said, the necessity for dose escalation in sleep muscle pain or twitching and ataxia. After pro- disorders is rare. longed high doses abrupt withdrawal may cause confusion, delirium, psychosis and convulsions. Dependence. Both animal and human research has The syndrome is ameliorated by resuming medica- shown that brain receptors do change in character tion but resolves in weeks; in a very few patients in response to chronic treatment with benzodiaze- it persists, and these people have been the subject pines and therefore will take time to return to pre- of much research, mainly focusing on their per- medication levels after cessation of medication. sonality and cognitive factors. Features of withdrawal and dependence vary. Commonly there is a kind of psychological depend- Withdrawal of benzodiazepines should be gradual ence based on the fact that the treatment works to after as little as 3 weeks' use but for long-term users 401
  6. 19 PSYCHOTROPIC DRUGS it should be very slow, e.g. about 0.125 (1/8) of the therapy may become pregnant. Benzodiazepines dose every 2 weeks, aiming to complete it in 6-12 cross the placenta and can cause fetal cardiac weeks. Withdrawal should be slowed if marked arrhythmia, and muscular hypotonia, poor suck- symptoms occur and it may be useful to substitute ling, hypothermia and respiratory depression in the a long tl/2 drug (diazepam) to minimise rapid newborn. fluctuations in plasma concentrations. Abandonment of the final dose may be particularly distressing. Interactions. All potentiate the effects of alcohol In difficult cases withdrawal may be assisted by and other central depressants, and all are likely concomitant use of an antidepressant. to exacerbate breathing difficulties where this is already compromised, e.g. in obstructive sleep Adverse effects. In addition to those given above, apnoea. benzodiazepines can affect memory and balance. Hazards with car driving or operating any machinery Overdose. Benzodiazepines are remarkably safe can arise from amnesia and impaired psychomotor in acute overdose and the therapeutic dose x 10 function, in addition to sleepiness (warn the patient). induces sleep from which the subject is easily Amnesia for events subsequent to administration aroused. It is said that there is no reliably recorded occurs with i.v. high doses, for endoscopy, dental case of death from a benzodiazepine taken alone by surgery (with local anaesthetic), cardioversion, and in a person in good physical (particularly respiratory) these situations it can be regarded as a blessing.5 health, which is a remarkable tribute to their safety Women, perhaps as many as 1 in 200, may expe- (high therapeutic index); even if the statement is not rience sexual fantasies, including sexual assault, absolutely true, death must be extremely rare. But after large doses of benzodiazepine as used in some deaths have occurred in combination with alcohol dental surgery, and have brought charges in law (which combination is quite usual in those seeking against male staff. Plainly a court of law has, in the to end their own lives) and from complications of absence of a witness, great difficulty in deciding prolonged unconsciousness. Flumazenil selectively whom to believe. No such charges have yet been reverses benzodiazepine effects and is useful in brought, it seems, by a man against a woman. diagnosis and in treatment (see below). Paradoxical behaviour effects (see above) and perceptual disorders, e.g. hallucinations, occur Temazepam is a benzodiazepine that was until occasionally. Headache, giddiness, alimentary tract recently the most popular hypnotic in the form of upset, skin rashes and reduced libido can occur. a soft gel liquid-filled capsule but, being readily Extrapyramidal reactions, reversible by flumazenil, injected, it was widely also abused and the formula- are rare. tion was withdrawn. Temazepam is now classed as a controlled drug; it is available as a tablet, with a Benzodiazepines in pregnancy. The drugs are not much longer absorption time and duration of action certainly known to be safe and indeed diazepam is making daytime hangover effect more likely. Con- teratogenic in mice. The drugs should be avoided sequently it is much less often prescribed. in early pregnancy as far as possible. It should be remembered that safety in pregnancy is not only a Benzodiazepine antagonist: flumazenil is a com- matter of avoiding prescription after a pregnancy petitive antagonist at benzodiazepine receptors and has occurred but that individuals on long-term it may have some agonist actions, i.e. it is a partial agonist. Clinical uses include reversal of benzo- diazepine sedation after endoscopies, dentistry and 5 Although one patient, normally a gentle man, believed he in intensive care. Heavily sedated patients become was being lied to when told his endoscopy had been alert within 5 minutes. The tl/2 of 1 h is much shorter performed. 'He assaulted his physician and was calmed only than that of most benzodiazepines (see Table 19.8), by a second endoscopy.' Later he was very embarrassed and apologised repeatedly (Lurie Y et al 1990 Lancet 336: 576). so that repeated i.v. administration may be needed. Another post-dental surgery patient purchased a bone china Thus the recovery period needs supervision lest teaset and later condemned his wife for extravagance. sedation recurs; if used in day surgery it is im- 402
  7. INSOMNIA 19 portant to tell patients that they may not drive a car it has no effect on psychomotor skills, including home. The dose is 200 micrograms by i.v. injection driving skills, when taken at least 5 hours before given over 15 seconds, followed by 100 micrograms testing. This means that it can be taken during the over 60 seconds if necessary, to a maximum of night (either when patients have tried getting off to 300-600 micrograms. Flumazemil is useful for sleep for a long time, or if they wake during the diagnosis of self-poisoning and also for treatment, night and cannot return to sleep) without hangover when 100-400 micrograms are given by continuous effect. i.v. infusion and adjusted to the degree of wakefulness. OTHER DRUGSTHAT ACT ONTHE Adverse effects of flumazenil can include brief GABAA-BENZODIAZEPINE RECEPTOR anxiety, seizures in epileptics treated with a benzo- diazepine and precipitation of withdrawal syn- Chloral hydrate, clomethiazole and barbiturates drome in dependent subjects. Rarely, vomiting is also enhance GABA function but at high doses induced. have the additional capacity directly to open the Buspirone (see p. 396). membrane chloride channel (see Figure 19.4); this may lead to potentially lethal respiratory depres- sion and explains their low therapeutic ratio. These Nonbenzodiazepine hypnotics that act at drugs also have a propensity for abuse/misuse and the GABAA-benzodiazepine receptor are very much second-line treatments. Although structurally unrelated to the benzodiaze- pines, these drugs act on the same macromolecular Chloral hydrate has a fast (30-60 min) onset of action receptor complex but at different sites from the and duration of action 6-8 h. It is a prodrug, being benzodiazepines; their effects can be blocked by rapidly metabolised by alcohol dehydrogenase into flumazenil, the receptor antagonist. Those described the active hypnotic trichloroethanol (t1/2 8h). Chloral is below are all effective in insomnia, have low pro- dangerous in serious hepatic or renal failure and pensity for tolerance, rebound insomnia, withdrawal aggravates peptic ulcer. Interaction with ethanol is to symptoms and abuse potential but there are few be expected since both are metabolised by alcohol data of their effects in long-term studies. dehydrogenase. Ethanol also appears to induce the formation of trichloroethanol which attains higher Zopiclone is a cyclopyrrolone in structure. It has a plasma concentrations if alcohol is co-administered, fairly fast (about 1 hour) onset of action which lasts increasing sedation. Triclofos (Tricloryl) and cloral for 6-8 hours, making it an effective drug both for betaine (Welldorm) are related compounds. initial and maintenance insomnia. It may cause fewer problems on withdrawal than benzodiazepines. Clomethiazole is structurally related to vitamin B Its duration of action is prolonged in the elderly 1 (thiamine) and is a hypnotic, sedative and anti- and in hepatic insufficiency. About 40% of patients convulsant. It is comparatively free from hangover; experience a metallic aftertaste. Care should be it can cause nasal irritation and sneezing. Depend- taken with concomitant medication that affects its ence occurs and use should always be brief. When metabolic pathway (see Table 19.2a). The dose is taken orally, it is subject to extensive hepatic first- 3.75-7.5 mg p.o. pass metabolism (which is defective in the elderly and in liver damaged alcoholics who get higher Zolpidem is an imidazopyridine in structure and peak plasma concentrations), and the usual tl/2 is 4 h has a fast onset (30-60 min) and short duration of (with more variation in the old than the young); it action. Patients over 80 years have slower clearance may also be given i.v. of this drug. Barbiturates have a low therapeutic index, i.e. Zaleplon is a pyrazolopyrimidine. It has a fast relatively small overdose may endanger life; onset and short duration of action. Studies of psycho- they also cause dependence and have been popular motor performance in volunteers have shown that drugs of abuse. The use of intermediate-acting drugs 403
  8. 19 PSYCHOTROPIC DRUGS (amylobarbital, butobarbital, secobarbital) is now Antipsychotics have been used to promote sleep limited to severe intractable insomnia in patients in resistant insomnia occurring as part of another already taking barbiturates (they should be avoided psychiatric disorder, probably due to a combination in the elderly). The long-acting phenobarbital is used of 5HT2-receptor, o1-adrenoceptor and histamine for epilepsy (see Chapter 20), and very short-acting Hj-receptor antagonism, in addition to their thiopental for anaesthesia (see p. 353). Overdose primary dopamine antagonist effects. Their long following self-poisoning by hypnotic barbiturates action leads to daytime sedation and extrapyra- may have severe features including hypotension midal movement disorders may result from dopa- (may lead to renal failure), hypothermia, respira- mine receptor blockade (see p. 380, Antipsychotics). tory depression and coma. Supportive measures Nevertheless, modern antipsychotics, e.g. quetia- may suffice with i.v. fluid to restore central venous pine, have been occasionally used for intractable pressure and so cardiac output and, if that fails, insomnia. using a drug with cardiac inotropic effect (see p. 457). A good urine volume (e.g. 200 ml/h) promotes Melatonin, the hormone produced by the pineal elimination of the drug. Urine alkalinisation accele- gland during darkness, has been investigated rates removal of phenobarbital (an acid, pKa 7.2) for insomnia but it appears to be ineffective. The as do repeated doses of activated charcoal. Active impressive nature of the diurnal rhythm in mela- elimination by haemoperfusion or dialysis may be tonin secretion has stimulated interest in its use needed in particularly severe and complicated cases. therapeutically to reset circadian rhythm to prevent jet-lag on long-haul flights and for blind or partially Other drugs used in insomnia sighted people who cannot use daylight to synch- ronise their natural rhythm. There is controversy Antihistamines. Most proprietary (over the counter) about dose and timing of treatment and in most sleep remedies contain antihistamines. Prometha- countries pharmaceutical preparations are not zine (Phenergan) has a slow (1-2 h) onset and long generally available. (t1/2 12 h) duration of action. It reduces sleep onset latency and awakenings during the night after a single dose but there have been no studies showing Herbal preparations. Randomised clinical trials enduring action. It is sometimes used as a hypnotic have shown some effect of valerian in mild to in children. There are no controlled studies showing moderate insomnia, and hops, lavender and other improvements in sleep after other antihistamines. herbal compounds show promise in pilot studies Trimeprazine (alimemazine) is used for short-term that are presently being pursued more fully. sedation in children. Most antihistamine sedatives have a relatively long action and may cause day- Summary of pharmacotherapy for time sedation. insomnia Antidepressants. In the depressed patient, improve- • Drug treatment may be effective for a short ment in mood is almost always accompanied by period (2-4 weeks). improvement in subjective sleep and therefore • Some patients may need long-term medication. choice of antidepressant should not usually involve • Intermittent medication, i.e. taken only on nights additional consideration of sleep effects. Never- that symptoms occur, is preferable and may theless, some patients are more likely to continue often be possible with modern, short-acting, with medication if there is a short-term improve- compounds. ment, in which case mirtazapine or nefazodone • Discontinuing hypnotic drugs is usually not a provide an effective antidepressant together with problem if the patient knows what to expect. sleep-promoting effects. There will be a short period (usually 1-2 nights) Antidepressant drugs, particularly those with of rebound insomnia on stopping hypnotic 5HT2-blocking effects, may occasionally be effective drugs which can be ameliorated by phased in long-term insomnia (but see Table 19.6). withdrawal. 404
  9. INSOMNIA 19 HYPERSOMNIA action, making it less liable to abuse. Its duration of effect is quite short (3—4 h) so patients with Sleep-related breathing disorders causing excessive narcolepsy need to plan the timing of their tablets daytime sleepiness are rarely treated with drugs. to fit with daily activities. It is also used in attention Sleepiness caused by the night-time disruption of deficit/hyperactivity disorder (see below). obstructive sleep apnoea syndrome is sometimes not Modafinil is a wake-promoting agent whose completely abolished by the standard treatment of specific biochemical mechanism of action is obscure. continuous positive airway pressure overnight, and It increases brain concentrations of dopamine the use of wake-promoting drugs, e.g. modafinil, is after chronic administration in animals but has being evaluated in these patients. no overtly stimulant effect like amphetamines. It appears to have a slow onset and its action lasts Narcolepsy is a chronic neurological disorder and 8-12 h; abuse potential is very low. Modafinil is is characterised by excessive daytime sleepiness used in narcolepsy and other hypersomnias and (EDS), usually accompanied by cataplexy (attacks of has also been studied in normal people who need to weakness on emotional arousal). These symptoms stay awake for long periods and function well. are often associated with the intrusion into wake- In narcolepsy, patients usually need a stimulant fulness of other elements of rapid eye movement for their hypersomnia and a TCA or SSRI for their (REM) sleep, such as sleep paralysis and hypnagogic cataplexy, so care should be taken when combining hallucinations, i.e. in a transient state preceding these. Dexamfetamine and methylphenidate must sleep. not be given with MAOIs. There is potential for Stimulants are effective in the treatment of EDS interaction between methylphenidate and TCAs due to narcolepsy. Suitable agents include dexamfe- (hypertension) and SSRI antidepressants. It appears tamine, methylphenidate, and modafinil. that modafinil, methylphenidate and dexamfeta- Amfetamines release stored neurotransmitters, mine may themselves be combined without adverse primarily dopamine and noradrenaline, in the outcome (modafinil is occasionally used regularly brain. This causes a behavioural excitation, with and dexamfetamine added intermittently when increased alertness, elevation of mood, increase in peak alertness is particularly critical). Modafinil physical activity. accelerates the metabolism of oral contraceptives, Dexamfetamine, the dextrorotatory isomer of reducing their efficacy. amfetamine, is about twice as active in humans as the laevo isomer and is the main prescribed Cataplexy is most effectively treated with 5HT amfetamine. It is rapidly absorbed and its duration uptake-blocking drugs such as domipmmine or of action varies among individuals; most people fluoxetine, or some other antidepressant drugs, e.g. with narcolepsy find twice daily dosing optimal to reboxetine. maintain alertness during the day. About 40% of narcoleptic patients find it neces- PARASOMNIAS sary to increase their dose, indicating tolerance. Although physical dependence does not occur, there Nightmares arise out of REM sleep and are is mental and physical depression on withdrawal. reported by the patient as structured, often stereo- Unwanted effects include edginess, restlessness, typed dreams that are very distressing. Usually the insomnia and appetite suppression, weight loss, patient wakes up fully and remembers the dream. and increase in blood pressure and heart rate. Psychological methods of treatment may be appro- Amphetamines are commonly abused because of priate, e.g. a program of rehearsing the dream, their stimulant effect but this is rare in narcolepsy. inventing different endings. In a small number of Methylphenidate releases stored dopamine but cases where adverse events such as angina have most of its action is to inhibit uptake of central been provoked by recurrent nightmares it may be neurotransmitters. Its effects and adverse effects are appropriate to consider drug treatment with an very similar to amphetamines. Methylphenidate antidepressant with a marked suppressing effect on has a low systemic availability and slow onset of REM sleep, such as the MAOI, phenelzine. Night- 405
  10. 19 PSYCHOTROPIC DRUGS mares of a particularly distressing kind are a feature described as 'crawling', 'aching', 'tingling' and is of post-traumatic stress disorder. Case reports indi- partially or completely relieved with leg motion, cate benefit from various pharmacological agents returning after movement ceases. Most if not all but no particular drug emerges as superior. Many patients with this complaint also have periodic limb prefer to use a 5HT-blocker such as trazodone or movements disorder (PLMD), which may occur nefazodone. independently of RLS. These periodic limb move- ments consist of highly stereotyped movements, Night terrors and sleep-walking arise from slow usually of the legs, that occur repeatedly (typically wave sleep and they are often coexistent. There is every 20-40 seconds) during the night. They may usually a history dating from childhood and often a wake the patient, in which case there may be a family history. Exacerbations commonly coincide complaint of daytime sleepiness or occasionally with periods of stress and alcohol will increase their insomnia, but often only awaken the sleeping likelihood. In a night terror patients usually sit or partner, who is usually kicked. RLS and PLMS are jump up from deep sleep (mostly early in the night) considered to be movement disorders and may with a loud cry, look terrified and move violently, respond to formulations of levodopa but dopamine sometimes injuring themselves or others. They agonists, e.g. ropinirole, and other treatments such appear asleep and uncommunicative, often return- as gabapentin are under investigation ing to sleep without being aware of the event. These terrors are thought to be a welling-up of anxiety Sleep scheduling disorders. Circadian rhythm from deep centres in the brain which is normally disorders are often confused with insomnia and inhibited by cortical mechanisms. They can occur in both can be present in the same patient. With such up to 30% of normal children but become trouble- sleep scheduling disorders, sleep occurs at the some and often dangerous in adults. They can 'wrong' time, i.e. at a time that does not fit with be successfully treated with the benzodiazepine, work, social or family commitments. A typical clonazepam or the SSRI, paroxetine. pattern may be a difficulty in initiating sleep for a Nocturnal panic attacks may be distinguished few nights due to stress, whereupon once asleep the from night terrors by the fact that the patient will subject continues sleeping well into the morning to wake fully before panic symptoms have reached a 'catch up' the lost sleep. Thereafter the 'time since peak and is fully aware. last sleep' cue for sleep initiation is delayed and the sleep period gradually becomes more delayed until REM behaviour disorder, first described by in the subject is sleeping in the day instead of at 1988, consists of lack of paralysis during REM night. A behavioural program with strategic light sleep which results in acting out of dreams, often exposure is appropriate, with pharmacological vigorously with injury to self or others. It can occur treatment as an adjunct, e.g. melatonin, to help reset acutely as a result of drug or alcohol withdrawal the sleep-wake schedule. but its chronic manifestation can be idiopathic or associated with neurological disorder (about 50% of each). It is much commoner among older patients. Successful treatment has been described with Drugs for Alzheimer's6 clonazepam or clonidine which decrease REM sleep without increasing awakenings. disease (dementia) Dementia is described as a syndrome 'due to disease OTHER SLEEP DISORDERS of the brain, usually of chronic or progressive nature in which there is disturbance of multiple Restless legs syndrome (RLS) is a disorder that higher cortical functions, including memory, think- usually occurs prior to sleep onset and is character- ing, orientation, comprehension, calculation, learn- ised by disagreeable sensations, that cause an almost ing capacity, language and judgement, without irresistible urge to move the legs. The sensation is clouding of consciousness.'7 Deterioration in 406
  11. DRUGS FOR ALZHEIMER'S DISEASE (DEMENTIA) 19 emotional control, social behaviour or motivation The beneficial effects of drugs are therefore to: may accompany or precede cognitive impairment. • stabilise the condition initially and sometimes Alzheimer's and vascular (multi-infarct) disease are improve cognitive function, the two most common forms of dementia, account- • delay the overall pace of decline (and therefore ing for about 80% of presentations. Alzheimer's the escalating levels of support required), disease is associated with deposition of beta-amyloid • postpone the onset of severe dementia. in brain tissue and abnormal phosphorylation of the intracellular tau proteins, causing abnormalities The severity of cognitive deficits in patients of microtubule assembly and collapse of the cyto- suffering from, or suspected of having, dementia skeleton. Pyramidal cells of the cortex and subcortex can be quantified by a simple 30-point schedule, the are particularly affected. mini mental-state examination (MMSE) of Folstein. In Western countries, the prevalence of dementia A score of 21-26 denotes mild, 10-20 moderate and is below 1% in those aged 60-64 years, but it doubles less than 12 severe Alzheimer's disease. The MMSE with each 5-year cohort to a figure of around 16% can also be used to monitor progress. in those aged 80-84 years. The emotional impact of Given the limited evidence of overall benefit in dementia on relatives and carers and the cost to relation to cost, the use of these drugs is the subject society in social support and care facilities are great. of debate but there follows a practical position. Hence the impetus for an effective form of The UK National Institute for Clinical Excellence treatment is compelling. (NICE) recommends that donepezil, galantamine Evidence indicates that cholinergic transmission is and rivastigmine should be available as adjuvant diminished in Alzheimer's disease. All agents that therapy for those with a MMSE score above 12 benefit the condition act to enhance acetylcholine points, subject to the following conditions: activity by inhibition of the acetylcholinesterase • Alzheimer's disease must be diagnosed and which metabolises and inactivates synaptically- assessed in a specialist clinic; the clinic should released acetylcholine. Consequently acetylcholine also assess cognitive, global and behavioural remains usable for longer. Individual drugs are functioning, activities of daily living, and the categorised by the type of enzyme inhibition they likelihood of compliance with treatment cause. Donepezil is classed as a 'reversible' agent as • treatment should be initiated by specialists but binding to the acetylcholinesterase enzymes lasts may be continued by general practitioners under only minutes, whereas rivastigmine is considered a shared-care protocol 'pseudo-irreversible' since inhibition lasts several • the carers' views of the condition should be hours. Galantamine is associated both with revers- sought before and during drug treatment ible inhibition and with enhanced acetylcholine • the patient should be assessed 2-4 months after action on nicotinic receptors.8 Clinical trials show maintenance dose is established; drug treatment that these agents produce an initial increase in should continue only if MMSE score has patients' cognitive ability. There may be associated improved or has not deteriorated and global benefits, including improvements in non- behavioural and functional assessment shows cognitive aspects such as depressive symptoms. But improvement the drugs do not alter the underlying process, and • the patient should be assessed every 6 months the relentless advance of the disease is paralleled by and drug treatment should normally continue reduction in acetylcholine production with decline only if MMSE score remains above 12 points and in cognition. if treatment is considered to have a worthwhile effect on the global functional and behavioural 6 Alois Alzheimer (1864-1915) German psychiatrist who condition. studied the brains of demented and senile patients and correlated hisological findings with clinical features. 7 ICD-10 diagnostic system. Doses p.o. are: 8 Irreversible antagonists exist but, not surprisingly, have no donepezil 5-10 mg nocte increasing to 10 mg nocte place in therapeutics (sarin nerve gas is an example). after one month, 407
  12. 19 PSYCHOTROPIC DRUGS galantamine 4 mg b.d. increasing to 8-12 mg b.d. at each of the three principal symptoms. It should be 4 weekly intervals, initiated only by a specialist in these conditions and rivastigmine 1.5 mg b.d. increasing to 3-6 mg b.d. should form part of a comprehensive treatment at intervals of 2 weeks. programme of psychological, educational and social measures. Periodic breaks in treatment once symp- Adverse effects inevitably include cholinergic toms have been stabilised ('drug holidays') are symptoms with nausea, diarrhoea and abdominal recommended to allow expected improvement in cramps appearing commonly. There may also function to be quantified. be bradycardia, sinoatrial or atrioventricular block. Unwanted effects include anxiety, anorexia and Urinary incontinence, syncope, convulsions, and difficulty sleeping, which usually subside. Methyl- psychiatric disturbances also occur. Rapid dose phenidate reduces expected weight gain and has increase appears to make symptoms more pro- been associated with slight growth retardation. nounced. Hepatotoxicity is a rare association with Monitoring of therapy should include height and donepezil. weight, also blood pressure and blood counts The deterioration of function in dementia of (thrombocytopenia and leucopenia occur). Alzheimer's disease is often accompanied by Methylphenidate should be avoided in children acute behavioural disturbance and the develop- with Tourette's syndrome or where there is a family ment of a range of psychotic symptoms. Therapy history of this disorder. Thyroid disease is also a with atypical drugs is then preferred because they contraindication. provoke fewer adverse effects than classical antipsychotics. Dexamfetamine is an alternative for it has similar Other substances that are being evaluated in efficacy in ADHD. Unwanted effects and contra- Alzheimer's disease include the antioxidant vit- indications are broadly similar to those of methyl- amin E, the monoamine oxidase type B inhibitor, phenidate. Dexamfetamine is the preferred drug in selegeline (see p. 425) and the plant extract gingko children who also have epilepsy. It has a greater biloba, which is though to have antioxidant and potential for abuse. cholinergic activity. Oestrogens and nonsteroidal Clonidine, tricyclic antidepressants and antipsycho- anti-inflammatory agents may also have protective tic agents (e.g. risperidone, sulpiride) may have a effects. role in ADHD where methylphenidate and dexam- fetamine are contraindicated or have failed to produce benefit. Drugs in attention deficit/ hyperactivity disorder Drugs and skilled tasks Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, impulsivity and motor Drugs can affect skilled tasks and car driving, and overactivity, present before the age of 7 years, and it is convenient to consider the implications of this causing pervasive impairment across situations as broad issue. opposed to occurring only at school or within the Many medicines affect performance, not only home. Some diagnostic systems use the narrower psychotropic drugs9 (amongst which sedative anti- definition of hyperkinetic disorder rather than ADHD. depressants, benzodiazepines, hypnotics and anti- Hyperkinetic disorder is reported to affect 1-2% of psychotics are the most obvious examples) but also school-aged children in the United Kingdom and antihistamines, antimuscarinics, analgesics including ADHD 5%. some NSAIDs, (e.g. indomethacin), antiepileptics, antidiabetics (hypoglycaemia) and some antihyper- Methylphenidate (see above) is effective in children tensives. Alcohol and cannabis are discussed on with ADHD and hyperkinetic disorder, reducing pages 178 and 190. 408
  13. DRUGS AND SKILLED TASKS 19 TABLE 19.9 Summary of indications for psychotropic drug Depressive disorders * *l Depressive disorders with psychotic symptoms * *1 * Bipolar affective disorder (prophylaxis) * Bipolar affective disorder (acute manic episode) * * * Generalised anxiety disorder *2 *3 * *4 Panic disorder * * Social phobia *5 *5 Obsessive-compulsive disorder *6 *7 Post-traumatic stress disorder *8 Schizophrenia * Acute behavioural disturbance * * Alcohol withdrawal * *9 *10 Insomnia *11 * * Eating disorders *I2 Dementia of Alzheimer's disease *I3 Attention deficit/hyperactivity disorder *I4 *I4 Key: *recognised indication; where numbers appear in the table, see notes below. Notes: (1) Lithium augmentation may be used in depression (p. 375). Lithium is given in combination with aTCA,SSRI or novel antidepressant, usually when the symptoms have proved resistant to adequate trials of two or more antidepressants. (2) Formerly, antidepressants were thought to be less effective in generalised anxiety disorder than in panic disorder. Evidence now suggests that the SSRI, paroxetine and the SNRI, venlafaxine are beneficial. (3) Antipsychotics may be used short-term for management of severe anxiety, but only where other drug options have failed (due to adverse effect). (4) Buspirone may be used in generalised anxiety disorder as an alternative to a benzodiazepine. (5) SSRIs and MAOIs are effective in social phobia. 3-adrenoceptor blockers may also be helpful, particularly in performance anxiety, combating tremor and other symptoms of autonomic overactivity. (6) Serotonergic antidepressants, including the tricyclic clomipramine and the SSRIs are effective in the treatment of obsessive-compulsive disorder. (7) Augmentation with classical or atypical antipsychotics may be attempted when obsessive-compulsive disorder is resistant to antidepressant treatment. (8)TCAs (especially imipramine and amitriptyline) and SSRIs may be effective in post-traumatic stress disorder. (9) Clomethiazole was an alternative to a benzodiazepine for alcohol withdrawal but is now rarely used due to concerns over respiratory depression and abuse potential. (10) Drugs for alcohol dependence and withdrawal are discussed in Chapter 10. (11) When a patient complaining of insomnia also has depression, a sedative antidepressant such as trazodone, nefazodone or mirtazapine should be considered. SSRIs do not provide direct sedation in such patients but may improve the quality of sleep over a longer period as mood improves. (12) Fluoxetine is licenced in the UK for the treatment of bulimia nervosa. (13) Acetylcholinesterase inhibitors provide transient improvement in cognitive and global functioning in mild to moderate dementia of Alzheimer's disease.They delay the onset of severe illness but cannot ultimately halt or change the course of the disease. (14)The CNS stimulants methylphenidate and dexamfetamine are drugs of choice for attention deficit/hyperactivity disorder. Second line treatment options include clonidine and the antipsychotic agents risperidone, haloperidol and sulpiride. 409
  14. 19 PSYCHOTROPIC DRUGS It is plain that prescribers have a major respons- The emphasis on psychomotor and physical ibility here, both to warn patients and, in the case aspects (injury) should not distract from the of those who need to drive for their work, to possibility that those who live by their intellect and choose medicines having minimal liability to cause imagination (politicians and even journalists may impairment. Patients who must drive when taking be included here) may suffer cognitive disability a drug of known risk (e.g. benzodiazepine) should from thoughtless prescribing. be specially warned of times of peak impairment. A patient who has an accident and who was not warned of drug hazard, whether orally or by labelling, may successfully sue the doctor in law. Summary It is also necessary that patients be advised of the additive effect of alcohol with prescribed medicines.10 Table 19.9 summarises indications of the major Car driving is a complex multifunction task that groups of psychotropic drugs. Psychiatric illnesses includes:11 are often associated with co-morbid conditions which may require treatment, e.g. schizophrenia • visual search and recognition may be associated with depression. • vigilance • information processing under variable demand • decision-making and risk-taking • sensorimotor control. GUIDETO FURTHER READING How the patient feels is not a reliable guide to recovery of skills and drivers may be more than Anderson IM, Nutt D J et al 2000 Evidence-based usually accident prone without any subjective guidelines for treating depressive disorders with feeling of sedation or dysphoria: the fact that they antidepressants: a revision of the 1993 British feel OK does not mean that they are OK. Association for Psychopharmacology guidelines. The criteria for safety in air-crew are more Journal of Psychopharmacology 14: 3-20 stringent than those for car drivers. Ballenger J C et al 1998 Consensus statement on panic Resumption of car driving or other skilled activity disorder from the International Consensus Group after anaesthesia is a special case, and an extremely on Depression and Anxiety. Journal of Clinical variable one, but where a sedative (e.g. i.v. benzo- Psychiatry 59: 47-54 diazepine, opioid or neuroleptic), or any general Ballenger J C et al 1998 Consensus statement on social anaesthetic has been used it seems reasonable not to anxiety disorder from the International Consensus drive for 24 h at least. Group on Depression and Anxiety. Journal of Clinical Psychiatry 59: 54-60 9 Ballenger J C et al 2000 Consensus statement on A dose-response relationship was found between benzodiazepine use and road-traffic accidents. Barbone F et posttraumatic stress disorder from the al 1998 Lancet 352: 1331-1336 International Consensus Group on Depression and 10 Nordic countries require that medicines liable to impair Anxiety. Journal of Clinical Psychiatry 61: 60-66 ability to drive or to operate machinery be labelled with a Ballenger J C et al 2001 Consensus statement on red triangle on a white background. The scheme covers generalized anxiety disorder. Journal of Clinical antidepressants, benzodiazepines, hypnotics, drugs for motion sickness and allergy cerebral stimulants, Psychiatry 62: 53-58 antiepileptics and antihypertensive agents. In the UK there Davies S J C et al 1999 Association of panic disorder are some standard labels that pharmacists are recommended and panic attacks with hypertension. American to apply, e.g. 'Warning. May cause drowsiness. If affected do Journal of Medicine 107: 310-316 not drive or operate machinery. Avoid alcoholic drink'. They Ferrier I N 2001 Developments in mood stabilisers. are offered as 'a carefully considered balance between the unintelligibly short and the inconveniently long' (see BNF). British Medical Bulletin 57:179-192 11 In: Willett R E et al (eds) 1983 Drugs, driving and traffic Fink M 2001 Convulsive therapy: a review of the first safety. WHO, Geneva. 55 years. Journal of Affective Disorders 63:1-15 410
  15. DRUGS AND SKILLED TASKS 19 Glassman A H, Bigger J T 2001 Antipsychotic drugs: inhibitors on cytochrome P450 enzymes. Journal of Prolonged QTc interval, Torsade de pointes, and Psychopharmacology 12: Supp B S89-S97 sudden death. American Journal of Psychiatry 158: Roth T et al 2001 Consensus for the pharmacological 1774-1782 management of insomnia in the new millennium. Kent J M 2000 SNaRIs, NaSSAs, and NaRIs: new International Journal of Clinical Practice 55: 42-52 agents for the treatment of depression. Lancet 355: Sack R L et al 1997 Sleep-promoting effects of 911-918 melatonin: at what dose, in whom, under what Kryger M H et al (eds) 2000 Principles And Practice Of conditions and by what mechanisms? Sleep 20: Sleep Medicine, Third Edition. Philadelphia: W B 908-915 Saunders Schultz S K, Andreasen N C 1999 Schizophrenia. Kuperberg G R, Murray R 1996 Advances in the Lancet 353:1425-1430 treatment of schizophrenia. British Journal of Shiloh R, Nutt D J, Weizman A 1999 Atlas of Psychiatric Clinical Practice 50: 315-323 Pharmacotherapy. London: Martin Dunitz Mayeux R, Sano M 1999 Treatment of Alzheimer's Whooley M A, Simon G E 2000 Managing depression disease. New England Journal of Medicine 341: in medical outpatients. New England Journal of 1670-1679 Medicine 343:1942-1950 Nelson J C 1997. Treatment of refractory depression. Wilson S J et al 1997 Adult night terrors and Depression and Anxiety 5:165-174 paroxetine. Lancet 350:185 Nutt D J, Malizia A L 2001. New insights into the role Yehuda R 2002 Post-traumatic stress disorder. New of the GABA-A benzodiazepine receptor. British England Journal of Medicine 346:108-114 Journal of Psychiatry 179: 390-396 Zametkin A J, Ernst M 1999 Problems in the Paykel E S 2001 Continuation and maintenance management of attention deficit hyperactivity therapy in depression. British Medical Bulletin 57: disorder. New England Journal of Medicine 340: 145-159 40-45 Preskorn S H 1998 Debate resolved: there are differential effects of serotonin selective reuptake 411
Đồng bộ tài khoản