Psychiatric effects of drugs for other disorders

TreaTmenT STraTegieS

Psychiatric effects of drugs for other disordersC Heather ashton

Abstractmany drugs used therapeutically for non-psychiatric disorders can cause

neuropsychiatric reactions. a wide range of such effects are reported

including sedation, sleep disturbance, anxiety, depression, mania, psy-

chosis, cognitive disturbance and delirium. The reactions are usually

dose-related but may occur at therapeutic doses or on drug withdrawal

after chronic use. They are more common in elderly or ill patients or

those with a psychiatric history and may be unpredictable or paradoxi-

cal. Some of the more common psychiatric effects of drugs used for

non-psychiatric disorders are reviewed briefly here. They include, among

others, dopaminergic and antimuscarinic drugs for parkinsonism; digi-

talis and β-adrenoceptor antagonists for cardiovascular disorders; can-

nabinoid receptor antagonists for obesity; corticosteroids for endocrine

disorders, asthma and allergic conditions; and anti-infective drugs for

bacterial, parastic and viral infections.

Keywords adverse drug reactions; corticosteroids; dopaminergic drugs;

neuropsychiatric reactions; opioids; side effects

Neuropsychiatric effects account for up to 30% of adverse drug reactions (ADRs). Many of these ADRs, ranging from anxiety states to delirium, are caused by therapeutically administered non-psychiatric drugs, and many drugs can cause a variety of psychiatric effects. The incidence of such reactions is not always known because the information usually depends on selected patient groups or individual reports. In general, psychiatric ADRs are more common in elderly or ill patients and in those with a psychiatric history. Other factors include metabolic status, drug interactions and personality. The ADRs are usually dose-related, and can occur at therapeutic doses and with plasma concentra-tions in previously normal individuals with no innate vulnerabil-ity. They may also occur on drug withdrawal. The mechanisms are often complex and vary between drugs and clinical situations. Management may be simple if the cause is known, but patients who are taking several different drugs may need careful assess-ment. A selection of the more common ADRs is given here.

Parkinson’s disease and parkinsonism

Dopaminergic and antimuscarinic agents – dopaminergic drugs can cause depression, agitation, paranoid psychosis, mania,

C Heather Ashton DM FRCP is Emeritus Professor of Clinical

Psychopharmacology at the University of Newcastle upon Tyne, UK.

Competing interests: none declared.

meDiCine 36:9 50

hypomania and excessive daytime sleepiness. The incidence of psychiatric problems was 20% in one series of 908 patients treated with levodopa for Parkinson’s disease.1 Delirious states occurring with bromocriptine can be serious, involving confu-sion, aggressiveness, florid delusions and hallucinations, which can last for weeks after discontinuation of the drug. Similar effects have been reported with apomorphine, lisuride, pergolide and selegiline. These effects are usually dose-related but are exacerbated by antimuscarinic agents, which are often used con-comitantly in Parkinson’s disease and can also cause delirium. In addition, they may cause dementia, and contribute to cognitive impairment in patients with Parkinson’s disease.

Management of psychiatric symptoms in parkinsonism involves withdrawal or dose reduction of the offending drug. The psychi-atric effects of dopaminergic agents may limit the dose that can be administered, which may still be subtherapeutic, particularly in elderly patients and those with post-encephalitic disease, and the appearance of symptoms may be delayed. Delirium caused by anticholinergic drugs or amantadine can be reversed rapidly with intravenous physostigmine (see also pages 463–466). Benzodiaz-epines may be helpful, but antipsychotic drugs with antimuscarinic effects should be avoided.

Other medical conditions – bromocriptine has caused schizo-phreniform or manic reactions when used for post-partum sup-pression of lactation and in the treatment of pituitary tumours.1 Use of mydriatic eye drops containing antimuscarinics has been associated with delirium, hallucinations and amnesia (Table 1).

Skeletal muscle relaxants such as baclofen used for chronic spastic conditions often cause sedation, and sometimes cause anxiety and agitation with insomnia. Other reported symptoms include euphoria, nightmares, confusion and hallucinations. The UK Committee on Safety of Medicines has warned that seri-ous side effects can occur on abrupt withdrawal of baclofen,

• rimonabant, a cannabinoid CB1 receptor antagonist, is

effective for weight loss in obesity but carries a 2.5-fold risk

of depression and a threefold risk of anxiety compared with

placebo

• nabilone, a synthetic cannabinoid receptor agonist similar

to tetrahydrocannabinol (THC), and sativex, a plant-

derived agent containing THC and cannabidiol, alleviate

pain in spastic disorders and neuropathic pain; psychiatric

side-effects are minimized by using modest doses and/or

combination with opioids or other analgesics

• abrupt withdrawal of baclofen may cause serious psychiatric

reactions, especially delirium, and after chronic use the drug

should be withdrawn gradually over several weeks

• isotretinoin has not been shown to increase the risk of

depression or suicide in adolescents treated for severe acne

but remains under suspicion of causing rare paradoxical

reactions

What’s new?

1 © 2008 elsevier Ltd. all rights reserved.


Psychiatric effects of some drugs for other disorders

Disorders and drugs Psychiatric effects

Parkinson’s disease, parkinsonismDopaminergic agents (e.g. levodopa, bromocriptine, amantadine,

apomorphine, lisuride, selegiline)

Delirium, depression, agitation, paranoid psychosis, mania, somnolence

antimuscarinic agents (benzatropine, biperiden, orphenadrine,

procyclidine, benzhexol)

exacerbate effects of dopaminergic agents; confusion and dementia

Chronic spastic conditionsSkeletal muscle relaxants (baclofen, dantrolene, tizanidine) anxiety, agitation, insomnia, nightmares, euphoria, confusion,

hallucinations, withdrawal effects

Cardiovascular disordersDigitalis preparations (digoxin, digitoxin) Delirium, depression, hallucinations, psychosis

Diuretics (causing potassium loss) (thiazides, frusemide,

bumetadine, torasemide)

may exacerbate toxic effects of digitalis preparations

β-adrenoceptor antagonists (e.g. propranolol, atenolol,

metoprolol, oxprenolol, sotalol)

Sleep disturbance, nightmares, hypnogogic or hypnocampic

hallucinations, depression, delirium

antiarrhythmic agents (e.g. lignocaine, procainamide, mexiletine) Psychotic reactions, depression

Calcium channel blockers (e.g. nifedipine, diltiazem) Psychotic reactions, depression

angiotensin-converting enzyme inhibitors (e.g. enalapril,

imidapril, quinapril, ramipril)

Confusion, depression, nervousness, sleep disturbance

ObesityCannabinoid CB1 receptor antagonist (rimonabant) Depression, anxiety

Endocrine disordersglucocorticoids (e.g. prednisolone, betamethasone,

dexamethasone, triamcinolone)

euphoria, mania, depression, psychosis, violent behaviour

Oestrogens and progestogens (contraceptives, hormone

replacement therapy, treatment of menstrual abnormalities)

Depression, premenstrual tension-like symptoms, changes in libido

male sex hormones and anabolic steroids (e.g. testosterone,

nandrolone, stanozolol)

Depression, anxiety, changes in libido; mania, psychosis, aggression

and withdrawal symptoms with high doses of anabolic steroids

Pain syndromesOpioids (e.g. morphine, diamorphine, pethidine, dihydrocodeine,

tramadol, pentazocine, nalbuphine, buprenorphine)

Dysphoria, depression, psychosis (especially mixed agonists/

antagonists), withdrawal symptoms

non-steroidal anti-inflammatory drugs (e.g. ibuprofen,

diclofenac, piroxicam, celecoxib)

nervousness, depression, drowsiness, insomnia; may aggravate

depression and other psychiatric disorders

Cannabinoids (nabilone) Sedation, euphoria, depression, cognitive impairment, psychosis

Gastrointestinal disordersH2 receptor antagonists and proton pump inhibitors

(e.g. cimetidine, ranitidine, omeprazole)

Depression, somnolence, insomnia, agitation, confusion, hallucinations

Bacterial, parasitic and viral infectionsantibiotics (e.g. chloramphenicol, streptomycin and related

drugs, cephalosporins, isoniazid, cycloserine, quinolones)

Delirium, psychosis; sleep disorders, hallucinations, convulsions

antimalarials (mefloquine, chloroquine, mepacrine, quinine) anxiety, panic, insomnia, nightmares, dysphoria, mania, psychosis,

delirium

antivirals (aciclovir and related drugs, zidovudine and

related drugs)

Drowsiness, hallucinations, delusions, depression, insomnia, anxiety

interferons (alpha and beta interferons) Depression and suicidal behaviour

Acne vulgarisisotretinoin Possible depression, psychosis

Table 1

which should be discontinued by gradual dose reduction over several weeks.2 If necessary delirium may be alleviated by rein-statement of baclofen and unremitting spasticity (e.g. constant severe hypertonus) by other agents including dantrolene and/or benzodiazepines.2

meDiCine 36:9 50

Cardiovascular disorders

Digitalis preparations can cause delirium, depression, halluci-nations and psychosis. The effects are usually dose-dependent and the likelihood of psychiatric toxicity increases progressively



with plasma digoxin concentration from 1.5–3 μg/litre. ADRs can also occur at normal doses, particularly in combination with diuretics causing potassium loss. The mechanisms are prob-ably multiple and include electrolyte disturbance and cerebral hypoxia resulting from cardiac failure. Management comprises discontinuation of the drug and correction of any hypokalae-mia. Digoxin-specific antibody fragments are available for life- threatening toxicity.

β-adrenoceptor antagonists – the most common psychiatric effect of these drugs is sleep disturbance, including drowsiness, insomnia, vivid dreams, nightmares, and hypnogogic or hypno-campic hallucinations. These occur mostly with the lipophilic agents (e.g. propranolol), with which the incidence of drowsi-ness and fatigue is about 4%; vivid dreams and hallucinations at onset of sleep or waking are more common. The effects are generally dose-related, but have been reported in individuals taking propranolol at a dose of only 30 mg/day. Similar symp-toms occasionally occur with water-soluble preparations such as atenolol. Both lipophilic and water-soluble agents (e.g. atenolol, mentioned above) can cause depression (incidence 1–5%) and both occasionally cause delirium.

Other cardiovascular drugs – psychotic reactions have been reported with several anti-arrhythmic agents and calcium chan-nel blockers. Angiotensin-converting enzyme inhibitors may cause confusion, depression and nervousness.

Obesity

Cannabinoid receptor antagonists – rimonabant, the canna-binoid CB1 receptor antagonist, has recently been marketed as an anti-obesity agent. Two meta-analyses of large randomized controlled clinical trials provide evidence of dose-related adverse psychiatric effects of this drug.3,4 Patients receiving 20 mg of rimonabant daily for obesity were 2.5-times more likely than those on placebo to discontinue treatment due to depression or depressive symptoms and 3-times more likely to stop treat-ment due to anxiety.3 These findings were especially worrying since patients with psychiatric disorders or depressed mood were excluded from the study. A four-year study of patients receiving rimonabant noted an increased incidence of psychiatric disor-ders (depression, anxiety, irritability, aggression) compared with those receiving placebo.4 The US Food and Drug Administration reported an increased risk (1.9) of suicide attempts or ideation in participants who took rimonabant 20 mg compared with placebo.5 Rimonabant also appears to be effective as a smoking-cessation aid,6 but depression and anxiety may limit its usefulness.

Sibutramine, a serotonin-noradrenaline reuptake inhibitor which is also used for obesity, may cause insomnia4 and has been associated with panic attacks and a psychotic episode.7

Endocrine disorders

Glucocorticoids – systemic glucocorticoids can cause a spectrum of psychiatric reactions. A review of two large meta-analyses report severe reactions in nearly six percent of patients and mild to moderate reactions in 28%.8 The most common effects of short-term therapy are euphoria and hypomania, while long-term use is associated with depression which may be suicidal. Other effects include insomnia, anxiety, cognitive impairment, violent

meDiCine 36:9 50

behaviour, psychosis and delirium. The effects may be dose-related and more common in patients with a psychiatric history, but may be unpredictable, usually occurring within the first six weeks of treatment. Long-term use leads to drug dependence, and psychiatric reactions of all types can occur on withdrawal. To minimize the risks, the maintenance dose should be kept as low as possible and withdrawal should be gradual. Management of patients with severe psychiatric reactions who cannot tolerate glucocorticoid cessation or dosage reduction may necessitate the use of mood stabilizers, antipsychotics or antidepressants.8

Oestrogens and progestogens carry a slight risk of depression, particularly in women taking high-dose oestrogen. They may also cause a premenstrual-like syndrome with sodium and fluid retention, and can cause headaches and changes in libido.

Testosterone and anabolic steroids – testosterone can cause depression, anxiety, asthenia and changes in libido. Anabolic steroids can cause euphoria or depression, particularly at higher doses. They are sometimes abused in large doses by body- builders and athletes, and can lead to dependence. Psychiatric effects are common in this setting and may occur both during use and on withdrawal. In some studies, the incidence of mania and hypomania has been reported to be more than 20%, and psy-chosis and hallucinations more than 10%. Irritability, aggression and violence are also common. Depression, with risk of suicide, may be severe on withdrawal, and 50–80% of abusers report milder symptoms of fatigue, restlessness, insomnia, reduced libido and craving.

Pain syndromes

Opioids – pure opioid agonists such as morphine may cause dysphoria in 1–2% of patients treated for chronic pain, but the incidence of dysphoria, including depression, is much higher (10%) with mixed agonists/antagonists such as pentazocine and nalbuphine. Buprenorphine may cause withdrawal symptoms in patients dependent on opioids. Morphine and other opioids occasionally cause paranoid thinking and hallucinations, but psychotic reactions are more common with pentazocine and the non-opioid analgesic nefopam. Dependence is seldom a prob-lem when the drugs are used clinically for pain relief. However, withdrawal reactions may occur, and discontinuation should be gradual and combined with other methods of pain control.

Non-steroidal anti-inflammatory drugs – all of these agents, including COX-2 inhibitors, can cause nervousness, depression, drowsiness or insomnia. The risk appears to be greatest with indomethacin, which may aggravate depression and other psy-chiatric disorders, epilepsy and Parkinson’s disease.

Cannabinoids – nabilone, a synthetic analogue of tetrahydro-cannabinol (THC) a cannabinoid CB1 receptor agonist, has been shown to alleviate pain in spastic disorders and neuropathic pain.6 It acts through a non-opioid pathway and has additive analgesic effects with morphine. Nabilone is also used as an antiemetic caused by cytotoxic chemotherapy. Side-effects are dose-related and may include sedation, euphoria, dysphoria, depression, anxiety, memory impairment, depersonalization, paranoia and hallucinations. These effects can be minimized by using modest doses or drug combinations. Sativex, a plant-derived mixture of THC and cannabidiol which can be deliv-ered as a sublingual spray, has similar analgesic effects in spastic



conditions but appears to have few psychiatric side-effects apart from sedation.9

Gastrointestinal disorders

Both H2-receptor antagonists and proton pump inhibitors can cause depression, somnolence or insomnia, agitation and con-fusion with hallucinations, particularly in elderly or severely ill patients.

Bacterial, parasitic and viral infections

Antibiotics seldom cause psychiatric side effects, but delirium and paranoid–hallucinatory psychosis have been reported with chloramphenicol, streptomycin and related drugs, cephalospo-rins and some antituberculous drugs. Quinolones can cause sleep disorders, restlessness, depression, confusion and hallucinations, and may induce convulsions in patients with or without a history of epilepsy.

Antimalarials – of these agents, mefloquine has the greatest propensity to cause neuropsychiatric effects. The incidence of severe reactions is only about 0.01%, but milder reactions are more common. The most common are anxiety, panic, insomnia, nightmares and dysphoria, which usually appear within 3 weeks of starting prophylactic dosing. Severe reactions include mania and paranoid/hallucinatory psychoses, which may also occur with chloroquine and mepacrine. Higher doses used for treat-ment of malaria may precipitate delirium. Mefloquine is contra-indicated in patients with a history of neuropsychiatric disorder.

Antivirals – aciclovir and related drugs can cause drowsiness and hallucinations; protease inhibitors are associated with mood disorders including depression and sleep disturbances. Zidovu-dine and related drugs may cause general malaise. There have been reports of delirium, psychosis and self-harming behaviour associated with the anti-influenza drugs oseltamivir and zana-mivir. The US Food and Drugs Administration noted that such reactions could be due to the influenza itself but recommended that the drug label should carry a warning of possible psychiatric effects.

Interferons – interferon-α and interferon-β may induce depres-sion and suicidal behaviour. Interferon-β is contraindicated in patients with a history of severe depression or suicidal ideation.

Acne vulgaris

Isotretinoin – There have been many anecdotal reports of depres-sion, suicidal behaviour and psychotic symptoms associated with the use of isotretinoin for acne vulgaris. However, large ret-rospective reviews10,11 and a smaller prospective review12 found no evidence that isotretinoin increases the risk of these disorders which are relatively common in adolescents with severe acne. Nevertheless, patients undergoing this treatment should be care-fully monitored by GPs and dermatologists as the possibility of rare idiosyncratic psychiatric reactions remains.11,12 ◆

REfEREnCEs

1 Davies Dm, Ferner re, de glanville H. Textbook of adverse drug

reactions, 5th edn. London: Chapman & Hall, 1998.

meDiCine 36:9 50

2 Leo r, Baer D. Delirium associated with baclofen withdrawal: a

review of common presentations and management strategies.

Psychosomatics 2005; 46: 503–7.

3 Christensen r, Kristensen PK, Bartels em, et al. efficacy and safety

of the weight-loss drug rimonabant: a meta-analyssis of randomised

trials. Lancet 2007; 370: 1706–13.

4 rucker D, Padwal r, Li SK, et al. Long term pharmacotherapy for

obesity and overweight: updated meta-analysis. BMJ 2007; 335:

1194–99.

5 mitchell PB, morris mJ. Depression and anxiety with rimonabant.

Lancet 2007; 370: 1671–72.

6 ashton H. Therapeutic uses of cannabis – an update. Syva Drug

Monitor 2005; 4: 50–54.

7 Taflinski T, Chojnacka J. Sibutramine-associated psychotic episode.

Am J Psychiatry 2000; 157: 2057–58.

8 Warrington TP, Bostwick Jm. Psychiatric adverse effects of

corticosteroids. Mayo Clin Proc 2006; 81: 1361–87.

9 nurmikko TJ, Serpell mg, Hoggart B, et al. Sativex successfully treats

neuropathic pain characterised by allodynia: a randomised, double-

blind, placebo-controlled clinical trial. Pain 2007; 133: 210–20.

10 Jick SS, maradit K, Vasilakis-Scaramozza C. isotretinoin use and risk

of depression, psychotic symptoms, suicide, and attempted suicide.

Arch Dermatol 2000; 136: 1231–36.

11 magin P, Pond D. isotretinoin, depression and suicide: a review of

the evidence. Br J Gen Pract 2005; 55: 134–38.

12 ng CH, Schweitzer i. The association between depression and

isotretinoin use in acne. Aust N Z J Psychiatry 2003; 37: 78–84.

fuRThER READinG

Bazire S. Psychotropic drug directory. Dinton: allen, 2001.

British national Formulary. London: British medical association, royal

Pharmaceutical Society of great Britain.

Davies Dm, Ferner re, de glanville H. Textbook of adverse drug

reactions, 5th edn. London: Chapman & Hall, 1998.

Dukes mng, aronson JK. meyler’s side effects of drugs, 14th edn.

amsterdam: elsevier, 2000.

Practice points

• neuropsychiatric adverse drug reactions, covering a whole

spectrum from anxiety to delirium, result from drugs used

for non-psychiatric disorders. if these occur, the drug chart

should be reviewed

• Such effects are usually dose-related but may occur at normal

therapeutic doses. elderly or ill patients are most susceptible

to psychiatric effects

• The occurrence of psychiatric effects may necessitate

withdrawal of the drug or reduction in dosage

• adverse psychiatric effects often occur at the start of

treatment but may also arise during drug withdrawal. Some

drugs need to be tapered slowly after chronic use (e.g.

glucocorticoids, opioids, baclofen)

• The adverse psychiatric effects may result from drug

interactions (e.g. dopaminergic and antimuscarinic agents)


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Psychiatric effects of drugs for other disorders