TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY
Psychiatric effects of drugs
for other disorders
Caroline Parker
Abstract
Psychiatric adverse drug reactions (ADRs) have been reported with
a diverse range of medicines used in the treatment of physical illness.
Whereas some are mild (such as transient sleep disturbances), others
are severe (such as psychosis) and warrant discontinuation of the sus-
pected causal agents. Some reactions are predictable, while others are
unpredictable. The mechanism by which they are mediated is often
unclear.
It is essential that serious psychiatric ADRs observed during routine
clinical practice be reported via the UK’s Yellow Card reporting scheme
as many are relatively uncommon and may only be detected through
postmarketing surveillance in the wider population. Patients have re-
ported finding symptoms of psychiatric ADRs extremely distressing and
sometimes frightening, and may be hesitant to mention these to
prescribers.
Keywords adverse drug reaction; psychiatric adverse effect; side effect
Adverse drug reactions
Adverse drug reactions (ADRs) are defined as unwanted or
harmful reactions experience after taking a medicine in the
intended, prescribed manner, where the medicine is thought to
have caused the reaction.1 Psychiatric ADRs are relatively
common and can be caused by a wide range of medicines
routinely prescribed in medical and surgical specialities. Patients
report reactions such as confusion, agitation, panic, mood swings
and suicidal ideation, all of which can be distressing and some-
times frightening.2 Certain ADRs should be reported via the
‘yellow card scheme’ (UK) if they are severe or unusual and
particularly if they are fatal, life-threatening or medically signif-
icant but also if they occur in children or concern recently
licensed medications (i.e. those given the black triangle symbol:
;). ADRs are generally classified into two groups:1
Type A reactions e augmented
These are predictable reactions, which are a result of the medi-
cine’s normal pharmacological activity (although they may be
unrelated to the intended clinical effect), and are commonly
dose-related. The majority of ADRs are of this type (Table 1).
Type B reactions e bizarre
These are idiosyncratic and unpredictable reactions that could
not have been predicted from the medicine’s known
Caroline Parker MSc MCMHP is a Consultant Pharmacist in Adult Mental
Health at St Charles Hospital, Central & North West London NHS
Foundation Trust, UK. Conflicts of interest: none declared.
MEDICINE 40:12
Characteristics of adverse drugs reactions
Type A ‘augmented’ Type B ‘bizarre’
Predictable Unpredictable
Usually dose dependent Rarely dose dependent
High morbidity Low morbidity
Low mortality High mortality
Responds to dose reduction Responds to drug withdrawal
Taken from MHRA website: http://www.mhra.gov.uk/Safetyinformation/
Reportingsafetyproblems/Reportingsuspectedadversedrugreactions/
Healthcareprofessionalreporting/Adversedrugreactions/index.htm
Table 1
pharmacological activity. These include hypersensitivity reac-
tions mediated by immunological factors and true allergic reac-
tions. These are less common than Type A reactions and are not
normally dose-related (Table 1).
Overview of psychiatric ADRs
Identifying psychiatric ADRs is complex, as the causes of most
psychiatric disorders are multifactorial. For example, depression
is relatively common and is more common in people with
chronic medical conditions (see Medicine 2012; 40(11):
591e595). Whereas it is possible to consider that a medicine was
a contributing factor in the onset of depressive episodes,3 it is
very difficult categorically to confirm that it caused depression.
This generalization is true for most psychiatric ADRs.4 The
pattern of psychiatric ADRs (both causal medicines and symp-
toms) reported in children differs from that in adults.5
Numerous medicines are known to be associated with
psychiatric ADRs, ranging from mild to severe and including
suicidal ideation. The incidence, pattern of reactions and rela-
tionship to dose varies between medicines and the onset of
symptoms may be delayed. Consequently certain medicines
should be used with great caution in patients with a previous
psychiatric disorder as this increases their risk of developing
psychiatric ADRs. Patients and their carers often find psychiatric
ADRs frightening. They should be forewarned of the possibility
and encouraged to look out for any such symptoms and report
them should they occur.
The following are selected examples and this list is neither
complete nor exhaustive. It specifically does not include the
psychiatric ADRs caused by psychotropics.
Specific drugs/groups (Table 2)
Anti-epileptics6
All anti-epileptics are centrally active and can therefore cause
psychiatric ADRs. Incidence and symptoms vary between agents,
and are related to the manner in which the medicines are used;
starting and discontinuing gradually can minimize the risk.
Delirium and cognitive changes are the more common effects.
Psychotic symptoms have been recognized with many anti-
epileptics, most notably topiramate8 which causes more psychi-
atric ADRs than other anti-epileptics. Gabapentin and lamotrigine
are not associated with psychiatric ADRs. Antidepressants and
691 Ó 2012 Elsevier Ltd. All rights reserved.
 TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY

Summary of psychiatric ADRs with commonly used non-psychotropic medicines

Drug Psychiatric ADR Comment

ACEIs
E.g. captopril, enalapril3,6 Fatigue, hallucinations, delirium, mood
disturbances
Analgesics
Opiates7 Sedation, dysphoria, confusion, mood Psychiatric reactions are relatively
changes including euphoria, sleep disturbances, common with opiates
hallucinations, psychosis, delirium, dependence
5-HT1 agonists (sumatriptan)6 Fatigue, anxiety, panic attacks

Antibiotics
Cephalosporins, penicillins, Sleep disturbances (insomnia and
quinolones,6 tetracyclines somnolence), delirium, hallucinations
Anti-epileptics6
Carbamazepine Depression, agitation, sedation, psychosis,
cognitive impairment, delirium
Ethosuximide Mood changes, irritability, sleep disturbances,
psychosis, delirium
Levetiracetam Irritability, sedation, psychosis
Phenytoin Agitation, insomnia, delirium, psychosis
Topiramate9 Psychosis, depression and emotional lability,
cognitive dysfunction, paraesthesia, behavioural
changes
Sodium valproate Sedation, hallucinations, depression, delirium
Vigabatrin Agitation, lethargy, irritability, depression,
psychosis, cognitive impairment
Antimuscarinics
E.g. biperiden, orphenadrine, Anxiety, agitation, insomnia, psychosis,
procyclidine, trihexyphenidyl6 delirium, visual hallucinations
All antibiotics can cause delirium.
Patients with underlying medical
conditions may be at higher risk
of developing psychiatric ADRs.
Of the quinolones, ciprofloxacin
causes the most psychiatric ADRs,
including mood disturbances8
agitation and confusion6
Psychosis has also been reported
with oxcarbazepine
Psychosis has also been reported
with fosphenytoin
Psychosis is much more common
with topiramate (6%) than with other
anti-epileptics
Paraesthesia and cognitive complaints
are the most common central nervous
system ADRs; paraesthesia is dose-related
Psychosis is more common with
vigabatrin (2e4%) than with other
anti-epileptics although it may be transient

Antimalarials
Chloroquine, mefloquine3,6,7,10 Anxiety, depression, suicidality, panic attacks, Symptoms begin very early in treatment
hallucinations, psychosis
Antiparkinsonian treatments
Levodopa6 Visual hallucinations, depression, hypomania,
sleep disturbances, abnormal dreams, cognitive
impairment, agitation, psychosis, delirium
Dopamine agonists6 Sedation, psychomotor agitation, anxiety, These are associated with more
akathisia, sleep disturbances, psychosis, psychiatric adverse effects than levodopa11
cognitive impairment, delirium, visual
hallucinations
Amantadine6 Decreased concentration, sleep disturbances,
visual hallucinations, irritability, anxiety,
depression, euphoria, fatigue, psychosis, delirium

MEDICINE 40:12 692 Ó 2012 Elsevier Ltd. All rights reserved.


Table 2 (continued )
Drug
Selegiline (MAO-B inhibitor)6
Entacapone (COMT inhibitor)6
Antiretrovirals e nucleoside reverse
transcriptase inhibitors (NRTI)
Didanosine6
Lamivudine12
Zidovudine12
Antiretrovirals e non-nucleoside
reverse transcriptase inhibitors
(NNRTI)
Efavirenz12,13
Cardiovascular agents
b-blockers (atenolol,
propranolol, sotalol)
Calcium channel blockers
(e.g. diltiazem, amlodipine)
Statins14 (simvastatin, atorvastatin,
fluvastatin, pravastatin)
Corticosteroids4,9,12,15
Glucocorticoids (e.g. betamethasone,
prednisolone, prednisone)
MEDICINE 40:12
TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY
Psychiatric ADR
Sleep disturbances, agitation, psychosis
Sleep disturbances, hallucinations, delirium
Lethargy, nervousness, anxiety, confusion,
sleep disturbance, mood disorders, psychosis
Insomnia, mood disorders
Sleep disturbance, vivid dreams, agitation,
mania, depression, psychosis, delirium
Agitation, depersonalization, hallucinations,
disturbed or vivid dreams, mood disorders
including depression, suicidality, hostility,
antisocial behaviour, irritability, psychosis,
catatonia, delirium, cognitive disturbances
Fatigue, sedation, sleep disturbances and
nightmares, cognitive impairment,
depression, hallucinations, psychosis,
delirium
Mood changes, lethargy, dysphoria,
mania, psychosis, delirium, akathisia12
Depression, suicidal tendency, emotional
lability, aggression, agitation, irritability,
anxiety, panic, euphoria, cognitive
disorder, sleep disorders, hallucinations,
paranoia
Mood disorders, suicidal ideation,
euphoria, agitation, sleep disturbances,
psychosis and delirium, dementia,
cognitive impairment
693
Comment
Psychiatric ADRs are usually dose related.
Efavirenz can cause psychiatric ADRs
in up to half of the patients treated.
Onset is often in the first 4 weeks.
Often symptoms are intolerable and
patients choose to stop treatment
prematurely. Severe depression or acute
psychosis may necessitate discontinuation.
Patients should be advised to seek
immediate medical attention if they
develop severe depressive symptoms,
suicidal ideation or psychotic symptoms14
Disturbances are more common with lipid
soluble b-blockers (e.g. propranolol).14
Propranolol is the b-blocker most clearly
associated with depressive symptoms,
but causality has not clearly been identified
even with this drug, only an association
through the use of proxy indicators4
Reports of psychiatric ADRs from numerous
clinical trials are mixed
Causal association is not clearly demonstrated4
Statins penetrate the blood-brain barrier and
simvastatin has the highest permeability
Causal association is clear with corticosteroids,
symptoms are often serious (warranting
psychiatric assistance or admission)
The onset of psychiatric ADRs are often very
sudden (e.g. within a few days of starting
treatment). They are usually dose-related and
respond to a decrease in dose, and have been
reported in association with several routes of
administration (including oral, parenteral and
inhaled)
Symptoms usually resolve on gradual
discontinuation of the corticosteroid, although
duration of symptoms varies considerably
(continued on next page)
Ó 2012 Elsevier Ltd. All rights reserved.
 TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY

Table 2 (continued)
Drug Psychiatric ADR Comment

Others agents
Interferons e a and b4,5 Depression, loss of efficacy of previously
effective antidepressants, suicidal ideation,
delirium, non-specific psychiatric symptoms
Rare case reports of psychosis and mania
with interferon-a16
Isotretinoin17,20 Depression, suicide, psychosis
Naltrexone12 Dysphoria, fatigue, sleep disturbances,
suicidal ideation, hallucinations, delirium
Postoperative cognitive Confusion, agitation, anxiety, poor
dysfunction (POCD)18 concentration, memory loss, sleep
disturbances, psychotic symptoms
Varenicline6,19 Exacerbation of pre-existing psychiatric
disorders, changes in behaviour,
hostility, acute psychosis, agitation,
depressed mood or worsening of
depression, suicidal ideation and
behaviour, attempted suicide
Psychiatric ADRs are relatively unlikely with
interferon- b, but are much more widely
reported with interferon-a
Interferon-a-associated depression responds
to antidepressants, use of which can be
preventative4
The increased risk of suicide continues
for up to 6 months after discontinuing
treatment. The risk is not higher in those
with suicide attempts before initiating
isotretinoin. The effect is not related to
dose or duration of treatment.18 If psychiatric
changes occur it should be discontinued
and psychiatric advice sought14
Onset is usually straight after surgery,
usually resolving within a few days.
Most common in the elderly
Suicidal ideation and behaviour in patients
with no pre-existing psychiatric disorder
Patients with a psychiatric history are at a
greater risk of developing psychiatric ADRs
A large postmarketing study showed 3%
of patients experienced symptoms of
depression6

ACEI, angiotensin-converting enzyme inhibitor; ADR, adverse reaction; COMT, catechol-O-methyltransferase; MAO, monoamine oxidase.

Table 2

antipsychotics used in the management of psychiatric ADRs b-blockers3

reduce the seizure threshold to varying degrees.
Antiparkinsonian treatments6
All antiparkinsonian medications can induce delirium and
psychosis as a direct result of their pharmacological activity.
Elderly patients with cognitive impairment are particularly
vulnerable to these effects. Psychotic symptoms such as visual
hallucinations usually respond to a dose reduction, and non-
pharmacological methods should also be considered. If these
strategies do not help, consider discontinuing the suspected
causal agents. If this is not successful or possible then consider
adding an atypical antipsychotic, although starting a dopamine
antagonist in this setting may compromise control of extrapyra-
midal symptoms. Clozapine is the only antipsychotic that has
clearly been shown to improve psychosis in Parkinson’s
disease.21
Antiretrovirals for HIV7
Numerous antiretrovirals have varying propensity to induce
a range of psychiatric ADRs. Efavirenz12 is the most problematic,
causing psychiatric ADRs (some of which are severe) in up to
half of the patients treated.
It has widely been thought that b-blockers cause depression,
although this is probably less common than initially thought.6
b-blockers commonly cause fatigue7 and this may have been
misinterpreted as a symptom of depression in some reports.3
Furthermore, the depressive symptoms reported with
b-blockers do not fulfil the full criteria for a diagnosis of
depression.3
Interferons4
Psychiatric ADRs such as depression, delirium and non-specific
psychiatric symptoms have been associated with interferon
use, particularly with interferon-a. Interferon-induced depression
responds to antidepressants. Initiation of treatment with inter-
feron-a has led to loss of efficacy of previously effective antide-
pressants as well as the emergence of suicidal ideation. A history
of psychiatric difficulties is not usually considered a reason to
withhold interferon treatment, but careful interdisciplinary team
working is required.13
Isotretinoin13
Isotretinoin has been associated with depression, suicide
attempts, aggression and psychosis. It was the only non-

MEDICINE 40:12 694 Ó 2012 Elsevier Ltd. All rights reserved.

 TREATMENT STRATEGIES AND PSYCHOPHARMACOLOGY
psychotropic associated with depression in the top 10 drugs lis-
ted in the US Food and Drug Administration database. Suicide
has not been associated with other treatments for acne (i.e.
antimicrobials).
Corticosteroids15,20
It has been long established that corticosteroids can cause
numerous and complex psychiatric ADRs. The most common are
affective (mania, depression, mood lability and mixed affective
states) as well as euphoria. Mania is usually seen in patients
taking short courses, whereas depression tends to be seen during
longer courses (>6 months). Psychosis and delirium have been
reported much less frequently. Cognitive impairment can occur
following both short and during longer courses; and dementia
has been reported. Developing psychiatric ADRs is unrelated to
previous experience of psychiatric illnesses, and the dose does
not predict the onset, severity, type or duration of the psychiatric
ADR. Depression and mania have frequently been reported when
decreasing or ceasing corticosteroids. Psychiatric ADRs may
manifest themselves differently in children to adults.5
Post-operative cognitive dysfunction18
Confusion after a major operation is relatively common, and
usually short lived. If it is accompanied by other changes in
mental function it is described as post-operative cognitive
dysfunction (POCD); the cause of this is not fully understood.
At the time of an operation lots of factors and influences may
converge making POCD more likely including the presence of
pre-existing conditions (e.g. dementia) and older age and frailty
or physical illness; immediately after the operation poor hydra-
tion, constipation, poor pain control, disturbed sleep, missing
regular medicines.
It is also thought to be influenced by the type of anaesthetic,
being less common if a regional anaesthetic is used rather than
a general, although this may not be true for longer lasting or
“late” POCD. However, during an operation and postoperatively
numerous medicines are usually administered including some
that have been associated with psychiatric adverse events e.g.
fentanyl22,23 and propofol.23
Varenicline
Although some early varenicline data did not find any significant
increase in psychiatric ADRs compared with placebo when used
in people without any psychiatric disorders, there were limita-
tions to these data.9 Subsequent post-licensing monitoring has
shown an association of neuropsychiatric symptoms (e.g.
depressive symptoms or a worsening of depression) with the use
of varenicline.19 A 21 Novartis Pharmaceuticals UK Ltd. Clozaril 25 mg and 100 mg Tablets
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FURTHER READING
Bazire S. Chapter 5: drug-induced psychiatric disorders. Psychotropic drug
directory. HealthComm UK Ltd, 2009.
695 Ó 2012 Elsevier Ltd. All rights reserved.