MANAGEMENT OF ANTIPSYCHOTICS SIDE EFFECT IN DETAIL

1. Prsented by-Dr Sadaf Siddiqui
Moderator-Prof S A Azmi
Management of Adverse effect of
antipsychotics

2.  Introduction
 Neurological side effects
 Neuroleptic induced movement disorder
 Other neurological side effects
 Non neurological side effects

3. INTRODUCTION
 The history of somatic therapies in schizophrenia can be
divided into two eras, with the discovery of
chlorpromazine (Thorazine)—the first clearly effective
antipsychotic drug—as the dividing line.
 Prior to introduction of antipsychotics in the early 1950s,
several treatments had been administered to individuals
with psychotic illness.
 In the early 1920s sleep treatment with barbiturates was
introduced.

4.  Insulin coma treatment was introduced during the 1930s
 Prefrontal lobotomy was proposed as a treatment for
serious mental illnesses by Moniz in 1935.
 Convulsive therapies were developed after it was observed
that some patients improved after a seizure.
 The first effective antipsychotic medications were probably
derived from extracts of the rauwolfia plant that is
reserpine.

5.  The discovery of chlorpromazine in the early 1950s may be
the most important single contribution to the treatment of
a psychiatric illness,but found to be associated with EPS.
 Clozapine, the first effective antipsychotic with negligible
extrapyramidal side effects (EPS).
 The introduction of risperidone, olanzapine, quetiapine,
ziprasidone, aripiprazole, and have given clinicians new
alternatives for treating a large number of patients with
schizophrenia.

6.  All first-generation antipsychotics (FGAs) and some second
generation antipsychotics (SGAs) can induce movement
disorders.
 This risk increased with age and illness chronicity.
 Emergence of atypical antipsychotics leads to advantage in
EPS/ Negative symptoms but associated with higher
metabolic abnormality.

7. DOPAMINE PATHWAYS
1. Mesolimbic
2. Mesocortical
3. Nigrostriatal
4. Tuberoinfundibular dopamine pathways

13. NEUROLOGICAL SIDE EFFECTS
Acute extrapyramidal syndromes
 Akathisia
 Acute dystonia
 Drug-induced parkinsonism
Neuroleptic malignant syndrome
Chronic extrapyramidal syndromes
 Tardive dyskinesia
 Perioral tremor

14.  More common with high potency typical.
 Uncommon with atypical
 With the exception of akathisia incidence of EPS with
olanzapine,arpiprazole and ziprasidone is not appreciably
different from that with placebo.
 These are dose dependant and reversible.

15.  D2 receptor occupancy in the corpus striatum with FGAs
greater than 78 percent is associated with increased risk of
extrapyramidal symptoms and levels of less than 65
percent with suboptimal efficacy.

18. ACUTE DYSTONIA
 High incidence in men
 Patients younger than 30 years
 Approximately 10% with FGAs
 Symptoms include abnormal positioning of the head and
neck; spasm of jaw muscles; impaired swallowing,
speaking, or breathing; thickened or slurred speech;
tongue protrusion or dysfunction; deviated eyes in any
direction (e.g., oculogyric crisis); and abnormal positioning
of limbs or trunk.

19.  Develop within days of starting or increasing the oral
antipsychotic dose or reducing a medication used to treat
extrapyramidal symptoms but may develop within minutes
of receiving injectable high-potency FGAs.
 Onset may be sudden or gradual and can be life-
threatening if laryngeal muscles are affected.
 Can be painful and frightening and often results in
noncompliance with future drug treatments.

20.  Risk factors
 Young black males
 Recent use of cocaine
 Liquid concentrate or parenteral formulation
 A family history of movement disorders

21.  Pathophysiology
 Acute saturation of D2 receptors.
 That occurs when central nervous system levels of
antipsychotic drug begin to fall between the doses.
 Patients given high dosage of high potency medication.
 Animal studies suggest sigma-1 and sigma-2 receptors,
which are found in the motor regions of the brain and
control posture and movement, may be involved in all
forms of dystonia

22.  Treatment Options and Implications
 Patients should always be informed of the risk.
 Parenteral benztropine (2 mg) or diphenhydramine (50mg)
typically produce rapid relief.
 Prophylactic use of oral anticholinergic medication is
strongly encouraged when use of a high potency
antipsychotic is considered.

23.  Where symptoms do not respond to simpler measures
including switching to an antipsychotic with a low
propensity for EPS, botulinuim toxin may be effective.
Maudsley prescribing guideline

24. NEUROLEPTIC-INDUCED ACUTE AKATHISIA
 Usually develops within the first 4 weeks of starting or
increasing the dose of medication or after decreasing the
use of medications used to treat EPS.
 Prevalence is estimated to be between 20 and 75 percent
of patients on an antipsychotic.
 This syndrome has also been reported with various
antidepressants, particularly SSRIs.

25.  The patient must complain of an inner sense of
restlessness and at least one of the following
objective, observable movements:
 Fidgeting or swinging of the legs, rocking from foot to
foot while standing, pacing, lifting the feet as if marching
in place, crossing and uncrossing the legs when sitting,
or the inability to sit or stand in one place for several
minutes.

26.  Chronic akathisia - persistent symptoms (i.e., 3 months or
longer) after the last change in medication dose.
 Tardive akathisia has a delayed onset and may persist even
after medication cessation.

27.  Pathophysiology
 Although the pathophysiology is unknown, there is
evidence that the impact on dopamine neurons in the
ventral tegmental area is contributing.
 Cholinergic, adrenergic, and serotonergic pathways have
also been implicated.

28.  Risk factors
 Drug-related
 Higher doses
 Rapid dose escalation
 Higher potency agents
 Individual-related
 Older age
 Female
 Preponderance of negative symptoms
 Iron deficiency
 Cognitive dysfunction
 Mood disorder

31.  In resistant cases, selegiline or the 5-HT2 antagonist
ritanserin may help.
 The use of low-dose mirtazapine for akathisia is supported
by two double-blind, placebo-controlled, short-term
studies, one of which reported efficacy comparable to
propranolol.

32. NEUROLEPTIC-INDUCED PARKINSONISM
 Occur in about 15% of patients treated with antipsychotics.
 Usually within 5 to 90 days of initiation of treatment.
 Rigidity, which can be continuous (“lead pipe”) or cog-
wheeling (a discontinuous, ratchet-like muscle motion);
 Bradykinesia
 Tremor (3 to 6 hz) - head, tongue, jaw, legs, and
extremities in a unilateral or symmetrical fashion.
 Only one is required for the diagnosis.

33.  Days to weeks of starting or increasing the dose of
medication or after reduction of medication used to treat
extrapyramidal symptoms.
 Women > men,
 Incidence is higher for those older than 60.
 Preexisting neurological damage

34.  Pathophysiology
 Diminution in nigrostriatal dopamine activity.
 Causes –
 Depletion of dopamine in presynaptic stores (reserpine),
 Dopamine-blocking agents (e.G., Antipsychotics)
 Atypical calcium blocking agent, cinnarizine.

35. Treatment options and implications
 Dose reduction or medication cessation
 Switching to a lower-potency FGA or SGA
 Anticholinergic agents.
 Nonanticholinergic dopamine agonists - Amantadine may
be used if anticholinergics are not tolerated or in the
elderly.

36.  Even after the antipsychotics are withdrawn,parkinsonian
symptom can last up to 2 weeks and even up to 3 months.
 With such pt clinician may continue the anticholinergic
medication after the antipsychotics has been stopped untill
parkinsonian symptom resolve completely.

37.  The majority of patient don’t require long term
anticholinergics, reviewed every 3 mth.
 Preliminary studies indicate that the addition of oral
dehydroepiandrosterone (DHEA) to existing antipsychotic
regimens may also improve parkinsonism.

38. NEUROLEPTIC MALIGNANT SYNDROME
Clinical presentation
 Typical symptoms
 Muscle rigidity
 Elevated temperature (greater than 38◦ C).
 Recent reports that with some SGA these core symptoms
may not always be present.
 Rapid or gradual onset.

39.  Two or more of the following symptoms are also required:
 Diaphoresis, tachycardia, elevated or labile blood
pressure
 Dysphagia, incontinence
 Tremor
 Changes in the level of consciousness, ranging from
confusion to coma
 Mutism
 Leukocytosis
 Laboratory evidence of muscle injury
 Liver enzyme elevation

40.  Can occur at any time during the course of DRA treatment.
 The symptom usually evolve over 24 to 72 hours and
untreated syndrome lasts 10 to 14 days.
 The mortality rate can reach 20-30% or even higher when
depot medications are involved.

41.  Pathophysiology
 NMS has been associated with dopamine antagonists, the
abrupt discontinuation of antiparkinsonism medications,
and, rarely, the abrupt discontinuation of an antipsychotic.
 Fluctuation in dopamine binding may be important in its
etiology.

42.  Blockade of dopamine receptors
 Corpus striatum  muscle contraction and rigidity that
initiate heat generation;
 Hypothalamus  impaired heat regulation.
 Spinal neurons  autonomic dysfunction
 Abnormal calcium availability in muscle cells may also be a
contributing factor given the massive muscle damage.

43.  Genetic factors
 The A1 allele of the dopamine D2 receptor gene may be
overrepresented in patients.

44.  Risk factors
 Concurrent medical and neuropsychiatric issues
 Dehydration
 Psychomotor agitation
 Comorbid neurological disorders
 Low serum iron levels
 Mood disorders
 Preexisting catatonia
 History of NMS

45.  Medications
 Acute parenteral antipsychotics
 High potency FGAs (e.g., haloperidol)
 Concurrent lithium treatment
 High doses of an antipsychotic
 Dosing increases or intermittent noncompliance
 Male gender
 Younger age

46.  Management
 Prevention: Antipsychotics should be used cautiously in
patients with
 Dehydration
 Catatonic symptoms
 Basal ganglionic disease
 History of NMS

47.  Treatments
 Withdrawal of the offending agent.
 Supportive interventions - IV hydration, temperature
control,monitoring of vital signs.
 In advanced cases, admission to an intensive care unit is
required, with a fatal outcome occurring in up to 10
percent of cases.

50. Restarting antipsychotics after NMS
 Allow time for symptoms and signs to resolve completely
 Begin with very small dose and increase very slowly with
close monitoring of temperature, pulse and blood
pressure.
 Consider using an antipsychotic structurally unrelated to
that associated with NMS or a drug with low dopamine
affinity (quetiapine or clozapine).
 Avoid depots and high potency conventional antipsychotics

51. NEUROLEPTIC-INDUCED TARDIVE DYSKINESIA
 Clinical Presentation
 Develop after at least 2months of exposure to a dopamine
blocking agent (or 1 month if the patient is 60 years or
older); while the patient is on medication or within 4weeks
of withdrawal from an oral agent (8 weeks from long-
acting injectable medication); and be present for at least 4
weeks.
 The patient must show involuntary movements of the
tongue (e.g., twisting, protrusion), jaw (e.g., chewing), lips
(e.g., smacking, puckering), trunk, or extremities.

52.  Patterns of movements may include rapid, jerky and non
repetitive movements (i.e., choreiform); slow, continuous
and sinuous movements (i.e., athetoid); or rhythmic
movements.

53.  Onset is gradual.
 MC in older people( 3:1)
 In older patients (55 years or older), the onset of tardive
dyskinesia is 25 percent at 1 year, 34 percent at 2 years,
and 53 percent after 3 years.
 Women are more likely to be affected.

54.  Tardive dyskinesia may also occur in never-medicated
schizophrenics.
 Risk factors include increasing age, preexisting
parkinsonism, previous brain damage, antipsychotic
treatment duration, and exposure to FGAs.

55.  Pathophysiology
 Sustained D2 receptor blockade resulting in receptor
hypersensitivity.
 Genetic studies indicate a possible relationship with
polymorphisms in the dopamine-2 receptor (DRD2),
dopamine-3 receptor (DRD3), dopamine transporter
(DAT1), and the serotonin 2A receptor genes.

57.  Oxidative stress and cell death secondary to increased
glutamatergic neurotransmission caused by blockade
of presynaptic dopamine receptors has also been
postulated.

58.  Treatment of established TD is often unsuccessful, so
prevention and early detection are essential.
 Treatment – first steps
 Most authorities recommend the withdrawal of any
anticholinergic drugs and a reduction in the dose of
antipsychotic as initial steps in those with early signs of TD
(dose reduction may initially worsen TD).
 Cochrane, however found little support for this approach.
Soares-Weiser K et al. Neuroleptic reduction and/or cessation and neuroleptics as specific treatments for tardive
dyskinesia. Cochrane Database Syst Rev 2006; CD000459.

59.  The use of clozapine is probably best supported.
 There is also few evidence in support of quetiapine,
olanzapine, resperidone and aripiprazole.
Duncan D et al. Tardive dyskinesia: how is it prevented and treated? Psychiatr Bull 1997;
21:422–425.
Simpson GM. The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry
2000;61 Suppl 4:39–44.

60.  Treatment – additional agents
 Switching or withdrawing antipsychotics is not always
effective and so additional agents are often used.
 Terabenazine - Licensed treatment for TD in UK. Dose is
25–200 mg/day
 Benzodiazepenes - Widely used and considered
effective. Most used are clonazepam 1–4 mg/day and
diazepam 6–25 mg/day
Duncan D et al. Tardive dyskinesia: how is it prevented and treated? Psychiatr Bull 1997; 21:422–425.
Simpson GM. The treatment of tardive dyskinesia and tardive dystonia. J Clin Psychiatry 2000;61 Suppl 4:39–44.
Jankovic J et al. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology 1997; 48:358–
362.

61.  Vit E - Numerous studies but efficacy remains to be
conclusively established. Dose is in the range 400–1600
IU/day.
Adler LA et al. Vitamin E treatment for tardive dyskinesia: adrenoceptor. Br J Psychiatry 1995; 167:412.
Zhang XY et al. The effect of vitamin E treatment on tardive dyskinesia and blood superoxide dismutase: a double-blind
placebo-controlled trial. J Clin
Psychopharmacol 2004; 24:83–86.

62.  Amino acids - Use is supported by a small randomised,
placebo-controlled trial. Low risk of toxicity
 Botulinum toxin - Case reports of success for localised
dyskinesia.
 Donepezil - Supported by a single open study and case
series. One negative RCT (n = 12). Dose is 10 mg/day
 Levetiracetam - Two published reports. One RCT. Dose up
to 3000 mg/day
Richardson MA et al. Efficacy of the branched-chain amino acids in the treatment of tardive dyskinesia in men. Am J Psychiatry 2003; 160:1117–
1124..
Tarsy D et al. An open-label study of botulinum toxin A for treatment of tardive dystonia. Clin Neuropharmacol 1997; 20:90–93.
Meco G et al. Levetiracetam in tardive dyskinesia. Clin Neuropharmacol 2006; 29:265–268.

63.  Melatonin - Use is supported by a well conducted trial.
Usually well tolerated. Dose is 10 mg/day
 Pyridoxine - Supported by a well conducted trial. Dose – up
to 400 mg/day
 Sodium oxybate - One case report. Dose was 8 g/day
 Transcranial magnetic stimulation (rTMS) - Single case
report
Shamir E et al. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen
Psychiatry 2001; 58: 1049–1052.
Lerner V et al. Vitamin B(6) in the treatment of tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Am J
Psychiatry 2001; 158 1511–1514.
Berner JE. A case of sodium oxybate treatment of tardive dyskinesia and bipolar disorder. J Clin Psychiatry 2008; 69:862.
Brambilla P et al. Transient improvement of tardive dyskinesia induced with rTMS. Neurology 2003; 61:1155.

64. Perioral Tremor
 Perioral tremor is an uncommon side effect of dopamine
receptor antagonists that appears after months or years of
drug treatment.
 The peculiar tremors of the mouth have led to this
disorder being called rabbit syndrome.

65. OTHER NEUROLOGICAL SIDE EFFECTS
Central anticholinergic activity
 Severe agitation
 Disorientation to time place and person
 Hallucination
 Fever
 Seizure
 Dilated pupil

66. Management
Treatment of anticholinergic toxicity consists of
 Discontinuing causal agent
 Close medical supervision
Physostigmine
 2 mg by slow iv infusion
 Repeat within 1 hour as necessary.

67. SEIZURE
 FGAs, especially low-potency agents, can lower the seizure
threshold in a dose-dependant manner which may lead to
generalized tonic-clonic seizures, even though the rate of
seizures is <1% for all FGAs.
 However, clozapine appears to be the most epileptogenic
of all antipsychotics, with a cumulative risk of 10% for
tonic-clonic seizures after 3.8 years of treatment (dose
range 25–900 mg).

68.  Patients with clozapine-induced seizures may be managed
by dose reduction or addition of an antiepileptic, usually
allowing continuation of therapy
Devinsky O, Pacia SV. Seizures during clozapine therapy. J Clin Psychiatry.1994

69. SEDATION
 Sedation is a common side effect of first-generation
antipsychotics (FGAs), especially low-potency agents, and
several second-generation antipsychotics (SGAs) including
clozapine, olanzapine, and quetiapine.
 mediated through histamine, dopamine, and adrenergic
receptors.
 It is most prominent in the initial phases of treatment,
when at times it can be helpful for the agitated patients.

70.  Some tolerance to somnolence develops in most patients
with continued treatment.
Management
 Somnolence can be managed by decreasing the total daily
dose,changing the dosing schedule to a single bedtime
dose, or changing to a less sedating antipsychotic

71.  Psychostimulants like modafinil may be useful in managing
daytime sedation.
 However, there are a few case reports of clozapine toxicity
at high clozapine serum levels and exacerbation of
psychosis on higher-than-recommended doses of
modafinil. Therefore, this combination must be used with
caution.
Dequardo JR. Modafinil-associated clozapine toxicity. Am J Psychiatry2002

72. HYPERPROLACTINEMIA
◻ Prolactin ⬄ anterior pituitary , inhibited by dopamine.
◻ A reduction in dopaminergic input to the lactotroph cells
results in a rapid increase in prolactin secretion.
◻ Such a reduction in dopamine can occur through the
administration of antipsychotics which act on dopamine
receptors (specifically D2) in the tuberoinfundibular
pathway of the brain.

73. Antipsychotic Association with
Hyperprolactinaemia
 All typical antipsychotics are associated with
hyperprolactinaemia to varying degrees.
 Of the atypicals, the highest prevalence is with
risperidone.
 It has been reported that 48%–93% of premenopausal
women and 42%–47% of men taking antipsychotic
medications have hyperprolactinemia.
 The effect of antipsychotics on prolactin appears to be
dose related.

74.  The increase of prolactin can begin as early as a few hours
after a dose and persists during the rest of the treatment, the
total effect depending on therapy duration.
 In treatments of 3–9 weeks, the prolactin levels have been
found to increase up to 10- fold from baseline, while during
long-term treatment, partial tolerance may lead to prolactin
normalization, though after long-term therapy prolactin
levels remain above normal in most cases.

75. Management of Hyperprolactinaemia
 The diagnosis of hyperprolactinaemia should not be
made based on a single blood test as stress can also
elevate prolactin levels.
 The ideal conditions for measuring prolactin levels are in
the morning at least 1 hour after waking and before
eating.
 In cases where the patient has an elevated prolactin
level which is due to antipsychotic treatment and where
physiological causes have been ruled out, follow the
suggested management steps.

77.  In a patient with suspected drug induced
hyperprolactinaemia, where a baseline prolactin level was
not obtained, consider stopping the antipsychotic, if
appropriate, for 72 hours followed by re-measurement of the
prolactin level.
 If the drug cannot be discontinued it is recommended to
obtain a pituitary magnetic resonance image (MRI) to
differentiate between medication-induced
hyperprolactinaemia and symptomatic hyperprolactinaemia
due to a pituitary or hypothalamic mass.

78. Pharmacological Treatment of Hyperprolactinaemia
 The primary goal of therapy in patients with
hyperprolactinaemia is to restore gonadal and sexual
function, to prevent inappropriate lactation and bone
demineralization from inadequate sex steroids by normalising
prolactin concentration levels.
 Only in cases where the causative agent cannot be reduced in
dose, discontinued or switched to an alternative, should
pharmacological treatment be employed.

79.  Treatment with Aripiprazole
 Before add-on therapy is considered, aripiprazole
monotherapy should be evaluated and tried where
possible.
 There are a few studies which have demonstrated the
effectiveness of aripiprazole as an add-on to normalise
prolactin levels.

80.  Recommended Dose and Monitoring
 The dose of aripiprazole is 5mg with prolactin levels
measured weekly to ascertain benefit. Higher doses than
5mg appear unnecessary.
 If prolactin levels do not appear to be normalising after 4
weeks of treatment aripiprazole should be discontinued

81.  Treatment with Dopamine Agonists
 Whether to treat a patient who has antipsychotic
induced hyperprolactinaemia with a dopamine agonist
remains controversial.
 Some studies suggest that dopamine agonist therapy will
normalise prolactin levels in only up to 75% of such
patients but may lead to exacerbation of the underlying
psychosis

82.  The dopamine agonists available and licensed for use are
bromocriptine, cabergoline (both ergot derived) and
quinagolide (non ergot-derived).
 Prolactin levels should be measured a month after
starting treatment with a dopamine agonist and monthly
thereafter

83.  Cabergoline used as first line because it has higher
efficacy and has a lower incidence of unpleasant side
effects.
 It also has a longer half life therefore it can be
administered only once or twice a week.

84.  DOSING
 250 - 500 micrograms weekly as a single dose or as 2
divided doses on separate days. Increased at monthly
intervals in steps of 500 micrograms until optimal
response is achieved.
 Dose rage of 0.25-2mg weekly; (doses up to 4.5mg
weekly have been used in hyperprolactinaemic
patients).

85.  Bromocriptine should be used as second line. However,
bromocriptine is generally considered to be
contraindicated in severe psychotic disorders.
 DOSING : 1-1.25mg at bedtime, increased gradually to
5mg every 6 hours.

86.  Quinagolide should only really be considered third line.
 DOSING: 25 micrograms at bedtime for 3 days. Increased
at intervals of 3 days in steps of 25 micrograms. Usual
maintenance dose of 75-150micrograms daily

87.  Amantadine is a weak dopamine agonist which has been
used to treat hyperprolactinaemia. It is unlicensed for this
indication.
 DOSING: 100 mg/day for the first week. This can be increased
by 100 mg weekly until a dose of 200-300 mg/day is reached.
Max. 400mg daily

88.  CAUTIONS
 All dopamine agonists have the potential to worsen
psychosis.
 Cabergoline and bromocriptine should be used with
caution in patients with a history of peptic ulcer.
 Cabergoline and bromocriptine have been associated
with fibrotic reactions.

89. Treatment with Oestrogen and Testosterone
 In patients with long term hypogonadism symptoms or bone
loss, the use of oestrogen in women in the form of HRT or
combined oral contraceptive, and exogenous testosterone in
men can be considered.
 This should only be considered in conjunction with specialist
advice

90.  Herbal Remedies
 Peony-glycyrrhiza decoction (PGD) in a small number of cases
has been shown to be effective in reducing drug induced
hyperprolactinaemia in patients with schizophrenia.
 The data is limited, and therefore this herbal remedy should
be used with caution.
 PGD may also interact with certain diseases or conditions
such as bleeding disorders or heart disease.

91. SEXUAL ADVERSE EFFECTS
 Individual susceptibilty varies and reversible.
 The mechanisms by which antipsychotic drugs may cause
sexual dysfunction are as follows:
1.Being bound to histaminergic receptors may impair arousal
by directly increasing sedation.
2.Dopaminergic receptor antagonism may decrease the
libido by inhibiting motivation and reward.

92. 3.Blockade of dopamine D2 receptors in the
tuberoinfundibular pathway by antipsychotics may
decrease the libido, impair arousal, and impair orgasm
indirectly, by leading to elevated prolactin levels.
4.Cholinergic receptor antagonism may induce erectile
dysfunction by reducing peripheral vasodilation.
5.Alpha-adrenergic alpha receptor antagonism can reduce
peripheral vasodilation, resulting in erectile dysfunction
in men and decreased lubrication in women.

93. Treatment with Butyrophenones or Phenothiazines:
 Loss of sexual interest: due to dopamine receptor antagonism
and secondary hyperprolactinaemia.
 Reduce sexual desire: due to sedation, extra-pyramidal effects
and weight gain.
Phenothiazines:
 Erectile failure
 Drug-induced Priapism - adrenergic blockade combined with
anticholinergic activity.
 Ejaculatory problems

94.  About 20% of cases of drug-induced priapism are due to
antipsychotic drugs; the risk seems independent of dosage
or duration of treatment
 Ejaculatory problems are a common side-effect of
conventional antipsychotics
Patel et al, 1996

95.  Retrograde ejaculation and Priapism associated with
Clozapine, Olanzapine and Risperidone.
 Quetiapine treatment is not associated with
hyperprolactinaemia and having low incidence of sexual
side effects.
 Rate of erectile failure was lower with Amisulpride

96.  The overall propensity of an antipsychotic to cause sexual
dysfunction is similar to its propensity to raise prolactin,
i.e. risperidone > haloperidol > olanzapine > quetiapine>
aripiprazole.
 Aripiprazole is relatively free of sexual side-effects when
used as monotherapy and possibly also in combination
with another antipsychotic.

97. Treatment
 Before attempting to treat sexual dysfunction, a thorough
assessment is essential to determine the most likely cause.
 Spontaneous remission may occasionally occur.
 The most obvious first step is to decrease the dose or
discontinue the offending drug where appropriate.

98.  The next step is to switch to a different drug that is less
likely to cause the specific sexual problem experienced.
 If this fails or is not practicable, ‘antidote’ drugs can be
tried.
 In male patients with erectile dysfunction, or in case of
patients presenting with other factors associated with SD
(including smokers, diabetic patients and so forth),
phosphodiesterase-5 inhibitors, such as sildenafil(50-100
mg 1-2 hrs prior to sexual act) and Tadalafil: 10-20 mg 30
min prior to sexual act.

99.  Amantadine:100 mg per day,used in proctin induced
reduction in desire and arousal.
 Bromocriptine, a dopamine agonist when administered in
doses of 2.5 mg two or three times per day, may improve
the libido of patients with hyperprolactinemia, normalize
the menstrual cycle in amenorrheic patients
 Another dopamine agonist is cabergoline, at a dose of 0.5
mg twice a week.

100.  Selegiline is a selective monoamine oxidase-B inhibitor; in
low doses it selectively inhibits the oxidation of dopamine
and phenylethylamine,Its metabolites, L-amphetamine and
L-methamphetamine, have sexual arousal properties.
Angrist B, Gershon S. Clinical effects of amphetamine and L-DOPA on sexuality and aggression. Compr Psychiatry.
1976;17(6):715-22.

101.  Alprostadil ,Bethanechol have all been used with varying
degrees of success but have a number of unwanted side-
effects and interactions with other drugs.
 Testosterone patches have been shown to increase libido
in women, although note though that breast cancer risk
may be significantly increased

102. METABOLIC SIDE EFFECTS
WEIGHT GAIN
 Antipsychotics have long been recognised as weight-
inducing agents.
 5HT 2C antagonism-causes weight gain via disinhibition of
neuropeptide Y and inhibition of pro-opiomelanocortin
neuron,may also influence leptin resistance.
 H 1 antagonism-via increase in hypothalamic AMP related
kinase activity which leads to increse appetite.
 D 2 receptor antagonism-via decrease in limbic
dopaminergic activity possibily increasing reward seeking
behaviour such as food intake and also due to
hyperprolactinaemia.

103.  There is no evidence that drugs exert any direct
metabolic effect: weight gain seems to result from
increased food intake and, in some cases, reduced
energy expenditure.
 Risk of weight gain appears to be related to clinical
response and may also have a genetic basis

104.  Low-potency typical antipsychotics (eg, chlorpromazine) pose a
moderate risk of weight gain12-14 whereas high-potency typical
antipsychotics (eg, haloperidol) have not been shown to cause
significant weight gain.2,12,15
 Overall, weight gain and obesity are more problematic with
atypical antipsychotics than with typical antipsychotics.
 The incidence of weight gain with clozapine is considered to be
the most significant at 4% to 31%,19and one study indicated
almost half of patients gained 20% or more of their initial body
weight.2,20The amount of weight gain with clozapine can be
related to duration of treatment and patients not being
overweight at baseline.21 Olanzapine follows clozapine in
significant weight gain with an incidence of 5% to 40%

106. Management
Monitoring
 Patients starting antipsychotic treatment or changing drugs
should, as an absolute minimum, be weighed and their
weight clearly recorded.
 Estimates of body mass index and waist circumference
should, ideally, also be made at baseline and later at least
every 6 months.
 Weekly monitoring of weight is recommended early in
treatment – for the first 3 months at least

107. Switching drugs
 Selection of appropriate candidates for switching is critical, and factors
to consider include the following41:
 •A clear relationship between psychotropic exposure and weight gain.
 •A new-onset health risk (obesity, diabetes, etc).
 •Nonadherence due to weight gain.
 •Abuse of other medications to offset the weight gain
 Switching always presents a risk of relapse but there is fairly strong
support for switching to aripiprazole or ziprasidone as a method for
reversing weight gain.
 It is possible that switching to other drugs with a low propensity for
weight gain is also beneficial.
 Another option is to add aripiprazole to existing treatment – weight
loss has been observed when aripiprazole was added to clozapine.

108. Behavioural methods
 Methods include calorie restriction, low-glycaemic-index
diet, Weight Watchers and diet/exercise programmes.
Pharmacological methods
 should be considered only where behavioural methods or
switching have failed or where obesity presents clear,
immediate physical risk to the patient.
 Positive findings have been reported in double-blind,
placebo-controlled trials involving amantadine, metformin,
nizatidine, and topiramate.39,42-44Reboxetine, sibutramine,
and dexfenfluramine have also shown efficacy39,42-44

109.  Metformin
 Mean weight loss of 2.93-2.94 kg
 Increase glucagon like peptide 1
 Dose-750-2550mg/d
 Gi discomfort,loose stools,lactic acidosis

110. Topiramate
 has produced positive results in several trials and
is considered a promising agent for this
indication.39,42,44 The aforementioned meta-
analyses by Fiedorowicz and colleagues42 and
Maayan and associates43 revealed mean weight
losses of 3.95 kg and 2.52 kg, respectively, in
patients treated with topiramate.
 Acts thru glutamatergic inhibition
 Dose-100-250mg/d
 sedation,memory problem,acute
myopia,metabolic acidosis,nephrolithiasis

111. Nizatidine
 Various histamine-2 antagonists (ie, famotidine,
nizatidine, ranitidine) have received attention in
the treatment of psychotropic-induced weight
gain, but nizatidine has been studied the most.
 Dose-300-600 mg/d
 Constipation,headache,dizziness,dr mouth

112. Amantadine
 significantly decreased weight gain compared to
placebo in two trials involving olanzapine-treated
patients, with one trial showing a large benefit
(loss of 0.4 kg versus gain of 4.0 kg) and the
other trial showing a more modest benefit (loss of
0.2 kg versus gain of 1.3 kg).42,44
 N-methyl Daspartate receptor antagonism
 Dose-100-300mg/d
 Anxiety,insomnia,agitation,exacerbation of
psychosis

113. DIABETES AND IMPAIRED GLUCOSE TOLERANCE
 The mechanisms involved in the development of
antipsychotic-related diabetes are unclear, but may include
5HT 2A /5HT 2C antagonism, increased lipids, weight gain
and leptin resistance.
 Schizophrenia seems to be associated with relatively high
rates of insulin resistance and diabetes,an observation that
predates the discovery of effective antipsychotics

114.  Phenothiazine derivatives have long been associated with
impaired glucose tolerance and diabetes.
 Prevalence of impaired glucose tolerance seems to be
higher with aliphatic phenothiazines than with
fluphenazine or haloperidol.
 Clozapine and has been strongly linked to hyperglycaemia,
impaired glucose tolerance and diabetic ketoacidosis

115.  As many as a third of patients may develop diabetes after 5
years of treatment.
 Risperidone and quetapine have lesser chance than
olanzapine.
 Amisulpride,aripiprazol and ziprasidone donot elevate the
plasma glucose.

116. Management

117. DYSLIPIDEMIA
 Morbidity and mortality from cardiovascular disease are
higher in people with schizophrenia than in the general
population.
 Phenothiazines are known to be associated with increases
in triglycerides and low-density lipoprotein (LDL)
cholesterol and decreases in high-density lipoprotein (HDL)
cholesterol, but the magnitude of these effects is poorly
quantified.

118.  olanzapine would seem to have the greatest propensity to
increase lipids; quetiapine, moderate propensity; and
risperidone, moderate or minimal propensity.
 Aripiprazole and ziprasidone have minimal adverse effect
on blood lipids and may even reverse dyslipidaemias
associated with previous antipsychotics.

119. Screening
 All patients should have their lipids measured at baseline.
 Those prescribed clozapine, olanzapine, quetiapine or
phenothiazines should ideally have their serum lipids
measured every 3 months for the first year of treatment.
 Those prescribed other antipsychotics should have their
lipids measured after 3 months then annually.

120. Treatment
 If moderate to severe hyperlipidaemia develops during
antipsychotic treatment, a switch to another antipsychotic
less likely to cause this problem should be considered in
the first instance.
 Aripiprazole seems at present to be the treatment of
choice in those with prior antipsychotic-induced
dyslipidaemia.
 Patients with raised cholesterol may benefit from dietary
advice, lifestyle changes and/or treatment with statins.

121. CARDIOVASCULAR EFFECTS
ECG changes
 Many psychotropic drugs are associated with ECG changes
and it is probable that certain drugs are causally linked to
serious ventricular arrhythmia and sudden cardiac death.
 Some antipsychotics block cardiac potassium channels and
are linked to prolongation of the cardiac QT interval, a risk
factor for the ventricular arrhythmia torsade de pointes,
which is occasionally fatal.

122.  The risk is probably a result of the arrhythmogenic
potential of antipsychotics,overall risk is clearly dose-
related.
 Other reported antipsychotic-induced changes include
atrial fibrillation, giant P waves, T-wave changes and heart
block .

124. Management
ECG monitoring
 Measure QTc in all patients prescribed antipsychotics:
1. on admission
2. before discharge and at yearly check-up.

126. Orthostatic hypotension
 Occurs most frequently during first few days of treatment.
 Tolerance often develop for this side effect which is why initial
dosing of these drugs is lower than usual therapeutic dose.
 Is mediated by adrenergic blockade.
 commonly associated with antipsychotic drugs that are
antagonists at postsynaptic adrenergic α 1 receptors. Examples
include clozapine, chlorpromazine, quetiapine and risperidone

127.  Most common with low potency drugs.
 Patients should be warned of this effect and instructed to
rise slowly after sitting or reclining.
 Should avoid all caffeine and alcohol
 use of support stockings, increasing salt intake,
maintaining adequate oral hydration, or as a last resort
taking fludrocortisone to increase intravascular volume by
salt/fluid retention.

128.  When using intramuscular low potency DRAs clinician
should measure the persons BP before and after first dose
and during the first few days of treatment.
 Pure alpha adrenergic pressor agents such as metaraminol
and norepinephrine are the drugs of choice.

129. Tachycardia
 may result from anticholinergic effects or from orthostasis
caused by antipsychotics.
 Up to 25% of patients treated with clozapine develop
tachycardia unrelated to orthostasis; therefore, patients
with heart disease should be monitored carefully,
especially during initiation of clozapine treatment.
 Tachycardia caused by anticholinergic effects without
orthostasis can be managed with a low dose of
peripherally acting β-blockers like atenolol.
Young CR, Bowers MB Jr, Mazure CM. Management of the adverse effects of clozapine. Schizophr Bull. 1998

130. Sudden cardiac death
 Decrease cardiac contractility
 Disrupt enzyme contractility in cardiac cells
 Increase circulating level of catecholamine.
 Low potency DRAs are more toxic than high potency
 Prescribe lowest dose possible and avoid polypharmacy.
 Perform ECG on admission,before discharge and at yearly
checkup.

131. GASTROINTESTINAL EFFECT
 The most common GI side effects of dopamine receptor
antagonists are related to their peripheral anticholinergic
effects.
 These include dry mouth, constipation, occasional
diarrhea, and urinary retention. Nausea and vomiting are
less common.
 Anticholinergic effects are most prevalent with low-
potency FGAs such as chlorpromazine or thioridazine and
are uncommon with high-potency drugs.

132.  Patients who experience a severe dry mouth should be
advised to rinse their mouth frequently and to chew
sugarless gum or candy.
 Sugar-containing candies may lead to fungal infections in
the mouth and increase the risk of dental caries

133. Constipation
 Should be treated with usual laxative preparations but
severe constipation can progress to paralytic ileus esp with
clozapine.
Management
 A decrease in DRA dosage or a change in less
anticholinergic drug is warranted in such cases.
 Pilocarpine can be used to treat paralytic ileus although
relief is only transitory.

134. Hypersalivation
 Suggested mechanisms include muscarinic M 4 agonism,
adrenergic α 2 antagonism and inhibition of the
swallowing reflex.
 Begins early in the treatment and is most evident at
night,patient report that their pillows are drenched with
saliva.
 Although reports suggest that clonidine or amitriptyline
may help to reduce hypersalivation,the most practical
solution is to put a towel over the pillow.

135. HEPATIC EFFECTS
Elevation of liver enzymes
 During treatment with DRA tend to be transient and not
clinically significant.
 A few patient may need to discontinue use of drug
because of transaminase elevation.

136. Chlorpromazine induced cholestatic jaundice
 It usually occurs in the first month of treatment and was
heralded by symptoms of upper abdominal pain,nausea
and vommiting.
 This is followed by fever,rash,eosinophilia bilirubin in
urine,increase in serum bilirubin,alkaline phosphatase and
transaminase.
 Reported cases are now extremely rare but if jaundice
occurs the medication should be discontinued.

137. HAEMATOLOGIC EFFECTS
Leukopenia
 Temporary with a WBC count of about 3500.
 Common but not a serious problem.
Agranulocytosis
 Life threatening hematologic problem,occurs in about 1 in
10000 persons treated withDRAs.
 Thrombocytopenic purpura,hemolytic anemia and pancytopenia
can occur rarely.

138.  Although routine complete blood counts are not indicated
but if a person reports a sore throat and fever a CBC
should be done immediately to check for the possibility.
 If the blood indices are low administration of DRAs sholud
be stopped and the person should be transferred to
medical facility.
 The mortality rate for the complication may be as high as
30 percent.

139. Clozapine and hematologic effect
 The risk for clozapine-induced agranulocytosis is 0.73
percent during the first year of treatment and 0.07 percent
in the second year.
 The risk for this adverse effect is greatest during the first 3
months of treatment.
 For neutropenia, the risk is 2.32 percent in the first year
and 0.69 percent in the second year.

140. The contraindication to the use of clozapine are-
 WBC count below 3500
 Previous bone marrow disorder.
 A history of agranulocytosis during clozapine treatment.
 The use of another drug that is known to suppress the
bone marrow for example carbamazepine.

141. Monitoring
 Before initiating therapy, WBC ≥ 3,500/mm3 and ANC ≥
2,000/mm3
 First 6months,weeklymonitoring, ifWBC≥ 3,500/mm3
andANC ≥ 2,000/mm3 then go to every 2 weeks.
 Six to 12 months, every 2 week monitoring, ifWBC ≥
3,500/mm3 and ANC ≥ 2,000/mm3 then every 4 weeks.
 The requirement for WBC count monitoring is continued
for as long as patients receive the drug and for at least 1
month after it is discontinued.

142.  If the patient has a WBC count below 2,000 cells per mm3
or a granulocyte count below 1,000 cells per mm3,
clozapine must be discontinued.
 Patients who develop agranulocytosis should not receive
clozapine again.

143. OPTHALMOLOGIC SIDE EFFECTS
Thioridazine retinal pigmentation
 Irreversible
 Above 1,000 mg daily—can result in retinal pigmentation
(retinitis pigmentosa).
 This condition can lead to serious visual impairment or
blindness.
 Moreover, this condition may not remit when thioridazine
is discontinued,as a result, thioridazine should not be
prescribed at doses over 800 mg daily.

144. CPZ pigmentation of eye
 Relatively benign
 develop granular deposits in the anterior lens and
posterior cornea, visualized on slit lamp examination,
seldom affect the patient’s vision.
 Occasionaly the conjuctive is discoloured by brown
pigmentation.
 No retinal damage is seen.
 Changing the patient to another drug will usually result in
a gradual improvement in the condition.

145. Quetapine and eye
 Initial concerns about cataract formation,based on animal
studies,have not been borne out since the drug has been
in clinical use.
 Nevertheless,it might be prudent to test for lens
abnormalities early in the treatment and periodically
thereafter.

146. DERMATOLOGIC SIDE EFFECTS
 Cutaneous reactions seen during the first weeks of
antipsychotic drug treatment include
urticarial,maculopapular, petechial, and edematous
reactions.
 These reactions usually improve when drugs are
discontinued, and sometimes clear even when drugs are
continued.
 Patients receiving low-potency FGAs, particularly
chlorpromazine, may develop photosensitivity reactions
consisting of severe sunburn or rash.

147.  Low-potency FGAs, especially chlorpromazine, are
associated with an uncommon discoloration of the skin.
 Skin areas that are exposed to sunlight, particularly the
face and neck develop blue-gray metallic discoloration.
 This skin reaction is usually associated with long-term
treatment with high-drug dosages.
 Changing to a highpotency drug will usually lead to gradual
improvement.

148. ANTIPSYCHOTIC ASSOCIATED HYPONATREMIA
Hyponatraemia can occur in the context of-
Water intoxication-
 A longitudinal study found that 10% of severely ill patients
with a diagnosis of schizophrenia had episodic
hyponatraemia secondary to fluid overload.
 It has been postulated that it may be driven, at least in
part, by an extreme compensatory response to the
anticholinergic side-effects of antipsychotic drugs.

149. Drug-induced syndrome of inappropriate antidiuretic
hormone (SIADH)
 The prevalence of SIADH is estimated to be as high as 11%
in acutely ill psychiatric Patients.
 It usually develops in the first few weeks of treatment with
the offending drug.
 Phenothiazines, haloperidol, pimozide, risperidone,
quetiapine,olanzapine, aripiprazole and clozapine have all
been implicated
Severe hyperlipidaemia and/or hyperglycaemia
 ‘pseudohyponatraemia’

150. Management
 Fluid restriction with careful monitoring of serum sodium,
particularly diurnal variation (Na drops as the day
progresses).
 Consider treatment with clozapine: shown to increase
plasma osmolality into the normal range and increase
urine osmolality (not usually reaching the normal range) .
 There are both positive and negative reports for
olanzapine and risperidone and one positive case report
for quetiapine

151.  If mild, fluid restriction with careful monitoring of serum
sodium.
 Switching to a different antipsychotic drug.
 Consider demeclocycline.
 Lithium may be effective but is a potentially toxic drug and
hyponatraemia predisposes to lithium toxicity

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154. Thank you

155. Thank you