NEI’s Master Psychopharmacology Program

Management Strategies for Common Psychotropic Side Effects

Gabriela Alarcón, Ph.D.

ABSTRACT

Psychotropic-induced side effects lead to medication nonadherence, which is associated with a host of negative
health outcomes that interfere with patient care management. Clinicians must address these side effects to
effectively manage a range of psychiatric issues that trouble their patients. Management strategies for some of the
most common side effects of psychotropic medications are presented in this article.

The Burden of Psychotropic Side Effects
Side effects due to psychotropic medications are
significantly associated with a reduced likelihood of
treatment adherence among patients with serious mental
illness.1,2 Moreover, patients who report more severe side
effects are more likely to be nonadherent than those with
moderate side effects.3 Consequently, nonadherence is a
significant risk factor for relapse,2,4 hospital and emergency
room use for mental health reasons,1,4 and suicide.2 Failure
to address side effects of psychotropic agents interferes
with appropriate patient care management. Some of the
most common psychotropic side effects reported to be
bothersome or leading to nonadherence include akathisia,
sweating, sedation, dry mouth, sexual dysfunction, and
weight gain.1,5 Recommended strategies for managing
common and, in some cases, medically serious side
effects are presented below for clinicians to implement in
patient care.
How to Manage Common Psychotropic Side Effects
Akathisia
• Most common with dopamine receptor blocking
agents, particularly first-generation antipsychotics
(FGAs; 21%) but also second-generation
antipsychotics (SGAs; 11%); polypharmacy with two
antipsychotics increases prevalence of akathisia (2
FGAs: 40%, 2 SGAs: 34%)6
• Among SGAs, cariprazine (13.04%), risperidone
(13.03%), and lurasidone (11.16%) are associated with
the highest rates of akathisia in patients with serious
mental illness; high doses of an SGA are generally
associated with an increased risk of akathisia7
• Consider the risk of akathisia when choosing an
antipsychotic treatment option and when deciding
whether to use antipsychotic polypharmacy (increases
risk of akathisia)6,7
• Avoid rapid escalation of antipsychotic dosage8
• Consider dose reduction (if possible) in patients with
persistent akathisia8
• In the case of antipsychotic polypharmacy, consider
discontinuing one of the antipsychotic medications or
switching to a different single antipsychotic8,9
• Consider switching to an agent with a perceived lower
liability for akathisia,9 such as clozapine, olanzapine, or
quetiapine8
• Withdrawal akathisia can occur; allow at least 6 weeks
before judging effectiveness of dose reduction/
medication switch
• If adjunctive medication is needed, propranolol (20–
120 mg/day) or mirtazapine (7.5–15 mg/day) should
be considered first-choice options8,10
• Clonazepam (0.5–1 mg/day) may be considered as a
short-term therapy option8
• Anticholinergics (benztropine, biperiden) should not
be routinely used for the treatment of akathisia8,9
• Switch to clozapine in case of intractable akathisia10
Antidepressant-induced excessive sweating (ADIES)
• ADIES occurs in approximately 10% of patients taking
an antidepressant,11 and is more common with the use
of serotonin norepinephrine reuptake inhbitors (SNRIs)
than selective serotonin reuptake inhibitors (SSRIs)12

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 NEI’s Master Psychopharmacology Program
• Lowering dosage or switching to another
antidepressant is a first-line strategy to manage
ADIES11
• Antiadrenergic treatments, particularly terazosin
(titration by 1 mg per week or slower), may be
effective for ADIES13,14
• Anticholinergic treatments, particularly glycopyrrolate
(1–2 mg up to three times a day), have been shown
to be an effective treatment for ADIES when used as
needed11,15-17
Antipsychotic-induced sedation
• All antipsychotics are associated with sedation,
especially asenapine, clozapine, quetiapine,
olanzapine, chlorpromazine, and thioridazine9,18,19
• Sedation is most prominent with treatment initiation,
but may dissipate to some extent with continued
treatment19
• Discontinue other sedating medications and rule out
comorbid conditions contributing to sedation18,19
• If possible, consolidate doses into one evening dose,
reduce total daily dose, or switch to less sedating
medication, such as aripiprazole, brexpiprazole,
cariprazine, or lumateperone9,18,19
• Morning caffeine may be helpful, but consider
potential interactions with medications (e.g.,
clozapine)18,19
• Psychostimulants have unclear benefits for improving
antipsychotic-induced sedation18,19
Dry mouth (xerostomia)
• When choosing a psychotropic agent to avoid
dry mouth, duloxetine, vortioxetine, fluvoxamine,
agomelatine (versus other antidepressants, particularly
sertraline) and SGAs (versus FGAs and mood
stabilizers) should be considered12,20
• Patients should be advised to sip water, use xylitol-
containing products (chewing gus, lozenges), and
avoid irritants like diuretics, alcohol, and smoking12,21
• Fluoride and saliva substitutes should also be
recommended12,20
• Severe dry mouth may benefit from salivary
stimulants like the muscarinic agonist pilocarpine and
cevimeline12
Sexual dysfunction (SD)
• SD following treatment with antidepressants
(particularly with strongest serotonergic properties,
i.e., SSRIs) and antipsychotics (particularly prolactin-
raising, i.e., risperidone, paliperidone, and FGAs)22 is
common
• In the case of antidepressant-induced SD:
• Waiting for spontaneous remission of SD is
not very effective, but may be acceptable for
patients with mild SD23,24
• Reduce antidepressant dose in patients who
have achieved a full therapeutic response;
monitor for signs of relapse of depressive
symptoms23,24
• Use of drug holidays is not recommended
overall due to risk of nonadherence23
• Augmentation with bupropion may be
appropriate for patients who have had
remission of depressive symptoms23,24
• Switch to another antidepressant with low
risk of SD (e.g., bupropion, mirtazapine,
vilazodone, vortioxetine),24 particularly for
patients with residual depressive symptoms23
• Phosphodiesterase-5 (PDE-5) inhibitors may
be effective for men and women23
• In the case of antipsychotic-induced SD:
• Waiting for spontaneous remission of SD is
not recommended25
• Can be dose related, but often occurs even
at low doses, so dose reduction is often not
helpful, and it carries a significant risk of
relapse9,25
• Select or switch to another antipsychotic
(particularly one that is prolactin-sparing, e.g.,
aripiprazole)9,25
• Low-dose aripiprazole may be added to
another antipsychotic to reduce prolactin and
improve SD9,25
• PDE-5 inhibitors may be a useful option for
erectile dysfunction25
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 NEI’s Master Psychopharmacology Program
Tardive dyskinesia (TD)
• TD prevalence is high among patients treated with
FGAs (30%), but still occurs in 7.2% of patients treated
with SGAs without previous exposure to FGAs26
• Do not treat TD with anticholinergics as they can
make symptoms worse; taper off any concomitant
anticholinergic medications9
• The vesicular monoamine transporter (VMAT) 2
inhibitors, valbenazine and deutetrabenazine, are first-
line treatment options
• If valbenazine and deutetrabenazine are unavailable,
tetrabenazine should be considered a first-line
treatment option27
• Clonazepam (short-term), Ginkgo biloba, and
amantadine may also be considered for treatment27-29
• There is insufficient evidence to support or refute the
use of the following treatment strategies: withdrawing
the dopamine receptor blocking agent, switching from
FGAs to SGAs, or botulinum toxin A27
• Switching to clozapine should be used in those
with other approved indications (e.g., suicidality,
treatment-resistant schizophrenia), not just moderate-
to-severe TD30
• For treatment-resistant cases of TD, deep brain
stimulation of the globus pallidus interna may be
considered27
Weight gain
• Psychotropic-induced weight gain is more easily
prevented than treated after the fact; when possible,
select agents with lower incidence of weight gain
(e.g., aripiprazole, ziprasidone, carbamazepine,
lamotrigine)9,31
• Regular monitoring of weight and metabolic
parameters is recommended, as long-term problems
can be predicted by immediate early weight gain
(≥5%)32 and elevation of fasting triglycerides9
• Diet and exercise can prevent and reverse
psychotropic-induced weight gain in motivated
patients9,31
• In the case of antipsychotic-induced weight gain:
• Strongly consider initiating metformin early
during treatment with olanzapine or clozapine
to prevent weight gain, especially if the
patient is already overweight or obese9
• Consider olanzapine-samidorphan rather than
olanzapine alone9
• If metformin and samidorphan are ineffective,
consider augmentation with aripiprazole,
naltrexone, or liraglutide
• Switching to aripiprazole or ziprasidone may
reduce weight gain33
• Topiramate or amantadine augmentation are
considerations if nothing else is effective9
• In the case of antiepileptic-induced weight gain,
metformin is recommended as the first-choice
treatment, but it is not recommended for preventive
use31
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