Current Clinical Strategies: Handbook of Psychiatric Drugs
Current Clinical Strategies: Handbook of Psychiatric Drugs
Handbook of Psychiatric
Drugs
2004 Edition
Lawrence J. Albers, MD
Assistant Clinical Professor
Department of Psychiatry and Human Behavior
University of California, Irvine, College of Medicine
Rhoda K Hahn, MD
Clinical Professor
Department of Psychiatry and Human Behavior
University of California, Irvine, College of Medicine
Christopher Reist, MD
Associate Professor and Vice Chair
Department of Psychiatry and Human Behavior
University of California, Irvine, College of Medicine
Serotonin-Specific Reuptake
Inhibitors
I. Indications
A. Serotonin-Specific Reuptake Inhibitors (SSRIs) are
the most widely prescribed class of antidepressants.
SSRIs have proven efficacy in the treatment of
major depression, dysthymia, obsessive-compulsive
disorder (OCD), panic disorder, bulimia nervosa,
post-traumatic stress disorder, generalized anxiety
disorder and social phobia (social anxiety disorder).
B. SSRIs are also effective in the treatment of bipolar
depression and premenstrual dysphoric disorder.
They may have some efficacy in the treatment of
pain syndromes, such as migraine headaches and
chronic pain. There is some evidence that they be
effective in impulse control disorders. These agents
have also been used to treat behavioral compon-
ents of borderline personality disorder.
II. Pharmacology
A. SSRIs block serotonin reuptake into presynaptic
nerve terminals, leading to enhanced serotonergic
neurotransmission.
B. The half-life for these agents is approximately 24
hours for the parent compound. Fluoxetine,
however, has a half-life of 2-4 days, and its active
metabolite, norfluoxetine, has a 7-10 day half-life.
Thus it takes fluoxetine over a month to reach
steady-state plasma concentrations while the other
SSRIs take approximately 5 days.
C. With the exception of fluvoxamine, the SSRIs are
highly bound to plasma proteins. SSRIs have
significantly less effect on muscarinic, histaminic,
and adrenergic receptors, compared to tricyclic
antidepressants (TCAs), and the SSRIs are
generally better tolerated.
III.Clinical Guidelines
A. Dosage: SSRIs have the advantage of once-daily
dosing. The dosage of fluoxetine, citalopram, and
paroxetine is 20 mg per day; the dosage should be
decreased to 10 mg per day in the elderly. The
initial dose of escitalopram is 10 mg/day. Sertraline
and fluvoxamine are dosed at 50 mg per day, but
the dosage is decreased to 25 mg per day in elderly
patients. There is no linear relationship between
SSRI dose and response. For many patients, the
dosage does not need to be increased.
B. Obsessive-Compulsive Disorder and Bulimia:
Higher dosages of SSRIs, such as 60-80 mg of
fluoxetine or 200-300 mg of sertraline, have been
used to treat obsessive-compulsive disorder and
bulimia. While high doses may be necessary in
some patients, many patients will respond to
standard dosing after 6-12 weeks. When greater
than 40 mg a day of fluoxetine is given, the dosage
should be divided into two doses to minimize side
effects.
C. Panic Disorder: Patients with panic disorder should
be started at a low dosage to prevent exacerbation
of anxiety in the initial weeks of treatment. Patients
should start at 12.5- 25 mg of sertraline, 5-10 mg of
paroxetine, 10-20 mg of citalopram, 5-10 mg of
escitalopram, and 5 mg of fluoxetine. After 1-3
weeks, the dosage may be increased gradually to
standard dosages.
D. Response Time: SSRIs require 2-4 weeks to begin
to alleviate symptoms of depression and treatment
should continue for 6-8 weeks before a patient is
considered treatment refractory.
E. Plasma Levels: There is no correlation between
plasma concentrations of SSRIs and clinical
efficacy. Measuring plasma levels is not clinically
indicated.
F. Safety: SSRIs are much safer in overdose than
other antidepressants such as TCAs or MAOIs.
IV. Adverse Drug Reactions
A. Tolerability: SSRIs are better tolerated than TCAs
or MAOIs.
B. Alpha-1 Blockade: SSRIs do not produce
orthostatic hypotension because they do not block
alpha-1 adrenergic receptors as the tricyclic agents
do.
C. Histaminic Blockade: SSRIs produce markedly
less sedation or weight gain than TCAs or MAOIs
because of minimal effect on histamine receptors.
D. Muscarinic Blockade: SSRIs usually do not cause
dry mouth, constipation, blurred vision, and urinary
retention because they have minimal effect on
muscarinic cholinergic receptors.
E. Seizures: SSRIs have a seizure rate of
approximately 0.2%, which is slightly lower than the
rate for TCAs.
F. Serotonergic Side Effects: The side effects of
SSRIs are primarily mediated by their interaction
with serotonergic neurotransmission:
1. Gastrointestinal effects, such as nausea and
diarrhea, are the most common adverse
reactions. Nausea usually improves after the first
few days of treatment. Giving the medication with
food often alleviates the nausea.
2. Decreased appetite is common early in
treatment because of nausea, and this problem
usually improves after several days.
3. Insomnia may occur with any of the SSRIs, but
it is more common with fluoxetine. Insomnia
usually responds to treatment with trazodone 50-
100 mg qhs. The SSRI should be given in the
morning if insomnia occurs.
4. SSRIs are less sedating than tricyclic
antidepressants, but sedation can occur with
paroxetine or fluvoxamine. If sedation occurs, the
medication should be given at bedtime.
5. Headaches occur occasionally upon initiation of
treatment. In some patients, headaches are
more persistent.
6. Sexual dysfunction such as decreased libido,
delayed ejaculation and anorgasmia can occur,
and this problem may be treated with Sildenafil
(Viagra) 50-100 mg taken one hour before sex,
bupropion (75-150 mg bid), buspirone (BuSpar)
5-20 mg bid-tid, mirtazapine 15-30 mg one hour
before sex, nefazodone 100 mg one hour before
sex or switching the antidepressant to bupropion,
nefazodone or mirtazapine.
7. Serotonin syndrome, characterized by nausea,
confusion, hyperthermia, autonomic instability,
tremor, myoclonus, rigidity, seizures, coma and
death, can occur when SSRIs are combined with
MAOIs. SSRIs should not be used for 2 weeks
before or after the use of an MAOI. For
fluoxetine, 5-6 weeks should elapse after
discontinuation because of its long half-life.
G. Miscellaneous Side Effects: SSRIs may also
cause sweating, anxiety, dizziness, tremors, fatigue,
and dry mouth.
H. Mania: SSRIs, like all other antidepressants, can
induce mania or rapid cycling in bipolar patients.
I. SSRI Discontinuation Syndrome: On
discontinuation, some patients may experience
dizziness, lethargy, nausea, irritability, and
headaches. These symptoms are usually transient
and are more likely to occur with short- acting
agents such as paroxetine and fluvoxamine. These
symptoms can be prevented by slowly tapering the
medication over several weeks when discontinuing
the drug. Discontinuation of paroxetine may be
complicated by cholinergic rebound symptoms,
such as diarrhea.
J. Restlessness: An akathisia-like syndrome has
been reported with fluoxetine, and it can be treated
by reducing the dose of the SSRI. The agitation with
this syndrome can be profound and often requires
discontinuation of the medication.
K. Teratogenic Effects: All SSRIs are pregnancy
category C. However, there is no evidence that
SSRIs cause major birth defects in humans. The
impact of untreated depression on the mother and
fetus must be considered when determining these
risk benefit decisions. Lack of treatment during
pregnancy can lead to severe adverse
consequences for the woman and fetus. Data on
behavioral teratogenicity is limited.
L. Breast Feeding: SSRIs are secreted into breast
milk, and mothers should not breast feed while
taking an SSRI.
V. Drug Interactions
A. Cytochrome P450 Enzymes: SSRIs are
competitive inhibitors of a variety of cytochrome
P450 liver enzymes. This can result in elevated
plasma levels of medications metabolized by these
enzymes. Elevated plasma levels may lead to toxic
side effects.
B. Potential Toxicity: An example of these
interactions is the toxic side effects of the TCA,
desipramine, which can be seen when it is given
concomitantly with an SSRI such as fluoxetine.
Desipramine is metabolized by the liver enzyme
cytochrome P4502D6 (CYP2D6) and fluoxetine is a
potent inhibitor of cytochrome CYP2D6. Fluoxetine
can elevate plasma desipramine levels up to 400%,
with subsequent increased sedation, anticholinergic
effects, tremors and potential increased risk of
seizures or cardiotoxicity.
C. Substrates/Inhibitors
1. Table 1 lists the substrates of several P450 liver
enzymes, and table 2 indicates the degree of
inhibition of the enzymes by each SSRI. The
greater the inhibition, the greater the likelihood of
a drug-drug interaction.
2. Drugs that have a narrow therapeutic index are
more likely produce toxic symptoms when
combined with a strong inhibitor of their
metabolism. These drugs include
antiarrhythmics, anticonvulsants, warfarin, and
theophylline.
D. Warfarin: All the SSRIs can increase levels of
warfarin via P450 interactions as well as
competition for plasma protein binding sites.
Prothrombin times should be monitored when
combining these agents.
Citalopram (Celexa)
Indications: Effective for a variety of depressive and
anxiety disorders.
Preparations: 20 and 40 mg scored tablets.
Dosage:
Depression: 20 mg per day, usually given at bedtime.
The dosage may be increased to 40 mg per day after
one week. Maximum dosage is 60 mg/day and this
should be reserved for treatment refractory patients
who have had a 4-6 week trial at 40 mg/day.
Elderly: 10 mg per day for one week, then increase to
20 mg/day. Treatment refractory patients may require
40 mg/day after a trial of 4-6 weeks on 20 mg/day.
Half-life: 35 hr.
Adverse Drug Reactions: Cytochrome P450: Modest,
but significant inhibition of the hepatic enzyme, CYP2D6,
may lead to mild elevations TCAs and antiarrhythmics.
Clinical Guidelines: Of the SSRIs citalopram has low
overall effects on P450 enzymes (see table 2).
Escitalopram (Lexapro)
Indications: Effective for a variety of depressive and
anxiety disorders.
Preparations: 10 and 20 mg scored tablets.
Dosage:
Depression: 10 mg per day, usually given at bedtime.
The dosage may be increased to 20 mg per day after
one week. Maximum dosage is 30 mg/day, and this
dosage should be reserved for treatment refractory
patients who have had a 4-6 week trial at 20 mg/day.
Elderly: 10 mg per day. Treatment refractory patients
may require 20 mg/day after a trial of 4-6 weeks on 10
mg/day.
Half-life: 30 hr.
Adverse Drug Reactions: Cytochrome P450: Modest
inhibition of the hepatic enzyme, CYP2D6, may lead to
mild elevations of TCAs and antiarrhythmics.
Clinical Guidelines: Compared to the SSRIs,
escitalopram has low overall effects on P450 enzymes
(see table 2). Compared to racemate (citalopram),
escitalopram has an improved side-effect profile (less
sedation and GI upset). Sexual side effects are similar.
Fluvoxamine (LuVox)
Indications: Effective for a variety of depressive and
anxiety disorders.
Preparations: 25, 50, 100 mg scored tablets
Dosage:
Initial Dosage: 50 mg/day, then titrate to 300 mg/day
maximum, over several weeks
Elderly: 25-150 mg/day
Children: 25 mg/day initially, then increase by 25 mg
per week as needed to 50-200 mg/day
Half-life: 16-20 hours.
Adverse Drug Reactions:
A. Theophylline: Potent inhibition of the hepatic
enzyme, CYP1A2, can produce toxicity in
combination with theophylline and elevate plasma
levels of other CYP1A2 substrates.
B. Clozapine: Potent inhibition of CYP1A2 can lead to
markedly elevated clozapine levels with potential for
seizures and hypotension.
C. Benzodiazepines: Significant inhibition of the
hepatic enzyme, CYP3A4, can lead to elevated
levels of some benzodiazepines, such as
alprazolam, with subsequent increased sedation
and psychomotor impairment.
D. Beta-Blockers: Significant inhibition of the hepatic
enzyme, CYP2C19, can lead to elevated plasma
concentrations of propranolol, with further
reductions in heart rate and hypotension.
E. Calcium Channel Blockers: Inhibition of the
hepatic enzyme, CYP3A4, can produce elevated
levels of calcium channel blockers, such as
diltiazem, with subsequent bradycardia.
F. Methadone: Fluvoxamine can significantly raise
plasma methadone levels.
G. Carbamazepine: Fluvoxamine may elevate
carbamazepine levels via CYP3A4 inhibition,
leading to toxicity.
H. Refer to general discussion of SSRI adverse drug
interactions for side effects typical to all SSRIs and
tables 1 and 2 for further potential drug interactions.
Clinical Guidelines: Patients often require bid dosing at
dosages above 100-200 mg per day. Many drug
interactions with cytochrome P450 metabolized
medications have been reported. The other SSRIs are
just as effective; therefore, it is not commonly used.
Sertraline (Zoloft)
Indications: Effective for a variety of depressive and
anxiety disorders.
Preparations: 25, 50, 100 mg scored tablets
Dosage:
Depression: 50 mg qAM, then increase by 50 mg/day
per month in patients with partial response (maximum
dose of 200 mg/day)
Obsessive-Compulsive Disorder: Begin with 50 mg
qAM and increase by 50 mg/day per month in partial
responders to a maximum of 200-300 mg/day
Panic Disorder/PTSD: Begin with 25 mg qAM and
increase dose by 25 mg every 2-4 weeks until
symptoms abate, to a maximum dose of 200 mg per
day. Patients with severe anxiety or sensitivity to
medication may be started at 12.5 mg for the first
week.
Elderly: 25-200 mg/day
Premenstrual Dysphoric Disorder (PMDD): 50 mg
per day throughout the menstrual cycle or limited to
the luteal phase.
Children: 25 mg/day for ages 6-12 and 50 mg/day for
adolescents age 13-17.
Half-life: 24 hours for sertraline and 2-4 days for its
metabolite, desmethylsertraline
Adverse Drug Reactions: Cytochrome P450: Modest,
but significant inhibition of the hepatic enzyme, CYP2D6,
may lead to mild elevations of TCAs and antiarrhythmics.
Clinical Guidelines: Sertraline is less likely to cause
sedation compared to paroxetine or fluvoxamine. It is less
likely to produce restlessness or insomnia compared to
fluoxetine. Sertraline,escitalopram and citalopram have
the lowest overall P450 enzyme effects of the SSRIs (see
table 2).
Duloxetine (Cymbalta)
I. Indications (FDA approval pending).
A. Duloxetine is effective for the treatment of major
depression.
II. Pharmacology
A. Duloxetine blocks serotonin and norepinephrine
transporters.
B. Half life is 12 hours.
III. Clinical Guidelines
A. Preparations: 20 mg capsules.
B. Dosage.
1. Initial dosage: 20 - 60 mg po q am.
2. Average dosage: 60 mg po q am.
C. Small increases in heart rate can be observed.
D. Abrupt discontinuation can be associated with
transient sleep disturbance and increases in HR.
IV.Adverse Drug Reactions
A. Common Adverse Reactions: nausea, dry mouth,
dizziness, constipation, headache.
V. Drug Interactions: Not yet determined.
Gepirone ER
I. Indications (FDA approval pending).
A. Gepirone is effective in the treatment of major
depression.
II. Pharmacology
A. Gepirone is a pyridinyl piperazine 5HT1A agonist.
B. Gepirone has differential action at presynaptic
(agonist) and post-synaptic (partial agonist) 5-HT1A
receptors. Compared to buspirone, it has much
less D2 receptor affinity.
III. Clinical Guidelines
A. Preparations: Extended-release 20 mg tablets.
B. Dosage
1. Initial dosage: 20 mg PO qAM, increase every
4 days by 20 mg.
2. Average dosage: 60 mg/day is likely to be the
most common dosage.
3. Dosage range: 40-80 mg/day.
C. Gepirone has minimal effects on weight, sexual
function, or sedation.
IV.Adverse Drug Reactions
A. Common Adverse Reactions: Dizziness, nausea,
insomnia, nervousness, dry mouth, and GI distress.
V. Drug Interactions
A. Gepirone does not inhibit P450 enzymes to a
significant extent.
B. Because it is metabolized through by the CYP3A4
enzyme primarily (CYP2D6 to a lesser extent),
inhibitors of CYP3A4 can alter kinetics.
Nefazodone (Serzone)
I. Indications
A. Nefazodone is effective in the treatment of major
depression, dysthymia, and the depressed phase of
bipolar disorder.
B. Nefazodone (Serzone) is also used clinically for
premenstrual dysphoric disorder, chronic pain, and
posttraumatic stress disorder.
II. Pharmacology
A. Nefazodone is the phenylpiperazine analog of
trazodone and has a half-life of 2-18 hours.
Nefazodone inhibits presynaptic serotonin reuptake
and blocks postsynaptic serotonin receptors (5HT-
2A).
B. Therapeutic levels have not been established.
III. Clinical Guidelines
A. Preparations: 50, 100, 150, 200, and 250 mg
tablets; the 100 and 150 mg tablets are scored.
B. Dosage
1. Initial dosage: 50-100 mg bid, then increase
gradually after several days to weeks by 50-100
mg per day.
2. Average dosage: 300-500 mg/day with bid
dosing.
3. Dosage range: 50-600 mg/day.
4. Elderly: Start with 50 mg/day, range: 100-200
bid.
C. REM Sleep: Nefazodone does not suppress REM
sleep, unlike most antidepressants.
D. Sexual Functioning: Unlike other antidepressants,
nefazodone has no adverse effects on sexual
functioning.
IV.Adverse Drug Reactions
A. Common Adverse Reactions: The most common
side effects are nausea, dry mouth, dizziness,
sedation, agitation, constipation, weight loss, and
headaches.
B. Hepatic Disease: Cases of life-threatening hepatic
failure have been reported at a rate of 1 case of
hepatic failure resulting in death or liver transplant
per 250,000-300,000 patient years of nefazodone
treatment. While there is no evidence that pre-
existing liver disease increases the likelihood of
liver failure ,nefazodone should not be initiated if
active liver disease or elevated transaminases are
present as it complicates monitoring. Patients who
develop increased transaminases more than three
times normal should be discontinued from
treatment.
C. Alpha Adrenergic Blockade: Nefazodone
produces less orthostatic hypotension than
trazodone or tricyclic antidepressants.
D. Histaminic Blockade: Nefazodone has little effect
on histamine receptors and produces less weight
gain than TCAs or trazodone.
E. Cardiac Effects: Nefazodone does not alter
cardiac conduction.
V. Drug Interactions
A. CYP3A4: Nefazodone is a significant inhibitor of the
hepatic CYP3A4 enzyme, and levels of all
medications metabolized by this enzyme may be
elevated. Levels of triazolam and alprazolam may
be increased.
B. Cytochrome P450 Inhibitors: A metabolite of
nefazodone, CPP, is inactivated by the cytochrome
P450 enzyme system. In the presence of a strong
inhibitor hepatic CYP2D6 enzyme, such as
fluoxetine, M-CPP is not broken down, resulting in
anxiety. When switching from fluoxetine or
paroxetine to nefazodone, a wash out period of 3-4
days for paroxetine and several weeks for fluoxetine
is recommended to avoid this adverse reaction.
C. Other Cytochrome P450 Enzymes: Nefazodone
does not appear to affect the metabolism of
medications metabolized by other P450 enzymes.
D. Digoxin: Nefazodone can produce modest
increases in digoxin levels.
E. MAOI: The combination of nefazodone with a MAOI
can lead to a serotonergic syndrome and severe
toxicity.
Trazodone (Desyrel)
I. Indications
A. Approved for use in depressive disorders. It is also
used clinically to reduce anxiety and decrease
agitation and aggression in elderly demented
patients.
B. Trazodone is commonly prescribed for insomnia,
and it is also effective in some patients with chronic
pain syndromes.
II. Pharmacology
A. Trazodone is a triazolopyridine with a half-life of 4-9
hours.
B. Its efficacy is related primarily to inhibition of
presynaptic serotonin reuptake, with possible mild
postsynaptic serotonergic agonism.
C. Plasma levels are not clinically useful.
III. Clinical Guidelines
A. Preparations: 50, 100, 150, and 300 mg tablets.
B. Dosage:
1. Initial dosage: 50-100 mg qhs, then increase by
50 mg/day as tolerated. May require bid dosing
initially.
2. Average dosage: 300-600 mg/day.
3. Dosage range: 200-600 mg/day.
4. Elderly: 50-500 mg/day.
5. Insomnia: 25-200 mg qhs.
C. Tolerability: Many patients are unable to tolerate
the sedation and hypotension associated with an
antidepressant dosage. This significantly limits its
utility in the treatment of depression. It is therefore
most often used for insomnia, especially in patients
with SSRI-induced insomnia.
IV.Adverse Drug Reactions
A. Histaminic Blockade: Trazodone is a potent
antihistamine and can lead to significant sedation
and weight gain.
B. Alpha-1 Adrenergic Blockade: Marked Inhibition
of alpha-1 adrenergic receptors often leads to
severe hypotension, especially at high doses.
Reflex tachycardia and dizziness may also occur.
C. Cholinergic Blockade: Trazodone has little impact
on muscarinic receptors and does not produce the
anticholinergic effects seen with TCAs.
D. Dry Mouth: Trazodone commonly causes dry
mouth.
E. Cardiac Effects: Trazodone has little effect on
cardiac conduction; however, there have been
reports of exacerbation of arrhythmias in patients
with preexisting conduction abnormalities. It should
be avoided in patients with recent myocardial
infarction.
F. Priapism: A prolonged, painful penile erection
occurs in 1/6000 patients, due to alpha-2 blockade.
Patients can be treated with intracavernal injection
of epinephrine.
G. Miscellaneous: Nausea, GI irritation and
headaches may occur.
H. Pregnancy/Lactation: Avoid use in pregnancy due
to potential teratogenicity. Patients should not
breast feed while using trazodone.
I. Overdose: Trazodone is much safer in overdose
than TCAs, but fatalities can occur with combined
overdose with alcohol or sedative/hypnotics.
J. ECT: Use of trazodone is not recommended during
ETC.
V. Drug Interactions
A. CNS Depressants: Trazodone may potentiate the
effects of other sedating medications.
B. Fluoxetine may elevate trazodone levels, but the
combination is generally safe and low-dose
trazodone is very effective in treating insomnia due
to fluoxetine.
C. Digoxin/Phenytoin: Trazodone may elevate
plasma levels of these drugs.
D. Warfarin: Trazodone has been reported to alter
prothrombin time in patients on warfarin.
E. MAOIs: Avoid combining trazodone with MAOIs
due to the potential of inducing a serotonergic
syndrome.
Clomipramine (Anafranil)
Indications: Depressive disorders and obsessive-
compulsive disorder.
Preparations: 25, 50, 75 mg capsules.
Dosage:
Initial dosage: 25 mg qhs, then increase over 1-4
week period.
Average dose: 150-250 mg/day
Dosage Range: 50-250 mg/day
Panic disorder: 25-150 mg qhs
Half-life: 20-50 hr.
Therapeutic Level: 150-300 ng/mL
Clinical Guidelines: FDA approved for the treatment of
OCD. OCD symptoms may require a longer duration of
treatment (2-3 months) to achieve efficacy. Clomipramine
may be especially useful in depressed patients with
strong obsessional features. The side-effect profile
(sedation and anticholinergic effects) often prevents
patients from achieving an adequate dosage.
Clomipramine has a higher risk of seizures than other
TCAs.
Imipramine (Tofranil)
Indications: Depressive disorders, anxiety disorders,
enuresis, chronic pain.
Preparations: 10, 25, 50 mg tablets; 75, 100, 125, 150
mg capsules; 25 mg/2 mL solution for IM injection.
Dosage:
Initial dosage: 25 mg qhs, then increase over 1-4
week period
Average dosage: 150-250 mg/day
Dosage range: 50-300 mg/day
Elderly: 25-75 mg qhs (max 200 mg/day)
Half-Life: 5-25 hr.
Therapeutic Levels: 150-300 ng/mL (imipramine and
desipramine)
Clinical Guidelines: Imipramine has well-documented
effectiveness in the treatment of panic disorder.
Imipramine is effective in the treatment of enuresis in
children. The dosage for enuresis is usually 50-100 mg
per day.
Trimipramine (Surmontil)
Indications: Depressive disorders, anxiety disorders.
Preparations: 25, 50, 100 mg capsules
Dosage:
Initial dosage: 25 mg qhs, then increase over 1-4
week period.
Average dosage: 150-200 mg/day
Dosage Range: 50-300 mg/day
Elderly: 25-50 mg qhs (max 200 mg/day)
Therapeutic Levels: Unknown
Clinical Guidelines: Trimipramine has no significant
advantages over other TCAs.
Desipramine (Norpramin)
Indications: Depressive disorders, anxiety disorders, and
chronic pain.
Preparations: 10, 25, 50, 75, 100, 150 mg tablets; 25, 50
mg capsules.
Dosage:
Initial dosage: 25 mg qhs, then increase over 1-4
week period
Average dosage: 150-250 mg/day
Dosage range: 50-300 mg/day
Elderly: 25-100 mg/day (max 200 mg/day)
Half-Life: 12-24 hr.
Therapeutic Levels: 125-300 ng/mL
Clinical Guidelines: Desipramine is one of the least
sedating and least anticholinergic TCAs. It should be
considered a first-line heterocyclic agents in elderly
patients. Some patients may require AM dosing due to
mild CNS activation.
Protriptyline (Vivactil)
Indications: Depressive disorders.
Preparations: 5, 10 mg tablets.
Dosage:
Initial dosage: 5 mg qAM, then increase over several
days to weeks.
Average dosage: 15-40 mg/day
Dosage range: 10-60 mg/day
Elderly: 5 mg tid (max 40 mg/day)
Half-Life: 50-200 hr.
Therapeutic Levels: 75-200 ng/mL
Clinical Guidelines: Protriptyline is the least sedating
and most activating TCA. Avoid giving near bedtime
because it can cause insomnia. It has no advantage over
other TCAs and is not commonly used.
Amoxapine (Asendin)
Indications: Depressive disorders, especially major
depression with psychotic features.
Preparations: 25, 50, 100, 150 mg tablets.
Dosage:
Initial dosage: 25-50 mg qhs, then increase gradually
over 1-4 week period.
Average dosage: 200-250 mg/day.
Dosage range: 50-300 mg/day.
Elderly: Start with 25 mg qhs; increase to 50 mg bid-tid
(maximum 300 mg/day).
Half-Life: 8 hr.
Therapeutic Levels: 100-250 ng/mL
Clinical Guidelines: Amoxapine is related to the
antipsychotic loxapine. Blockade of dopamine receptors
may produce extrapyramidal symptoms (EPS) due to
dopamine antagonism of its metabolite loxapine (eg,
dystonia, akathisia, Parkinsonian symptoms). Dopamine
receptor blockade can lead to hyperprolactinemia with
subsequent gynecomastia, galactorrhea, or amenorrhea.
Amoxapine is associated with higher rates of seizure,
arrhythmia, and fatality in overdose than many other
antidepressants. The antipsychotic properties of loxapine
may be useful in the treatment of major depression with
psychotic features. It has added risks of dopamine
antagonist side effects such as tardive dyskinesia.
Maprotiline (Ludiomil)
Indications: Depressive disorders.
Preparations: 25, 50, 75 mg tablets.
Dosage:
Initial dosage: 75 mg qhs for 2 weeks, then increase
in 25 mg increments over the next few weeks.
Average dosage: 100-150 mg/day .
Dosage range: 50-200 mg/day.
Elderly: Start with 25 mg qhs. Increase to 50-75 qhs
(max 100 mg/day).
Half-Life: 21-25 hr.
Therapeutic Levels: 150-300 ng/mL
Clinical Guidelines: Maprotiline is associated with higher
rates of seizure, arrhythmia, and fatality in overdose than
many other antidepressants. Avoid medications that lower
seizure threshold, and avoid use in patients with risk of
alcohol or sedative/hypnotic withdrawal syndrome. Do not
use in patients with a history of seizures. The long half-life
may necessitate a longer period of observation after
overdose. Maprotiline is rarely used.
Mirtazapine (Remeron)
Indications: Depressive disorders.
Mechanism: Selective alpha-2 adrenergic antagonist that
e n h a n ce s n o r a d r e n e r g i c a n d se rotonergic
neurotransmission.
Preparations: 15 and 30 mg scored tablets.
Soltabs: Orally disintegrating tablets (15,
30 and 45 mg).
Dosage:
Initial Dosage: Begin with 15 mg qhs and increase to
30 mg after several days to a maximum of 45 mg qhs.
Elderly: Begin with 7.5 mg qhs and increase by 7.5
mg each week to an average of 30 mg qhs.
Half-life: 20-40 hr.
Therapeutic levels: Not established.
Clinical Guidelines: Mirtazapine has little effect on
sexual function. It may have some efficacy in anxiety
disorders, and its antagonism of 5-HT3 receptors may
help in patients with stomach upset. It has little effect on
drugs metabolized by cytochrome P450 enzymes.
Sedation is the most common side effect and may be
marked initially, but usually decreases over the first week
of treatment. Increase in appetite is frequent with an
average weight gain of 2.0 kg after six weeks of
treatment. Dry mouth, constipation, fatigue, dizziness,
and orthostatic hypertension may occur. Agranulocytosis
has occurred in two patients, and neutropenia has
occurred in one patient during clinical trials with 2,800
patients. If a patient develops signs of an infection along
with a low WBC, mirtazapine should be discontinued.
Drug Interactions: Mirtazapine has a low liability for drug
interactions.
I. Indications
A. Monoamine oxidase inhibitors(MAOIs) are used in
the treatment of depressive and anxiety disorders.
MAOIs are particularly useful in the treatment of
major depression with atypical features, such as
mood reactivity, increased appetite, hypersomnia,
and sensitivity to interpersonal rejection.
B. These agents also have significant efficacy in
anxiety disorders such as social phobia and panic
disorder with agoraphobia and obsessive-
compulsive disorder.
C. Given the dietary restrictions and risk of
hypertensive crisis, most clinicians use MAOIs only
after more conventional treatments have failed.
II. Pharmacology
A. Monoamine oxidase inhibitors irreversibly inhibit the
enzyme, monoamine oxidase, located in the central
nervous system, gut and platelets, leading to lack of
degradation of monoamines.
B. The human body requires two weeks after
discontinuing an MAOI to replenish the body with
normal amounts of the monoamine oxidase enzyme.
C. MAOIs inhibit monamine oxidase in the gut wall
which leads to increased absorption of tyramine.
Tyramine can act as a false neurotransmitter and
elevate blood pressure.
III.Clinical Guidelines
A. Dietary Restrictions: These agents require
patients to adhere to a low tyramine diet in order to
avoid a hypertensive crisis.
B. Dose Titration: In order to minimize side effects,
these agents must be started at a low dose and
titrated upward over days to weeks. This is a major
disadvantage compared to SSRIs.
C. Response Time: These agents require at least 3-4
weeks for an adequate therapeutic trial and patients
may respond after 6-8 weeks.
D. Efficacy: May be slightly more effective than other
antidepressant treatments, especially with atypical
depression.
E. Clinical Utility: Given the side-effect profile and
dietary restrictions, these agents are generally
reserved for use in patients who are refractory to
other antidepressant treatments.
IV. Adverse Drug Reactions
A. Alpha-1 Blockade: Alpha-1 adrenergic blockade
can lead to marked orthostatic hypotension. This is
actually the most common side effect despite the
fact that more clinical attention is focused on
hypertensive crisis. This can be treated with salt
supplements, support hose, or the
mineralocorticoid, fludrocortisone. Dizziness and
reflex tachycardia may also occur.
B. Histaminic Blockade: Antihistaminic properties can
lead to sedation and significant weight gain.
C. Hypertensive Crisis: Hypertensive crisis from
consuming tyramine containing foods is
characterized by markedly elevated blood pressure,
headache, sweating, nausea and vomiting,
photophobia, autonomic instability, chest pain,
cardiac arrhythmias, and even coma and death.
D. Treatment of Hypertensive Crisis: Treatment
involves the use of nifedipine, 10 mg sublingual,
while carefully monitoring blood pressure to make
sure it does not drop too far. Alternatively,
chlorpromazine, 50 mg orally, may be given. These
agents can be given to patients to keep with them if
they develop symptoms; however, they must be
careful not to take these agents when they may be
experiencing symptoms of hypotension. If patients
present to the emergency room, they can be given
phentolamine, 5 mg IV, followed by 0.25-0.5 mg IM
every 4 to six hours as indicated.
E. MAOI Diet: Foods to be avoided: Soy sauce,
sauerkraut, aged chicken or beef liver, aged
cheese, fava beans, air-dried sausage or other
meats, pickled or cured meat or fish, overripe fruit,
canned figs, raisins, avocados, yogurt, sour cream,
meat tenderizer, yeast extracts, caviar, and shrimp
paste. Beer and wine are generally contraindicated;
however, recent studies indicate that they contain
very little tyramine.
F. Pyridoxine Deficiency: Pyridoxine deficiency,
manifesting with paraesthesias, may occur and can
be treated with vitamin B6, 50 mg per day.
G. Overdose: Overdose can be fatal and acidification
of the urine or dialysis may be helpful along with
other supportive treatment. Death may occur from
arrhythmias, seizures or renal failure.
H. Surgery: Discontinue MAOIs 14 days before
surgery to prevent hypertensive crisis from
anesthetics.
I. Mania: MAOIs can induce mania or rapid cycling in
patients with bipolar disorder.
J. Comorbid Medical Illness: Use with caution in
patients with liver disease, abnormal liver function
tests, cardiovascular disease, migraine headaches,
renal disease, hyperthyroidism, or Parkinson’s
disease.
K. Pregnancy: Avoid use of MAOIs in pregnancy
secondary to teratogenic potential.
L. Miscellaneous: Other side effects include, liver
toxicity, agitation, dry mouth, constipation, seizures,
sexual dysfunction, insomnia, and edema.
V. Drug Interactions
A. Serotonergic Syndrome: A serotonergic syndrome
characterized by nausea, confusion, hyperthermia,
autonomic instability, tremor, myoclonus, rigidity,
seizures, coma and death, can occur when MAOIs
are combined with SSRIs, TCAs, or carbamazepine.
Wait fourteen days after discontinuing a MAOI
before starting a TCA or SSRI. Discontinue
sertraline, fluvoxamine and paroxetine for 14 days
before beginning an MAOI and wait 5-6 weeks after
discontinuing fluoxetine due to the long half-life of
norfluoxetine.
B. Opioids: Opiate analgesics, especially meperidine,
may lead to autonomic instability, delirium and
death.
C. Sympathomimetics: Sympathomimetic agents
such as amphetamines, cocaine, ephedrine,
epinephrine, norepinephrine, dopamine, isoproter-
e n o l , m e t h yl p h e n i d a t e , o xym e t a z o l i n e ,
phenylephrine, phenylpropanolamine metaraminol
can lead to a hypertensive crisis.
D. Antihypertensives: Antihypertensive agents can
further increase the likelihood of hypotension.
E. Oral Hypoglycemics: MAOIs can potentiate
decreases in blood glucose when combined with
oral hypoglycemics.
Phenelzine (Nardil)
Indications: Effective for atypical depression. Also used
for anxiety disorders such as panic disorder with
agoraphobia, social phobia, and obsessive-compulsive
disorder.
Preparations: 15 mg tablets.
Dosage:
Initial dosage: 15 mg bid; increase by 15 mg/day each
week.
Average dosage: 30-60 mg/day.
Dosage range: 15-90 mg/day.
Elderly: Start with 7.5-15 mg/day; max 60 mg/day.
Therapeutic Levels: Not established.
Clinical Guidelines: Major morbidity and mortality risks
are associated with MAOI use. Phenelzine is associated
with a higher incidence of weight gain, drowsiness, dry
mouth, and sexual dysfunction than tranylcypromine.
Tranylcypromine (Parnate)
Indications: Approved for atypical depression. Also used
for anxiety disorders, such as panic disorder with
agoraphobia, social phobia, and obsessive-compulsive
disorder.
Preparations: 10 mg tablets
Dosage:
Initial dosage: 10 mg bid. Increase by 10 mg/day each
week.
Average dosage: 20-40 mg/day.
Dosage range: 10-60 mg/day.
Elderly: Start with 5-10 mg/day; max 30-40 mg/day.
Therapeutic Levels: Not established.
Clinical Guidelines: Major morbidity and mortality risks
are associated with MAO-I use. Phenelzine is associated
with higher incidences of weight gain, drowsiness, dry
mouth, and sexual dysfunction than tranylcypromine.
Tranylcypromine is more likely to cause insomnia than
phenelzine.
Aripiprazole (Abilify)
Class: Quinolinone
Mechanism: Aripiprazole is a new partial agonist at the
dopamine D2 and the serotonin 5-HT1A receptors, and it is
an antagonist of the serotonin 5-HT2A receptor.
Indications: Aripiprazole is indicated for psychotic
disorders that are refractory to treatment with typical
antipsychotics. They are indicated for patients with tardive
dyskinesia or severe side effects associated with other
neuroleptics.
Preparations: 10 mg, 15 mg, 20 mg, and 30 mg tablets;
no IM preparation is available.
Dosage:
Initial Dosage: 10-15 mg qAM and increased to 20
to 30 mg per day after 2-4 weeks if needed;
however, clinical trials have not found greater
efficacy for doses above 10-15 mg.
Maintenance: 10-30 mg per day.
Elderly: While aripiprazole clearance is reduced by
20% in patients over 65, no dosage adjustment is
required or recommended at this time. Begin with a
lower dosage in debilitated elderly patients.
Metabolism: Half-life is 75 hours for aripiprazole and 94
hours for its active metabolite, dehydro-aripiprazole.
Hepatic metabolism is mainly through CYP2D6 and
CYP3A4. Poor metabolizers who lack CYP2D6, have an
80% increase in aripiprazole plasma levels and a 30%
decrease in dehyro-aripiprazole levels compared to
normal.
Therapeutic Level: Not established.
Side-Effect Profile: The most common side effect is
nausea, with occasional vomiting, which usually resolves
within one week. The incidence of sedation is low, but can
occur especially at higher dosages. Anxiety and insomnia
may occur, especially early in treatment. Orthostatic
hypotension occurs rarely. The incidence of
extrapyramidal symptoms is comparable to placebo.
Aripiprazole does not appear to effect QTC intervals.
Clinical Guidelines: Aripiprazole should be given in the
morning due to lack of sedation compared to other
agents. It is recommended that aripiprazole can be added
to a current antipsychotic medication regimen with
tapering of the other antipsychotic gradually over time.
Early data seems to indicate a low liability for weight gain,
or changes in glucose or lipid levels. Aripiprazole does
not elevate serum prolactin.
Drug Interactions:
A. Coadminisration of aripiprazole with potent
inhibitors of CYP2D6, such as quinidine, fluoxetine
or paroxetine, can markedly increase blood levels
(112% with quinidine) and requires dosage
adjustment to one-half of its normal dosage.
B. Ketoconazole or other potent inhibitors of CYP3A4
require adjusting aripiprazole to one-half of its
normal dosage.
C. Carbamazepine, a CYP 3A4 inducer, can lower
plasma aripiprazole levels and the dose of
aripiprazole should be doubled when
coadministered.
D. Aripiprazole does not appear to effect levels of
other cytochrome P450 substrates metabolized by
CYP2D6,CYP2C9, CYP2C19, or CYP3A4.
Clozapine (Clozaril)
Class: Dibenzodiazepine
Mechanism: Multiple receptor antagonism: serotonin
5HT2A receptor, dopamine D1, D2, and D4 receptors.
Indications: Psychotic disorders which are refractory to
treatment with typical antipsychotics. They are indicated
for patients with tardive dyskinesia or severe side effects
associated with other neuroleptics.
Preparations: 25, 100 mg scored tablets; no IM
preparation available
Dosage:
Initial Dosage: 25 mg bid, then increase by 25-50
mg every 2-3 days to achieve total daily dose of
between 300-600 mg. Dose may need to be given tid
if side effects occur.
Maintenance: 400-600 mg/day; some patients may
require higher doses but rarely more than 900
mg/day.
Metabolism: Half-life 11 hours, hepatic metabolism,
CYP1A2.
Therapeutic Level: >350 ng/mL.
Side-Effect Profile: Orthostatic hypotension (high),
sedation (high), anticholinergic (high), extrapyramidal
symptoms (absent). Most common: sedation, dizziness,
hypotension, tachycardia, constipation, hyperthermia,
hypersalivation. Hypersalivation can be treated with
anticholinergic agents.
Clinical Guidelines: Clozapine does not cause tardive
dyskinesia or neuroleptic malignant syndrome. Clozapine
is often effective against symptoms that are resistant to
typical agents. It is more effective than typical agents in
treatment of the negative symptoms of schizophrenia.
Clozapine may decrease the risk of suicide in
schizophrenia and an FDA advisory panel has
recommended expanding the indications for clozapine to
include suicide prevention.
Drug Interactions:
A. Cimetidine (Tagamet) may increase clozapine
levels. Use ranitidine (Zantac) instead.
B. Fluvoxamine can double clozapine levels
C. TCAs can increase risk for seizures, cardiac
changes, sedation
Contraindications: Clozapine is contraindicated in
patients with granulocytopenia or a history of
agranulocytosis induced by clozapine. Do not use
clozapine with drugs that suppress bone marrow or have
a risk of agranulocytosis (eg, carbamazepine,
sulfonamides, captopril).
Adverse Effects:
A. Clozapine has a 1-2% incidence of agranulocytosis.
Patients should be instructed to report the onset of
fever, sore throat, weakness or other signs of
infection promptly. Discontinue the drug if the WBC
drops below 3,000/mcL, or 50% of patient's normal
count, or if granulocyte count drops below
1,500/mcL. Once the WBC normalizes, the patient
may be rechallenged. WBC should be monitored
weekly for the first 3 months of treatment.
Thereafter, monitoring can be reduced to every 2
weeks.
B. A 5% incidence of seizure has been noted in
patients taking more than 600 mg/day of clozapine.
If seizures develop, discontinue drug use and
consider restarting with concurrent use of
divalproex sodium (Depakote).
C. Rare myocarditis(5-100 cases/100,000 patient
years) has been seen especially during, but not
limited to the first month of clozapine treatment.
Consider myocarditis if patients present with
unexplained fatigue, dyspnea, tachypnea, fever,
chest pain, palpitations, other signs of heart failure,
or ECG changes such as ST-T wave abnormalities
or arrhythmias.
D. Use clozapine with caution and at low doses in
patients with hepatic or renal disease.
E. Monitor patients for hypotension and tachycardia.
When discontinuing clozapine, the dosage should
be tapered over two weeks because anticholinergic
rebound may occur.
Risperidone (Risperdal)
Class: Benzisoxazole.
Mechanism: Antagonist of serotonin-2A, dopamine-2 and
alpha-1 receptors.
Preparations: 0.25, 0.5, 1, 2, 3, 4 mg tablets (1 mg tablet
is scored); 1 mg/mL oral soln; the long-acting IM
preparation (Consta) is likely to be approved in 2003.
Dosage:
Initial Dosage: 1 mg bid, then increase by 1 mg every
2-3 days to 2-3 mg bid.
Acute agitation: No acute IM dose available.
Maintenance: 2-8 mg bid, many patients can be
treated with 4 mg given as a single dose.
Long-acting IM formulation (Consta)(FDA approval
pending):
25 - 50 mg IM every month (no evidence to increase
beyond 50 mg).
Elderly: reduced dosage (1-4 mg/day).
Metabolism: Half-life is 3-20 hours. Hepatic metabolism
to an active metabolite. Renal clearance. No risperidone-
specific drug interactions.
Therapeutic Level: Not established.
Side-Effect Profile: Orthostatic hypotension and reflex
tachycardia (alpha 1 receptor mediated, minimized with
slow upward titration), insomnia, and agitation are the
most frequent. Incidence of extrapyramidal symptoms is
very low. Risperidone can cause weight gain and increase
prolactin levels (usually not clinically significant). May
prolong QT interval.
Clinical Guidelines: Risperidone is generally very well
tolerated. A low incidence of extrapyramidal symptoms is
associated with doses less than 6 mg. Risperidone may
be given in once-a-day dose schedules. There is
increasing experience with successful use of risperidone
in elderly populations. There have been a number of
case reports of neuroleptic malignant syndrome.
Quetiapine (Seroquel)
Class: Dibenzothiazepine.
Mechanism: Quetiapine (Seroquel) is an antagonist at
the serotonin-2A, dopamine-2, alpha-1 and 2, and
histamine-1 receptors.
Preparations: 25 mg, 100 mg, and 200 mg tablets.
Dosage:
Initial dosage: 25-50 mg bid, increased by 25-50 mg
every 1 to 3 days to a total daily dose of 400-600 mg.
Maintenance: Required daily dose can range
between 150-750 mg.
Elderly: Clearance is reduced by 40% in elderly;
dosage should be reduced in this population.
Therapeutic Level: Not established.
Metabolism: Half-life is 6 hours, hepatic metabolism
(P450 3A4), no active metabolites. Low potential for drug
interactions.
Side-Effect Profile: Orthostatic hypotension may occur
during initial dose titration due to alpha-blockade.
Somnolence and weight gain may occur due to H1
blockade. Dyspepsia, abdominal pain, and dry mouth may
also occur. There are reports of new onset diabetes or
diabetic ketoacidosis.
Clinical Guidelines:May be effective for primary negative
symptoms of schizophrenia. Minimal weight gain. Well
tolerated. No anticholinergic side effects. Very low
incidence of EPS. No sustained elevation of prolactin.
Requires bid or tid dosing.
Ziprasidone (Geodon)
Class: Benzisothiazolyl piperazine.
Indications: Psychotic disorders.
Mechanism: D2, D3, 5HT2A, 5HT1A antagonism; also
blocks reuptake of monoamines.
Preparations: 40 mg capsules, IM formulation: 20 mg/ml
dose vial.
Maintenance Dosage: Target dose is between 40-80 mg
bid;
IM Preparation: 10 mg IM every 2 hours or 20 mg IM
every 4 hours to maximum daily dose of 40 mg.
Therapeutic Level: Not established.
Metabolism: Inactive metabolites, half-life 4 hours. Low
potential for drug interactions.
Side-Effect Profile: Dizziness, nausea, and postural
hypotension are the most common side effects. Prolactin
elevation can occur. Sedation is more common with the
IM preparation.
Advantages/ Disadvantages: Very low incidence of
extrapyramidal symptoms. Minimal incidence of
cardiovascular problems. Prolactin elevation is minimal.
The incidence of weight gain, lipid abnormalities, and
glucose intolerance appears to be lower than other
atypical antipsychotics. Ziprasidone can increase QT
interval. While there are no reports linking this to cardiac
arrhythmias, caution should be exercised in patients with
pre-existing increased QT interval (from medications or
cardiac disease). These patients should have a baseline
ECG. QT prolongation has not been observed with the IM
formulation.
Fluphenazine (Prolixin)
Class: Piperazine
Indications: Psychotic disorders.
Preparations: 1, 2.5, 5, 10 mg tablets; 2.5, 5 mg/mL oral
solution; 2.5 mg/mL parenteral solution (IM); 25 mg/mL
decanoate (IM).
Dosage:
Initial: 2.5-10 mg/day, may be titrated to 40 mg/day.
Maintenance: 10-20 mg/day.
Acute agitation: 2.5-5 mg IM, should not exceed daily
dose of 10 mg IM
Elderly: 0.5-2mg bid/tid.
Chronic noncompliance: Switch to decanoate
formulation. Give 12.5 mg IM of decanoate every two
weeks for every 10 mg of oral dose.
Potency: (equivalent to 100 mg chlorpromazine): 2 mg.
Metabolism: Hepatic metabolism, half-life 10-20 hours.
The decanoate formulation has a typical duration of action
of 2 weeks.
Therapeutic Level: Not established.
Clinical Guidelines: Fluphenazine is a weak antiemetic.
Decanoate formulation available.
Haloperidol (Haldol)
Class: Butyrophenone
Indications: Psychotic disorders, Tourette’s Syndrome.
Preparations:
Haloperidol tablets: 0.5, 1, 2, 5, 10, 20 mg.
Haloperidol lactate: 2 mg/mL conc. (PO), 5 mg/mL soln.
(IM).
Haloperidol decanoate: 50, 100 mg/mL (IM - depot).
Dosage:
Initial: 5-10 mg/day.
Maintenance: 5-20 mg/day.
Acute agitation: 5.0 - 10 mg IM. Should not exceed
daily dose of 20 mg IM.
Elderly: 0.5-2 mg bid/tid.
Chronic noncompliance: Switch to haloperidol
decanoate at 10-20 times the daily dose, given on
monthly basis. Maximum initial dose of 100 mg/day
IM. Give balance of dose 4-5 days later if necessary.
Do not give more than 3 mL per injection site.
Tourette’s disorder in children: 0.05- 0.1 mg/kg in
2 or 3 divided doses
Potency: (equivalent to 100 mg chlorpromazine): 2 mg
Metabolism: Hepatic metabolism to active metabolite.
Half-life 10–20 hours. Duration of action of decanoate is
approximately 4 weeks.
Therapeutic Level: 5-20 ng/mL..
Major Safety Concerns: High incidence of
extrapyramidal symptoms. May possibly lower seizure
threshold in patients with a history of seizures.
Pimozide (Orap)
Class: Diphenylbutylpiperdines.
Indications: Psychotic disorders, Tourette's Syndrome.
Preparations: 2.0 mg tablets.
Dosage:
Tourette's: 0.5-1 mg bid, then increase dose every
other day as needed (max 0.2 mg/kg/day or 10 mg).
Antipsychotic maintenance: 1-10 mg/day.
Potency: (equivalent to 100 mg chlorpromazine): 1 mg.
Metabolism: Hepatic metabolism. Half-life 55 hours.
Therapeutic Level: Not established.
Contraindications: Pimozide is contraindicated in
patients with a history of cardiac arrhythmia or with drugs
that prolong QT interval.
Major Safety Concerns: Pimozide may cause ECG
changes, including prolongation of QT interval, T-wave
inversion, and appearance of U waves and alter effects of
antiarrhythmic agents.
Cardiac side effects of pimozide make haloperidol safer
first-line treatment for Tourette's Syndrome. Use caution
in patients with a history of hypokalemia.
Thiothixene (Navane)
Class: Thioxanthene.
Indications: Psychotic disorders.
Preparations: Capsules: 1, 2, 5, 10, 20 mg.
Thiothixene hydrochloride: 5 mg/mL oral solution; 5
mg/mL parenteral (IM).
Dosage:
Initial dosage: 2-5 mg bid-tid. Titrate to 20-40 mg/day
(max 60 mg/day).
Maintenance: 5-20 mg/day.
Acute agitation: 5 mg IM 4 hour prn.
Elderly: 1-15 mg/day.
Potency (equivalent to 100 mg chlorpromazine): 5 mg.
Metabolism: Hepatic metabolism. Half-life 10 – 20 hours.
Therapeutic Level: Not established. Some suggest 2-57
ng/mL.
Major Safety Concerns: May produce ocular pigmentary
changes. Periodic ophthalmological examination is
recommended.
Trifluoperazine (Stelazine)
Class: Piperazine.
Preparations: 1, 2, 5, 10 mg tablets; 10 mg/mL oral
solution, 2 mg/mL soln. (IM).
Dosage:
Initial: 2-5 mg bid-tid. Titrate to 20-40 mg/day (max 60
mg/day).
Maintenance: 5-20 mg/day.
Acute agitation: 5 mg IM q 4 hour prn (max of 20
mg/day). Do not repeat dosage in less than 4 hrs.
Elderly: 1-15 mg/day.
Potency (equivalent to 100 mg chlorpromazine): 5 mg.
Metabolism: Hepatic metabolism. Half-life 10–20 hours.
Therapeutic Level: Not established.
Clinical Guidelines: Associated with few ECG changes.
Loxapine (Loxitane)
Class: Dibenzoxapine.
Preparations: 5, 10, 25, 50 mg capsules; 25 mg/mL oral
solution: 50 mg/mL parenteral solution (IM).
Dosage:
Initial dosage: 10 mg bid. Titrate as needed to max
of 250 mg/day in divided doses.
Maintenance: 50-100 mg/day.
Acute agitation: 12.5-50 mg IM q4-6h prn.
Elderly: 5-25 mg/day.
Potency (equivalent to 100 mg chlorpromazine): 12.5 mg.
Metabolism: Hepatic metabolism to active metabolite.
Half-life 5-15 hours.
Therapeutic Level: Not established.
Clinical Guidelines: Loxapine may be associated with a
higher risk of seizure than other high- and mid-potency
agents. Concurrent use with medications that lower the
seizure threshold should be avoided.
Molindone (Moban)
Class: Dihydroindolones
Preparations: 5, 10, 25, 100 mg tablets; 20 mg/mL conc.
(PO)
Dosage:
Initial: 15-20 mg tid. Titrate to 10-40 mg tid-qid (max
225 mg/day)
Maintenance: 50-100 mg/day
Potency (equivalent to 100 mg chlorpromazine): 10 mg
Metabolism: Hepatic metabolism, half-life 10–20 hours.
Therapeutic Level: Not established
Clinical Guidelines: Studies suggest molindone is
associated with less weight gain, amenorrhea, and
impotence than other typical antipsychotics. Molindone
appears less likely to cause seizures than other
antipsychotics.
Perphenazine (Trilafon)
Class: Piperazine.
Preparations: 2, 4, 8, 16 mg tablets; 16 mg/5 mL oral
solution; 5 mg/mL parenteral solution (IM).
Dosage:
Initial: 4-8 mg tid, titrate to 8-16 mg bid-tid (max 64
mg/day).
Maintenance: 4-40 mg/day.
Acute agitation: 5-10 mg IM q 6h. prn (max 30
mg/day).
Potency (equivalent to 100 mg chlorpromazine): 10 mg.
Metabolism: Hepatic metabolism, half-life 10-20 hours.
Therapeutic Level: Not established.
Clinical Guidelines: Perphenazine has antiemetic
properties.
Chlorpromazine (Thorazine)
Class: Aliphatic Phenothiazine.
Preparations:
Tablets: 10, 25, 50, 100, 200 mg; Slow-release capsules:
30, 75, 100, 200, 300 mg. Oral liquid preparations: 30
mg/mL and 100 mg/mL conc; 10 mg/5 mL syrup.
Parenteral injection: 25 mg/mL (IM). Suppositories: 25,
100 mg (PR).
Dosage:
Initial: 10-50 mg PO bid-qid, titrate to 200-800 mg/day
in divided doses (max 2000 mg/day).
Acute agitation: 25-50 mg IM q 4-6h.
Maintenance: 200-800 mg/day.
Elderly: Not recommended due to orthostatic
hypotension.
Potency (equivalent to 100 mg chlorpromazine): 100 mg.
Metabolism: Hepatic metabolism to many metabolites.
Therapeutic Level: Not useful due to many active
metabolites.
Major Safety Concerns:
Higher risk than most other typical antipsychotics for
seizure, jaundice, photosensitivity, skin discoloration
(bluish), and granular deposits in lens and cornea.
Prolongation of QT and PR intervals, blunting of T-waves,
ST segment depression can occur. Associated with a high
incidence of hypotensive and anticholinergic side effects.
Chlorpromazine has high lethality in overdose. It has a
higher risk than many other antipsychotics for life-
threatening agranulocytosis. Use chlorpromazine with
caution in patients with a history of cardiovascular, liver,
or renal disease. Avoid use in pregnancy (especially in
first trimester).
Clinical Guidelines:
Can be used for treatment of nausea or vomiting (10-25
mg po qid; 25 mg IM qid; 100 mg suppository tid) and
intractable hiccups (25-50 mg qid).
Mesoridazine (Serentil)
Class: Piperidine
Preparations: 10-, 25-, 50-, 100-mg tablets; 25 mg/mL
oral solution; 25 mg/mL parenteral solution (IM).
Dosage:
Initial: 25-50 mg po tid. Titrate to 300 mg/day (max
400 mg/day).
Acute agitation: 25-50 mg IM. Dose may be repeated
q 4-6 hour.
Maintenance: 100-400 mg/day.
Elderly: Avoid because of hypotension risk.
Potency (equivalent to 100 mg chlorpromazine): 50 mg.
Metabolism: Hepatic metabolism to many metabolites.
Half-life 24-48 hours.
Therapeutic Level: Not established.
Major Safety Concerns: Because of its association with
QT prolongation and subsequent increased risk for fatal
arrhythmias, mesoridazine is reserved for only those
patients who have not responded to other antipsychotic
agents.
Thioridazine (Mellaril)
Class: Piperidine
Preparations: 10, 15, 25, 50, 100, 150, 200 mg tablets;
5 mg/mL, 30 mg/mL and 100 mg/mL oral solution.
Dosage:
Initial dosage: 25-100 mg tid; titrate to 100-400 mg
bid (max 800 mg/day)
Maintenance: 200-800 mg/day; never exceed 800
mg/day No IM form available.
Elderly: avoid because of hypotension risk.
Potency (equivalent to 100 mg chlorpromazine): 100 mg.
Metabolism: Hepatic metabolism to active metabolites
including mesoridazine, half-life 10-20 hours.
Therapeutic Level: Not established.
Major Safety Concerns: Because of its association with
significant QT prolongation and subsequent increased
risk for fatal arrhythmias, thioridazine is reserved for only
those patients who have not responded to other
antipsychotic agents. Permanent pigmentation of retina
and potential blindness occurs with doses above 800
mg/day. Life-threatening agranulocytosis rarely occurs.
Retrograde ejaculation occurs more frequently with
thioridazine.
Anxiolytics
Benzodiazepines
I. Indications
A. Benzodiazepines are used for the treatment of
specific anxiety disorders, such as Panic Disorder,
Social Phobia, Generalized Anxiety Disorder, and
Adjustment Disorder with Anxious Mood (anxiety due
to a specific stressful life event). All anxiolytic
benzodiazepines can cause sedation.
II. Pharmacology
A. Benzodiazepines bind to benzodiazepine receptor
sites, which are part of the GABA receptor.
Benzodiazepine binding facilitates the action of
GABA at the GABA receptor complex, which
surrounds a chloride ion channel. GABA binding
causes chloride influx into the neuron, with
subsequent neuroinhibition.
B. The benzodiazepines differ in their absorption rates,
lipid solubility, metabolism and half-lives. These
factors will affect onset of action, length of action,
drug interactions and side-effect profile.
C. The long half-life of diazepam, chlordiazepoxide,
clorazepate, halazepam and prazepam (>100 hrs) is
due to the active metabolite desmethyldiazepam.
D. Most benzodiazepines are metabolized via the
microsomal cytochrome P450 system in the liver.
Hepatic metabolism involves discreet families of
isozymes within the cytochrome system and most
benzodiazepines are metabolized by the 3A3/4
isoenzyme family. Notable exceptions to this are
lorazepam, oxazepam, temazepam and
clonazepam.
III. Clinical Guidelines
A. Non-psychiatric causes of anxiety, including medical
disorders, medications and substances of abuse
should be excluded before beginning
benzodiazepine treatment.
B. Choosing a benzodiazepine should be based on the
patient’s past response to medication, family history
of medication response, medical conditions, current
medications (drug interactions), and whether or not
to choose a long half-life or short half-life drug. Long
half-life drugs can be given less frequently, and they
have less serum fluctuation and less severe
withdrawal. These agents have a higher potential for
drug accumulation and daytime sedation.
C. The initial dosage should be low and titrated up as
necessary, especially when using long half-life
drugs, since these may accumulate with multiple
dosing over several days. The therapeutic dose for
benzodiazepines is far below the lethal dose. Long-
term use of benzodiazepines is associated with
tolerance and dependence. Continued use of
benzodiazepines for more than 3 weeks is
associated with tolerance, dependence and a
withdrawal syndrome.
1. Tolerance develops most readily to the sedative
side effect of benzodiazepines.
2. Cross-tolerance may develop between
benzodiazepines and other sedative hypnotic
drugs, including alcohol.
3. Withdrawal symptoms include heightened
anxiety, tremor, shakiness, muscle twitching,
sweating, insomnia, tachycardia, hypertension
with postural hypotension, and seizures.
D. Avoidance of an abstinence syndrome requires
gradual tapering upon discontinuation. One-fourth of
the dose per week is a good general guideline.
IV. Adverse Drug Reactions
A. Side Effects: The most common side effect is
sedation. Dizziness, ataxia and impaired fine motor
coordination can also occur. Some patients
complain of cognitive impairment.
B. Anterograde amnesia has been reported, especially
with benzodiazepines that reach peak levels quickly.
C. Respiratory depression is rarely an issue even in
patients who overdose on benzodiazepines alone.
However, patients who overdose with
benzodiazepines and other sedative-hypnotics
(commonly alcohol) may experience respiratory
depression. Patients with compromised pulmonary
function are more sensitive to this effect and even
therapeutic doses may cause respiratory
impairment.
D. Diazepam (Valium) and chlordiazepoxide (Librium)
should not be used in patients with hepatic
dysfunction because their metabolism will be
impaired and toxicity risk increases.
E. Clonazepam should be avoided in patients with
renal dysfunction because its metabolism will be
impaired and the risk of toxicity will be high.
V.Drug Interactions
A. The concomitant use of benzodiazepines and other
CNS depressant agents, including sedative-
hypnotics, will enhance sedation and increase the
risk of respiratory depression. Alcohol use should be
limited.
B. Most benzodiazepines are metabolized via the liver
enzyme CYP3A4; therefore, any other drug also
metabolized via this pathway may increase the level
of the benzodiazepine (except lorazepam,
oxazepam, temazepam and clonazepam). Other
agents that increase benzodiazepine levels include
cimetidine, fluoxetine, ketoconazole, metoprolol,
propranolol, estrogens, alcohol, erythromycin,
disulfiram, valproic acid, nefazodone, and isoniazid.
Benzodiazepine levels may be decreased by
carbamazepine, rifampin (enzyme induction), and
antacids (absorption).
Alprazolam (Xanax)
Indications: Panic Disorder, Social Phobia. Can be used
in Generalized Anxiety Disorder (GAD) and Adjustment
Disorder with Anxious Mood.
Preparations: 0.25, 0.5, 1, 2 mg tablets.
Dosage: 0.25-2 mg tid-qid.
Elderly: reduce dosage.
Half-Life: Up to 12 hrs.
The clinical duration of action is short despite moderate
serum half-life.
Clinical Guidelines: Fast onset provides quick relief of
acute anxiety. Alprazolam has a relatively short duration
of action and multiple dosing throughout the day is
required (some patients require as much as Qid dosing).
It is associated with less sedation but a high incidence of
inter-dose anxiety. Dependence and withdrawal are
serious problems with this drug. Since SSRIs and other
antidepressants are as effective in anxiety disorders,
Alprazolam is no longer a first-line drug for the treatment
of anxiety disorders.
Chlordiazepoxide (Librium,
Libritabs)
Indications: Anxiety and alcohol withdrawal.
Preparations: 5, 10, 25 mg capsules.
Dosage:
Anxiety: 5-25 mg tid-qid.
Alcohol withdrawal: 25-50 mg every 2-4 hours
(maximum 400 mg/day) prn.
Dose range: 10-100 mg/day.
Elderly: Avoid use
Half-Life: >100 hrs.
Clinical Guidelines: This drug will accumulate with
multiple dosing. Because this drug is metabolized by
P450 isoenzymes. Metabolism can be slowed in the
elderly and patients with hepatic impairment. If used for
anxiety, once-a-day dosing may be possible. Slower
onset of action than Valium.
Clonazepam (Klonopin)
Indications: Approved as anticonvulsant. Used in Panic
Disorder, Social Phobia and general anxiety. Useful in
acute treatment of Mania.
Preparations: 0.5, 1, 2 mg tablets.
Dosage:
Anxiety: 0.25-6 mg Qod, in divided dose bid-tid.
Mania: 0.25-10 mg Qod, in divided dose bid-tid.
Elderly: 0.25-1.5 mg Qod.
Half-Life: 20-50 hrs. No active metabolites.
Clinical Guidelines: Rapid onset provides prompt relief.
Clonazepam, with its long half-life, may be substituted for
shorter acting benzodiazepines, such as alprazolam, in
the treatment of benzodiazepine withdrawal and panic
disorder. Its long half-life allows for once-a-day dosing.
Clorazepate (Tranxene)
Indications: Anxiety
Preparations: 3.75, 7.5, 11.25, 15, 22.5 mg tablets; 3.75,
7.5, 15 mg capsules
Pharmacology: Clorazepate is metabolized to
desmethyldiazepam in the GI tract and absorbed in this
active form.
Dosage:
Anxiety: 7.5 mg tid or 15 mg qhs. Increase as needed.
Dose range: 15-60 mg/day (maximum 90 mg/day).
Elderly: Avoid use in the elderly.
Half-Life: >100 hrs.
Clinical Guidelines: This drug will accumulate with
multiple dosing and over time. Because this drug is
metabolized by P450 isoenzymes, metabolism can be
slowed in the elderly and patients with hepatic
impairment. If used for anxiety, once-a-day dosing may be
possible.
Diazepam (Valium)
Indications: Anxiety, alcohol withdrawal.
Preparations: 2, 5, 10 mg tablets; 15 mg capsules
(sustained release); 5 mg/mL solution for IV use. IM
administration not recommended due to erratic
incomplete absorption.
Dosage:
Anxiety: 2-40 mg/day divided bid-tid.
Alcohol withdrawal: 5-10 mg q 2-4 hr prn withdrawal
signs for first 24 hrs, then slow taper. Maximum of 60
mg/day.
Dose range: 2-60 mg/day.
Elderly: Use with caution because metabolism is
significantly delayed.
Half-Life: 100 hrs.
Clinical Guidelines: Diazepam is the most rapidly
absorbed benzodiazepine. Due to its long half-life, it may
accumulate with multiple dosing. Because this drug is
metabolized by P450 isoenzymes, metabolism can be
slowed in the elderly and patients with hepatic
impairment. If used for anxiety, once-a-day dosing may be
possible.
Halazepam (Paxipam)
Indications: Anxiety.
Preparations: 20, 40 mg tablets.
Dosage:
Anxiety: 20-80 mg/day (divided doses).
Dose range: 40-160 mg/day. Use with caution in
elderly.
Half-Life: >100 hrs .
Clinical Guidelines: This medication has no unique
advantages over other benzodiazepines that have long
half-lives and are metabolized by P450 isoenzymes.
Lorazepam (Ativan)
Indications: Anxiety, alcohol withdrawal, and adjunct in
the treatment of acute psychotic agitation.
Preparations: 0.5, 1, 2 mg tablets; 2 mg/mL, 4 mg/mL
soln (IV, IM).
This is the only benzodiazepine available in IM form that
has rapid, complete, predictable absorption.
Dosage:
Anxiety: 0.5-6 mg/day (divided doses).
Alcohol withdrawal: 0.5-2 mg q 2-4 hr prn signs of
alcohol withdrawal; or 0.5-1.0 mg IM to initiate
treatment. Maximum dose of 10 mg/day.
Elderly: Metabolism is not significantly affected by age;
elderly may be more susceptible to side effects.
Half-Life: 15 hrs. No active metabolites
Clinical Guidelines: Metabolism is not P450 dependent
and will only be affected when hepatic dysfunction is
severe. The inactive glucuronide is renally excreted; it is
the benzodiazepine of choice in patients with serious or
multiple medical conditions. It is the only benzodiazepine
available in IM form with rapid and complete absorption.
Its metabolism is not affected by age. These properties
make it ideal for alcohol withdrawal in a patient with liver
dysfunction or who is elderly. Since the half-life is
relatively short, accumulation with multiple dosing usually
does not occur. The IM form is useful in rapid control of
agitation, resulting from psychosis, or drug-induced
agitation. It is also widely used on a PO basis as a prn
adjunct to fixed doses of antipsychotic medication.
Buspirone (BuSpar)
Category: Non-benzodiazepine, non-sedative hypnotic
anxiolytic.
Mechanism: Serotonin 1A agonist.
Indications: Generalized Anxiety Disorder (GAD). May
be used to augment antidepressant treatment of Major
Depressive Disorder and Obsessive- Compulsive
Disorder (OCD). Often useful in the treatment of
aggression and agitation in dementia and in patients with
developmental disabilities.
Preparations: 5, 10, 15 and 30 mg tablets (15 mg and 30
mg tablet is scored so that it can be either bisected or
trisected).
Dosage:
Initial Dosage: 7.5 mg bid, then increase by 5 mg
every 2-3 days as tolerated.
Dose Range: 30-60 mg/day (maximum 60 mg/day).
Elderly: 15-60 mg/day.
Antidepressant Augmentation: 15-60 mg/day if a
patient has a suboptimal response to a 4-6 week trial of
an antidepressant.
Half-Life: 2-11 hours. No active metabolites.
Side Effects: Dizziness, headache, GI distress, fatigue.
Clinical Guidelines: Buspirone lacks the sedation and
dependence associated with benzodiazepines, and it
causes less cognitive impairment than the
benzodiazepines. It is less effective in patients who have
taken benzodiazepines in the past because it lacks the
euphoria and sedation that these patients may expect
with anxiety relief. Unlike benzodiazepines, buspirone
does not immediately relieve anxiety. Onset of action may
take 2 weeks. The patient may be started on a
benzodiazepine and buspirone for two weeks, followed by
slow tapering of the benzodiazepine.
I. Indications. Insomnia.
II. Pharmacology
A. The major difference between the anxiolytic and
hypnotic benzodiazepines is the rate of absorption.
B. Benzodiazepine hypnotics are rapidly absorbed from
the GI tract and achieve peak serum levels quickly,
resulting in rapid onset of sedation.
III. Clinical Guidelines
A. Hypnotics are recommended for short-term use only.
Insomnia treatment should include exercise, stress
reduction, sleep hygiene, and caffeine avoidance.
B. Prolonged use of benzodiazepines (generally
greater than 3 weeks) is associated with tolerance,
dependence and withdrawal syndromes.
C. The choice of benzodiazepine hypnotic is usually
dictated by the need for sleep onset or sleep
maintenance, half-life, and drug interactions.
IV. Adverse Drug Reactions
A. Daytime sedation or morning “hangover” is a major
complaint when patients take hypnotics with long
half-lives. Dizziness and ataxia may occur during the
daytime or if the patient awakens during the night.
Anterograde amnesia has been reported.
B. Benzodiazepines may depress respiration at high
doses. Patients with compromised pulmonary
function are more sensitive to this effect.
V.Drug Interactions
A. Other CNS depressant agents, including the
sedative-hypnotics will enhance the sedative effect
of hypnotic benzodiazepines. Alcohol use should
also be determined.
B. Since triazolam, estazolam, flurazepam and
quazepam are metabolized via the liver enzyme,
CYP3A4, concomitant use of other medications with
similar metabolism will increase the half-life effect
and potential for toxicity.
Flurazepam (Dalmane)
Indications: Insomnia.
Preparations: 15, 30 mg tablets.
Dosage: Insomnia: 15-30 mg qhs, less in elderly.
Half-Life: 100 hrs.
Clinical Guidelines: Fast onset is useful in treatment of
early insomnia. Long duration is useful in treatment of late
insomnia but may result in morning sedation. Shorter half-
life medications are preferable to flurazepam.
Estazolam (ProSom)
Indications: Insomnia.
Preparations: 1, 2 mg tablets.
Dosage:
Insomnia: 1-2 mg qhs
Elderly: 0.5-1.0 mg qhs.
Half-Life: 17 hrs.
Clinical Guidelines: Fast onset of action is useful for
treatment of early insomnia. Medium half-life should help
patients stay asleep throughout the night. Estazolam
offers no real advantage over temazepam (Restoril). More
clinicians are familiar with the use of estazolam.
Estazolam is not commonly used.
Quazepam (Doral)
Indications: Insomnia.
Preparations: 7.5, 15 mg tablets.
Dosage:
Insomnia: 7.5-30 mg qhs.
Elderly: 7.5 mg qhs.
Half-Life: 100 hrs.
Clinical Guidelines: Long duration of action may result
in morning sedation. It has no unique properties; it is not
commonly used.
Temazepam (Restoril)
Indication: Insomnia.
Preparations: 7.5, 15, 30 mg capsules.
Dosage: Insomnia: 7.5-30 mg qhs (less for elderly).
Half-Life: 10-12 hrs.
Clinical Guidelines: Short duration of action limits
morning sedation.
Triazolam (Halcion)
Indication: Insomnia.
Preparations: 0.125, 0.25 mg tablets.
Dosage: Insomnia: 0.125-0.25 mg qhs. Reduce dosage
in elderly.
Half-life: 2-3 hrs.
Clinical Guidelines: Ultra-short half-life results in
minimal AM sedation. It is best for sleep initiation.
Patients may report waking up after 3-4 hours when blood
level drops. It is not recommended for patients who have
trouble maintaining sleep throughout the night. Use
should be limited to 10 days.
Non-Benzodiazepine
Hypnotics
Zolpidem (Ambien)
Category: Non-benzodiazepine hypnotic.
Mechanism: Binds to the GABA receptor, but is a non-
benzodiazepine.
Indications: Insomnia.
Preparations: 5, 10 mg tablets.
Dosage: 10 mg qhs (5.0 mg for elderly).
Half-Life: 2-3 hrs.
Side Effects: Dizziness, GI upset, nausea, vomiting.
Anterograde amnesia and morning “hangover” occur at
dosages.
Drug–Drug Interactions: Potentiation of other CNS
depressants (eg, alcohol). Higher serum levels reported
in patients with hepatic insufficiency, but not with renal
insufficiency.
Clinical Guidelines: Zolpidem has a rapid onset. It is
especially useful for initiating sleep. Zolpidem is not
associated with dependence or withdrawal. Zolpidem is
rated a pregnancy category B.
Zaleplon (Sonata)
Category: Non-benzodiazepine hypnotic.
Mechanism: Binds to the GABA receptor, but is a non-
benzodiazepine.
Indications: Insomnia.
Preparations: 5-, 10-mg tablets.
Dosage: 10 mg qhs (5.0 mg for elderly).
Half-Life: 1 hr.
Side Effects: Dizziness, dyspepsia, and diarrhea.
Drug–Drug Interactions: Potentiation of other CNS
depressants (eg, alcohol). Higher serum levels reported
in patients with hepatic insufficiency, but not with
moderate renal insufficiency. Cimetidine can increase
serum levels.
Clinical Guidelines: Zaleplon has a rapid onset. It is
especially useful for initiating sleep and is not associated
with dependence or withdrawal. Because of its short half-
life, a repeat dose may be given. It is rated pregnancy
category
Diphenhydramine (Benadryl)
Category: Antihistamine.
Mechanism: Histamine receptor antagonist (sedation),
acetylcholine receptor antagonist (extrapyramidal
symptom control).
Indications: Mild insomnia, neuroleptic-induced
extrapyramidal symptoms, antihistamine.
Preparations: 25, 50 mg tablets; 25, 50 mg capsules; 10
mg/mL and 50 mg/mL soln. (IM, IV), 12.5 mg/5 mL elixir
(PO).
Dosage:
Insomnia: 50 mg PO qhs.
Extrapyramidal symptoms: 25-50 mg PO bid, for acute
extrapyramidal. symptoms 25-50 mg IM or IV.
Half-Life: 1-4 hrs.
Side Effects: Dry mouth, dizziness, drowsiness, tremor,
thickening of bronchial secretions, hypotension,
decreased motor coordination, GI distress.
Interactions: Diphenhydramine has an additive effect
when used with other sedatives and other medications
with anticholinergic activity. May cause exacerbation of
narrow angle glaucoma and prostatic hypertrophy. MAO
inhibitor use is contraindicated within 2 weeks of
diphenhydramine.
Clinical Guidelines: Diphenhydramine is a very weak
sedative, and it is minimally effective as a hypnotic. It is
non-addicting.
I. Indications
A. There are very few psychiatric indications for
barbiturates since benzodiazepines are safer and
just as effective. The phenobarbital challenge test is
also used to quantify sedative-hypnotic abuse in
patients abusing multiple sedative hypnotics,
including alcohol.
B. Given the availability of equally effective and safer
benzodiazepines, it is difficult to justify the long-term
use of barbiturates.
II. Pharmacology
A. Barbiturates bind to barbiturate receptor sites, which
are part of the GABA receptor. Barbiturate binding
facilitates the action of GABA at the GABA receptor
complex, resulting in inhibition.
B. Barbiturates induce hepatic microsomal enzymes
and may reduce levels of other medications with
hepatic metabolism.
III. Clinical Guidelines
A. Continued use of barbiturates for more than 3-4
weeks is associated with tolerance, dependence and
withdrawal syndrome.
1. Tolerance develops to the sedative side effects.
Cross-tolerance between barbiturates and other
sedative hypnotic drugs, including alcohol, may
develop.
2. Withdrawal symptoms include: heightened
anxiety, tremor, muscle twitching, sweating,
insomnia, tachycardia, hypertension with postural
hypotension and seizures.
3. The severity of withdrawal is determined by the
rate of decreasing serum level. Faster rates of
decline are associated with more sever
withdrawal.
B. Avoidance of an abstinence syndrome requires
gradual tapering upon discontinuation. A long half-
life benzodiazepine (eg, clonazepam) helps to
reduce the severity of withdrawal.
C. Barbiturates should not be used in pregnancy.
Infants born to habituated mothers may have
respiratory depression at birth and will go into
withdrawal.
IV. Adverse Drug Reactions
A. The most common side effect is sedation and
impaired concentration. Dizziness, ataxia and
impaired fine motor coordination can also occur.
B. Barbiturates should not be used in patients with
hepatic dysfunction since their metabolism will be
impaired and toxicity may occur. Barbiturates are
contraindicated in patients with acute intermittent
porphyria since they may cause the production of
porphyrins.
V.Drug Interactions
A. The concomitant use of benzodiazepines and CNS
depressant agents, including sedative-hypnotics, will
enhance sedation and increase the risk of
respiratory depression. Alcohol use should be
limited.
B. Barbiturates enhance the metabolism of a number of
commonly used medications because they induce
hepatic enzymes. Reduced effectiveness of these
medications can occur. These include
anticoagulants, tricyclic antidepressants,
propranolol, carbamazepine, estrogen (oral
contraceptives), corticosteroids, quinidine, and
theophylline.
C. The effect of barbiturates on phenytoin metabolism
is unpredictable, phenytoin levels should be
monitored. Valproate inhibits barbiturate
metabolism.
Amobarbital (Amytal)
Preparations: 30, 50, 100 mg tablets; 65, 200 mg
capsules; 250 mg/5 mL, 500 mg/5 mL solution (IM, IV).
Dosage:
Sedation: 50-100 PO or IM.
Hypnosis: 50-200 mg IV (max 400 mg/day).
Half-life: 8-42 hrs.
Clinical Guidelines: Lorazepam has largely replaced the
use of amobarbital for emergent control of psychotic
agitation. The use of amobarbital in clinical diagnosis has
also decreased.
Pentobarbital (Nembutal)
Preparations: 50, 100 mg capsules.
Dosage: 200 mg PO.
Half-Life: 15-48 hrs.
Pentobarbital Challenge Test: The pentobarbital
challenge test is a useful method of quantifying the daily
intake of sedative hypnotics so that patients can be
detoxified. Patients are given 200 mg orally and after one
hour, the level of intoxication is assessed. If no signs of
intoxication, 100 mg is given, and the patient is
reassessed after one hour. Repeat procedure every two
hours until signs of intoxication occur (Nystagmus is the
most sensitive sign and sleep is the most obvious sign).
Maximum dose 600 mg. The dose required to show signs
of intoxication is the equivalent dose to the daily habit of
sedative hypnotics. Substitute a long half-life drug in
divided doses and gradually taper by 10% per day.
Carbamazepine (Tegretol)
I. Indications
A. Carbamazepine is used for the treatment of the
acute manic phase of bipolar disorder and for
maintenance treatment of bipolar disorder. It may
be used alone or in combination with lithium. It is
more effective than lithium in treating rapid-cycling
bipolar disorder and mixed episodes.
B. Carbamazepine is more effective in the treatment
and prophylaxis of manic episodes than the
depressed episodes of bipolar disorder. When
treating the depressed episode of bipolar disorder
with an antidepressant, it is necessary to maintain
carbamazepine treatment to prevent an
antidepressant-induced manic episode or rapid
cycling.
C. Carbamazepine is also used in the treatment of
cyclothymia and schizoaffective disorder. It is
frequently used with antipsychotics and/or lithium in
schizoaffective disorder.
D. Carbamazepine augmentation of antipsychotic
medication can be useful in patient with
schizophrenia when there is inadequate response
to antipsychotics alone. It is particularly helpful for
aggressive or impulsive behavior.
E. Carbamazepine may be helpful in treating certain
impulse control disorders, such as those seen in
patients with developmental disabilities. It may also
be helpful to reduce symptoms of impulsivity and
affective instability in patients with severe
personality disorders.
F. Augmentation of antidepressant treatment with
carbamazepine might be helpful in depressed
patients who are treatment-resistant.
II. Pharmacology
A. The mechanism of carbamazepine in psychiatric
disorders is unknown.
B. Carbamazepine is metabolized by the liver
(CYP3A4) and its metabolites are excreted renally.
It will induce it’s own metabolism and serum levels
tend to decrease with time, requiring an increase in
the dosage. Initially, the half-life can be 25-65
hours. After several weeks, the serum half-life can
decrease to 12-17 hours.
C. Preparations: 100, 200 mg tablets; 100 mg/5 ml oral
suspension.
III.Clinical Guidelines
A. Pre-Carbamazepine Work-Up
1. Non-psychiatric causes of mood disorder or
manic symptoms, including medical disorders,
medications and substances of abuse should be
excluded before beginning carbamazepine
treatment.
2. Screening labs should include a basic chemistry
panel, CBC and an EKG in patients over 40 years
old or with pre-existing cardiac disease.
Pregnancy should be excluded in women of
childbearing age.
B. Carbamazepine should not be given to patients with
pre-existing liver, cardiac, or hematological disease.
It is not recommended for patients with renal
dysfunction because it has active metabolites that
are renally excreted.
C. If carbamazepine is used in patients who have not
responded to lithium, the carbamazepine should be
added to the drug regimen. If the patient responds,
the lithium should be withdrawn in an attempt to
manage the patient with a single mood stabilizer.
D. Dosage and Administration
1. Starting dose is 200 mg Bid. The average dose
range is 600–1200 mg/day. The dosage should
be reduced by one-half in the elderly.
2. Dosage increases, especially when initiating
treatment, can cause proportionally larger
increases in serum level; therefore, the dosage
should not be increased by more than 200
mg/day at a time.
3. Carbamazepine should be titrated to a serum
level of 8-12 :g/mL. Serum carbamazepine levels
should be obtained after five days at any given
dosage. Serum levels should be drawn 12 hours
after the previous dose, usually in the morning
before the AM dose.
4. Serum levels should be monitored weekly for the
first 1-2 months, then biweekly for another 2
months. Carbamazepine will induce its own
metabolism, decreasing the serum level. The
dosage may need to be increased in order to
maintain a serum level within therapeutic range
after initial stabilization. Frequent monitoring of
serum level is recommended during the first three
months of treatment.
5. A patient who has been stable on carbamazepine
for a year can be monitored every 3-4 months.
CBC and liver function, electrolytes and renal
function should be checked after one month, then
quarterly for the first year.
E. Therapeutic Response: Therapeutic effect may
take 2-4 weeks.
F. Pregnancy and Lactation: Pregnancy category C.
Carbamazepine is contraindicated during pregnancy
or lactation. There may be an association between
use of carbamazepine in pregnancy and congenital
malformations, including spina bifida.
IV. Adverse Drug Effects
A. Side Effects: The most common side effects are GI
complaints (nausea, vomiting, constipation,
diarrhea, loss of appetite) and CNS complaints
(sedation, dizziness, ataxia, confusion). These can
be prevented or significantly reduced by increasing
the daily dosage slowly.
B. Hematological
1. Carbamazepine causes life-threatening
thrombocytopenia, agranulocytosis, and aplastic
anemia in 0.005% of patients. Patients should
contact their physician immediately with any signs
of infection (fever, sore throat) or bleeding
abnormality (easy bruising, petechiae, pallor). A
CBC should be drawn immediately.
Carbamazepine should be discontinued if the
WBC declines to less than 3000 mm3, absolute
neutrophil count <1500 mm3 or platelet count
decreases to <100,000 per mm3.
2. Transient and minor decreases in blood cell
indices can occur in the early phase of treatment
and do not warrant discontinuation of
carbamazepine.
C. Hepatic: Hepatitis and cholestatic jaundice may
occur. The medication should be discontinued
immediately.
D. Dermatological: Rash and urticaria are relatively
common. Photosensitivity reactions may rarely
occur. Potentially dangerous, but extremely rare,
dermatological side effects include exfoliative
dermatitis, toxic epidermal necrolysis and Stevens-
Johnson syndrome, requiring immediate
discontinuation of the drug.
E. Anticholinergic: Carbamazepine has mild
anticholinergic activity and may exacerbate
glaucoma and prostatic hypertrophy.
F. Cardiac: Uncommon side effects include AV
conduction defects, arrhythmias, and congestive
heart failure.
G. Metabolic/Endocrine: SIADH with hyponatremia
has been reported.
H. Genitourinary: Urinary frequency, urinary retention,
azotemia, renal failure and impotence are
uncommon.
I. Toxicity: Signs of toxicity include confusion, stupor,
motor restlessness, ataxia, mydriasis, muscle
twitching, tremor, athetoid movements, nystagmus,
abnormal reflexes, oliguria, nausea and vomiting.
Cardiac arrhythmias do not generally occur unless
very large doses are ingested.
V. Drug Interactions
A. The following medications inhibit the metabolism of
carbamazepine with resultant increase in serum
levels and neurotoxicity:
1. Verapamil and diltiazem.
2. Danazol.
3. Erythromycin.
4. Fluoxetine.
5. Cimetidine (transient effect). Not seen with
ranitidine or famotidine.
6. Isoniazid.
7. Ketoconazole.
8. Loratadine.
B. The following medications cause cytochrome P450
enzyme induction and decreased carbamazepine
levels:
1. Rifampin.
2. Cisplatin.
C. Anticonvulsant Interactions with Carbamazepine
1. Phenobarbital will lower carbamazepine levels
due to microsomal enzyme induction.
2. When phenytoin and carbamazepine are given at
the same time, the levels of both drugs may be
decreased.
3. Decreased ethosuximide levels due to
cytochrome P450 enzyme induction.
4. Felbamate can decrease carbamazepine levels
but increase the active metabolite, which has
been implicated in toxicity.
5. Lamotrigine and valproate can increase the
active metabolite. Patients may have signs of
toxicity with normal carbamazepine levels.
Carbamazepine will cause decreased valproate
levels.
D. Carbamazepine will induce hepatic microsomal
enzymes and enhance the metabolism, decrease
serum levels and decrease the effectiveness of the
following medications:
1. Acetaminophen (may also enhance
hepatotoxicity in overdose).
2. Clozapine and haloperidol.
3. Benzodiazepines (especially alprazolam,
triazolam).
4. Oral contraceptives.
5. Corticosteroids.
6. Cyclosporine.
7. Doxycycline.
8. Mebendazole.
9. Methadone.
10. Theophylline (can also decrease
carbamazepine levels).
11. Thyroid supplements (may mask compensatory
increases in TSH).
12. Valproate.
13. Warfarin.
E. Diuretics should be used with caution since
hyponatremia can occur with carbamazepine alone.
F. A minimum 14-day washout should elapse before
beginning an MAOI due to the molecular similarity
between tricyclic antidepressants and
carbamazepine.
Gabapentin (Neurontin)
I. Indications
A. While initial studies with gabapentin showed
promise in the treatment of cyclic affective illness,
data does not currently indicate significant efficacy
for this medication in monotherapy or as an
adjunctive agent.
B. Gabapentin is still often used as an adjunctive agent
in cyclic affective illness and other psychiatric
conditions to alleviate anxiety and assist with sleep
and low-grade iritability.
II. Pharmacology
A. Gabapentin is chemically related to the
neurotransmitter GABA, but it does not act on GABA
receptors. It is not converted into GABA and does
not effect GABA metabolism or reuptake. The
mechanism in psychiatric disorders is unknown.
B. Gabapentin is excreted renally in an unchanged
state. Reduced clearance of gabapentin with age is
largely caused by reduced renal function.
C. Half-life: 5-7 hrs.
D. Preparations: 100, 300, 400, 600, 800 mg capsules
III. Clinical Guidelines
A. Pre-Gabapentin Work-Up: Non-psychiatric causes
of mood disorder or mood symptoms (mania and
depression), including medical disorders,
medications and substances of abuse should be
excluded before beginning gabapentin treatment.
Screening laboratory exams should be ordered to
monitor renal function. In females of childbearing
age, pregnancy should be excluded.
B. Dosage and Administration
1. Starting dose can be 300 mg qhs, then
increasing by 300 mg each day. The average
daily dose is between 900 and 1800 mg/day, but
doses up to 2400 have been used.
2. Monitoring of serum levels is not necessary.
There is no information available regarding a
therapeutic window.
3. Significantly lower doses should be given to
patients with impaired renal function or reduced
creatinine clearance.
C. Therapeutic Response: 2-4 weeks
D. Pregnancy and Lactation: Pregnancy category C.
There are no controlled studies in pregnant women.
Gabapentin should be avoided during the first
trimester. Use after the first trimester must be on a
risk-benefit basis. Mothers should be encouraged
not to breast feed since the risks are unknown.
IV. Adverse Drug Reactions
A. Side Effects
1. The most common side effects are somnolence,
fatigue, ataxia, nausea and vomiting and
dizziness.
2. Metabolic: Weight gain, weight loss, edema.
3. Cardiovascular: Hypertension.
4. GI: Loss of appetite, increased appetite,
dyspepsia, flatulence, gingivitis.
5. Hematological: Easy bruising.
6. Musculoskeletal: Arthralgia.
7. CNS: Nystagmus, tremor, diplopia, blurred vision.
8. Psychiatric: Anxiety, irritability, hostility,
agitation, depression.
V. Drug Interactions
A. There are no interactions with other anticonvulsants.
B. Gabapentin has reduced absorption with antacids,
and it should be taken at least 2 hours after antacid
administration.
Lamotrigine (Lamictal)
I. Indications
A. Lamotrigine has efficacy in the treatment of bipolar
depression as an adjunctive agent or as
monotherapy. It has also been shown to decrease
relapse to depression in stable bipolar patients by
itself. Its efficacy in the treatment of bipolar mania
or rapid cycling is not supported by current data. It
is recommended that lamotrigine be used primarily
as an adjunctive agent due to lack of proven efficacy
in the treatment or prevention of mania.
B. It is more effective in depression compared to other
mood stabilizers, prompting use in treatment-
resistant unipolar depression. Controlled studies are
currently underway.
II. Pharmacology
A. The mechanism of action is unknown. It may have
an effect on sodium channels that modulate release
of glutamate and aspartate. It also has a weak
inhibitory effect on 5-HT3 receptors.
B. Lamotrigine is hepatically metabolized via
glucuronidation with subsequent renal excretion of
the inactive glucuronide.
C. Half-Life: 25 hours.
D. Preparations: 25, 100, 150, 200 mg scored tablets.
III. Clinical Guidelines
A. Non-psychiatric causes of mood disorder or mood
symptoms (mania and depression), including
medical disorders, medications and substances of
abuse should be excluded before beginning
lamotrigine treatment.
B. Screening laboratory exams should be ordered to
monitor renal and hepatic function. In females of
childbearing age, pregnancy should be excluded.
C. Dosage and Administration
1. The initial dose is 25 mg/day increased weekly to
50 mg/day, 100mg/ day, and then 200 mg/day.
2. In patients taking valproate, the dosage is 25 mg
every other day for two weeks, then 25 mg per
day for the next two weeks. In patients taking
phenytoin, carbamazepine, phenobarbital or
primidone without valproate, the dosage is 50
mg/day for two weeks, then 50 mg bid for the
next two weeks. Average daily dose: 100-200
mg/day. Antidepressant effect may require up to
400 mg/day which may be given in a divided
dose.
3. Renal dysfunction does not markedly affect the
half-life of lamotrigine. However, caution should
be used when treating patients with renal disease
since there is very little data in this population.
D. Therapeutic Response: Clinical effect: 2-4 weeks.
E. Pregnancy and Lactation
1. Pregnancy category C. There are no controlled
studies in pregnant women. Lamotrigine should
be avoided during the first trimester.
2. Use after the first trimester must be on a risk-
benefit basis. Lamotrigine is excreted in breast
milk. Mothers should be encouraged not to breast
feed because the risks are unknown.
IV. Adverse Drug Effects
A. Side Effects: The most common side effects are
dizziness, sedation, headache, diplopia, ataxia, and
decreased coordination.
B. Dermatological: The side effect most likely to
cause discontinuation of the drug is rash (10%
incidence), which can be quite severe – Stevens-
Johnson syndrome (toxic epidermal necrolysis).
Rash is most likely to occur in the first 4-6 weeks.
C. Metabolic: Weight gain.
D. GI: Nausea and vomiting.
E. Psychiatric: Agitation, irritability anxiety, depression
and mania.
V. Drug Interactions
A. Carbamazepine-induced enzyme induction will
enhance lamotrigine metabolism, with subsequent
lower levels than expected. Lamotrigine will
increase the levels of carbamazepine and its
metabolites.
B. Valproate will increase lamotrigine levels (as much
as two times), and lamotrigine will decrease
valproate levels slightly.
C. Phenobarbital-induced enzyme induction will lower
lamotrigine levels.
D. Phenytoin will decrease lamotrigine levels.
E. No interaction with lithium has been reported.
F. Alcohol may enhance the side effects of lamotrigine.
G. Lamotrigine can be used with MAO inhibitors.
Topiramate (Topamax)
I. Indications
A. Open label studies suggest that it may have efficacy
as a mood stabilizer in patients with bipolar disorder.
One recent double-blind, placebo controlled study
was discontinued, however, due to lack of efficacy.
B. Other open label clinical studies have suggested
potential effectiveness of topiramate in bulimia,
migraine, and post traumatic stress disorder.
II. Pharmacology
A. The mechanism of action is unknown.
B. Topiramate is not extensively metabolized and is
mostly excrete unchanged in the urine.
C. Half-life: approximately 21 hours.
D. Preparations: 25, 100 and 200 mg tablets; 15 and
25 mg sprinkle capsules.
III. Clinical Guidelines
A. Non-psychiatric causes of mood disorder or mood
symptoms (mania and depression), including
medical disorders, medications and substances of
abuse should be excluded before beginning
topiramate treatment.
B. Screening laboratory exams should be ordered to
monitor renal and hepatic function. In females of
childbearing age, pregnancy should be excluded.
C. Topiramate is associated with appetite suppression
and possible weight loss, a side effect that may be
considered in a positive light by both the patient and
the treating physician. Minimal hepatic metabolism
may make it preferable over other anticonvulsants.
D. Dosage and administration (adults)
1. Initial dose: 25-50mg q hs then increase in 25-
50mg increments per week up to 400 mg/day in
divided doses.
2. Patients with renal impairment should take ½ the
recommended dose.
3. No adjustments are necessary for the elderly
based on age alone.
E. Pregnancy and Lactation: Pregnancy category C.
IV. Adverse Effects
A. The most common side effects are fatigue,
somnolence, dizziness, nausea, anorexia,
decreased concentration, ataxia, anxiety, and
paresthesias.
B. The potential for appetite suppression and weight
loss may be welcome side effects, since a significant
number of psychotropic medications can cause
weight gain.
V.Drug Interactions
A. Carbamazepine-induced enzyme induction will
reduce topiramate levels.
B. When given with valproic acid, topiramate and
valproic acid levels may decrease.
C. When given with phenytoin, topiramate levels were
decreased and phenytoin levels were increased.
D. Concomitant use of phenobarbital can decrease
topiramate levels.
E. Concomitant use of acetazolamide will increase the
risk of nephrolithiasis and should be avoided.
F. Topiramate may decrease serum digoxin levels.
G. Topiramate may reduce the effectiveness of oral
contraceptives by reducing estrogen availability.
Pregabalin
I. Indications (FDA approval pending): Pregabalin is
currently under investigation for the treatment of
epilepsy, neuropathic pain, generalized anxiety
disorder, social phobia, and panic disorder. Recent
studies indicate comparable efficacy to
benzodiazepines, venlafaxine and SSRIs in the
reduction of generalized anxiety.
II. Pharmacology
A. Pregabalin binds to calcium channels, not GABA
receptors, and modulates calcium influx, resulting in
anxiolytic, analgesic and anticonvulsant activity.
III. Clinical Guidelines
A. Dosage and Administration. The dosage of
pregabalin in anxiety studies has ranged from 300 to
600 mg per day, usually given tid. The optimal
dosage has yet to be determined.
B. Response Time. Time to response is likely similar
to antidepressants, but some preliminary data
indicates that pregabalin may have a more rapid
onset of action.
C. Adverse Drug Reactions: Not fully established, but
dizziness and drowsiness are common.
IV. Drug Interactions: Not established to date.
Dextroamphetamine (Dexedrine)
I. Indications
A. Dextroamphetamine has been approved for the
treatment of narcolepsy symptoms and Attention-
Deficit Hyperactivity Disorder deficit hyperactivity
disorder (ADHD). It is used in the treatment of
ADHD in children and adults.
B. Dextroamphetamine is used as an adjunct to
antidepressants in patients who have had an
inadequate response to antidepressants. It has also
been used effectively in depressed medically ill or
elderly patients who have not been able to tolerate
antidepressants.
II. Pharmacology
A. Dextroamphetamine is the d-isomer of
amphetamine. It is a centrally acting
sympathomimetic amine and causes the release of
norepinephrine from neurons. At higher doses, it
will also cause dopamine and serotonin release. It
inhibits CNS MAO activity.
B. Peripheral effects include increased blood pressure
and pulse, respiratory stimulation, mydriasis, and
weak bronchodilation.
C. Preparations: Dextroamphetamine sulfate
(Dexedrine) – 5, 10, 15 mg tabs; elixir 5 mg/5 mL;
Dexedrine Spansule (sustained release) - 5, 10, 15
mg caps.
D. Half-Life: 8-12 hrs
III. Clinical Guidelines
A. Dextroamphetamine is a schedule II controlled
substance, requiring a triplicate prescription.
Dextroamphetamine has a high potential for abuse
since it increases energy and productivity.
Tolerance and intense psychological dependence
develop.
B. Symptoms upon discontinuation may include
fatigue and depression. Chronic users can become
suicidal upon abrupt cessation of the drug.
C. Pre-Dextroamphetamine Work-Up
1. Blood pressure and general cardiac status
should be evaluated prior to initiating
dextroamphetamine.
2. Since dextroamphetamine can precipitate tics
and Tourette’s syndrome, careful screening for
movement disorders should be completed prior
to beginning treatment.
D. Dextroamphetamine is contraindicated in patients
with hypertension, hyperthyroidism, cardiac disease
or glaucoma. It is not recommended for psychotic
patients or patients with a history of substance
abuse.
E. Dosage and Administration
1. Attention-Deficit Hyperactivity Disorder: Initial
Dosage 2.5-5.0 mg bid-tid. Increase gradually in
divided doses (7 am, 11 am or noon, 3 pm) until
optimal response. Maximum dose approximately
1.0 mg/kg/day for children. Maximum 40 mg/day
for adults. Spansule preparation can be given
bid.
2. Depression (medically ill): 5-20 mg/day.
3. Narcolepsy: 10-60 mg/day in divided doses.
4. Children under the age of 3 should not be given
dextroamphetamine.
F. Weight and growth should be monitored in all
children. Weight loss and growth delay are reasons
to discontinue medication.
G. Pregnancy and Lactation: Pregnancy category C.
There is an increased risk of premature delivery
and low birth weight in infants born to mothers
using amphetamines. Dextroamphetamine is
contraindicated in pregnancy or breast feeding.
IV.Adverse Drug Reactions
A. Side Effects: The most common side effects are
psychomotor agitation, insomnia, loss of appetite,
and dry mouth. Tolerance to loss of appetite tends
to develop. Effect on sleep can be reduced by
making sure no drug is given after 12 pm.
B. Cardiovascular: Palpitations, tachycardia,
increased blood pressure
C. CNS: Dizziness, euphoria, tremor, precipitation of
tics, Tourette’s syndrome, and, rarely, psychosis.
D. GI: Anorexia and weight loss, diarrhea,
constipation.
E. Growth inhibition: Chronic administration of
psychostimulants has been associated with growth
delay in children. Growth should be monitored
during treatment.
F. Toxicity/Overdose: Symptoms include insomnia,
irritability, hostility, psychomotor agitation,
psychosis with paranoid features, hypertension,
tachycardia, sweating, hyperreflexia, tachypnea. At
very high doses, patients can present with
arrhythmias, nausea, vomiting, circulatory collapse,
seizures and coma.
V. Drug Interactions
A. High blood levels of propoxyphene can enhance the
CNS stimulatory effects of dextroamphetamine,
causing seizures and death
B. Dextroamphetamine will enhance the activity of
tricyclic and tetracyclic antidepressants, and will
also potentiate their cardiovascular effects.
C. Dextroamphetamine may antagonize the effects of
antihypertensives.
D. Typical antipsychotics and lithium can inhibit the
CNS stimulatory effects of dextroamphetamine
E. Fatal reactions are likely if psychostimulants are
given with MAOIs. Hypertensive crisis and seizures
may occur. MAOIs should be discontinued for at
least 14 days prior to the initiation of
dextroamphetamine.
F. Dextroamphetamine will delay the absorption of the
anticonvulsants ethosuximide, phenobarbital and
phenytoin.
Dextroamphetamine and
Amphetamine (Adderall, Adderall
XR)
I. Indications
A. Adderall is indicated for the treatment of Attention-
Deficit and Hyperactivity Disorder (ADHD) and
Narcolepsy.
II. Pharmacology
A. Adderall is a combination of two closely related
amphetamines and has a similar pharmacology to
Dexedrine.
B. Preparations: Adderall 5-, 7.5-, 10-,12.5-, 15-, 20-
,30-mg tablets; Adderall XR 5-, 10-, 15-, 20-, 25-,
30-mg capsules
C. Dosing: 5-10 mg/day with the average dose of 20-
30 mg/day for ADHD and 5-60 mg for narcolepsy.
Maximum dose is 40 mg for children and 60 mg for
adults.
III. Clinical Guidelines
A. Adderall is a schedule II controlled substance,
requiring a triplicate prescription. Adderall has a
high potential for abuse since it increases energy
and productivity. Tolerance and intense
psychological dependence develop.
B. Symptoms upon discontinuation may include
fatigue and depression. Chronic users can become
suicidal upon abrupt cessation of the drug.
C. Pre-Adderall Work-Up
1. Blood pressure and general cardiac status
should be evaluated prior to initiating
dextroamphetamine.
2. Since Adderall can precipitate tics and
Tourette’s syndrome, careful screening for
movement disorders should be completed prior
to beginning treatment.
D. Adderall is contraindicated in patients with
hypertension, hyperthyroidism, cardiac disease or
glaucoma. It is not recommended for psychotic
patients or patients with a history of substance
abuse.
E. Weight and growth should be monitored in all
children. Weight loss and growth delay are reasons
to discontinue medication.
F. Pregnancy and Lactation: Pregnancy category C.
There is an increased risk of premature delivery
and low birth weight in infants born to mothers
using amphetamines. Adderall is contraindicated in
pregnancy or breast feeding.
IV.Adverse Drug Reactions
A. Side Effects: The most common side effects are
psychomotor agitation, insomnia, loss of appetite,
and dry mouth. Tolerance to loss of appetite tends
to develop. Effect on sleep can be reduced by
making sure no drug is given after 12 pm.
B. Cardiovascular: Palpitations, tachycardia,
increased blood pressure
C. CNS: Dizziness, euphoria, tremor, precipitation of
tics, Tourette’s syndrome, and, rarely, psychosis.
D. GI: Anorexia and weight loss, diarrhea,
constipation.
E. Growth inhibition: Chronic administration of
psychostimulants has been associated with growth
delay in children. Growth should be monitored
during treatment.
F. Toxicity/Overdose: Symptoms include insomnia,
irritability, hostility, psychomotor agitation,
psychosis with paranoid features, hypertension,
tachycardia, sweating, hyperreflexia, tachypnea. At
very high doses, patients can present with
arrhythmias, nausea, vomiting, circulatory collapse,
seizures and coma.
V. Drug Interactions
A. High blood levels of propoxyphene can enhance the
CNS stimulatory effects of Adderall, causing
seizures and death
B. Adderall will enhance the activity of tricyclic and
tetracyclic antidepressants, and will also potentiate
their cardiovascular effects.
C. Typical antipsychotics and lithium can inhibit the
CNS stimulatory effects of dextroamphetamine.
D. Fatal reactions are likely if psychostimulants are
given with MAOIs. Hypertensive crisis or seizures
may occur. MAOIs should be discontinued for at
least 14 days prior to the initiation of Adderall.
E. Adderall will delay the absorption of the
anticonvulsants ethosuximide, phenobarbital and
phenytoin.
Pemoline (Cylert)
Pemoline is chemically unrelated to amphetamine and its
mechanism and site of action is unknown. It has
pharmacological activity similar to the psychostimulants.
Because of its association with life threatening hepatic
failure, pemoline should not be used as first-line therapy
for Attention-Deficit Hyperactivity Disorder.
Modafinil (Provigil)
I. Indications: Excessive Daytime Sleepiness
associated with Narcolepsy. Some evidence exists for
the effectiveness of modafinil (300 mg q am) for
ADHD.
II. Pharmacology
A. Modafinil is metabolized by the liver (3A4 enzyme).
3A4 inhibitors or inducers may affect the
metabolism of modafinil.
B. Preparations: 100 and 200 mg tablets.
C. Absorption is delayed by food.
D. Half-Life: 15 hrs.
III. Clinical Guidelines
A. Modafinil is generally well tolerated, with little effect
on nighttime sleep. It has less side effects and less
abuse potential than amphetamine-like stimulants.
B. Limited data suggests that modafinil may be useful
in antidepressant augmentation.
C. Dosage and Administration: Initial dosage is 200
mg/day (8 AM). Elderly and patients with hepatic
impairment require lower dose. Some patients may
benefit from a mid-afternoon dose (100-200 mg).
The maximum recommended daily dose is 400
mg/day.
D. Pregnancy and Lactation: Pregnancy Category C.
IV.Adverse Drug Reactions
A. Side Effects: The most common side effects are
headache, nausea, diarrhea, and anorexia.
Anxiety, nervousness, and insomnia have been
reported but are less frequent compared to
methylphenidate.
B. Toxicity/Overdose: Symptoms include
nausea/diarrhea, palpitations, tremor, sleep
disturbance, irritability, aggressiveness, and
confusion.
V. Drug Interactions. Potential interactions exist with
inducers, substrates, or inhibitors of 3A4 hepatic
enzyme. Other potential interactions may exist with
the 2D6 and 2C19, enzymes. Use with monoamine
oxidase inhibitors should be avoided.
Atomoxetine (Strattera)
I. Indications: Attention-Deficit Hyperactivity Disorder.
II. Pharmacology
A. Atomoxetine is a newly approved medication that
works via presynaptic norepinephrine transporter
inhibition with subsequent enhancement of
noradrenergic function. Atomoxetine is not
considered a psychostimulant and is not a
controlled substance.
B. Metabolism: Atomoxetine is metabolized via the
CYP2D6 enzyme.
C. Half-Life: Approximately 4 hours.
D. Preparations: 10, 18, 25, 40, and 60 mg capsules.
E. Dosage:
1. In children (<70 kg) the dose should be initiated
at 0.5 mg/kg and increased to target a dose of
1.2 mg/kg/day. The dose should not exceed 1.4
mg/kg or 100 mg/day, whichever is less.
2. In adults (>70 kg), initial dose is 40 mg/day,
which is increased to 80 mg/day. Dose can be
increased to 100 mg/day after 2-4 weeks. The
dose should not exceed 100 mg.
3. The dose can be given in the morning or divided
between morning and late afternoon/early
evening.
III. Clinical Guidelines
A. Dividing the dose may reduce some side effects.
B. Dose reductions are necessary in the presence of
moderate hepatic insufficiency.
C. Atomoxetine should not be used within 2 weeks of
discontinuation os a MAO inhibitor.
D. Atomoxetine should be avoided in patients with
narrow angle glaucoma and, it should be used with
caution in patients with tachycardia, hypertension or
cardiovascular disease.
E. Atomoxetine can be discontinued without taper.
F. Pregnancy and Lactation: Pregnancy Category C.
IV. Adverse Drug Reactions
A. Cardiovascular: Increased blood pressure and
heart rate (similar to those seen with conventional
psychostimulants).
B. Gastrointestinal: Anorexia, weight loss, nausea,
abdominal pain.
C. Miscellaneous: Fatigue, dry mouth, constipation,
urinary hesitancy and erectile dysfunction.
V. Drug Interactions: Individuals with decreased activity
of the CYP2D6 enzyme or who are taking CYP2D6
inhibitors (eg, fluoxetine, paroxetine) will have
significantly greater plasma levels (fivefold) and the
drug will have a longer half-life (24 hours).
M a n a gem e nt of Substance
Dependence
I. Clinical Guidelines for the Management of
Substance Dependence
A. Alcohol Dependence/Withdrawal: Prolonged use
of large amounts of alcohol leads to dependence
and withdrawal upon discontinuation. If untreated,
withdrawal can be fatal in cases where a patient
develops delirium tremens and subsequent
electrolyte abnormalities or cardiac arrhythmias.
Benzodiazepines, such as lorazepam and
chlordiazepoxide, are used to prevent withdrawal
symptoms.
B. Alcohol Relapse: Disulfiram and naltrexone are
used to help prevent relapse once a patient has
been detoxified. These agents in conjunction should
be used with a behavior modification program, such
as Alcoholics Anonymous, in order to yield
maximum benefit.
C. Opioid Dependence/Withdrawal: Opioid
withdrawal can lead to severe symptoms and
discomfort. Typical signs and symptoms of opioid
withdrawal include nausea, emesis, stomach
cramps, diarrhea, sweating, rhinorrhea, anxiety,
muscle cramps, bone pain, and severe craving.
Detoxification with methadone can alleviate the
withdrawal syndrome. Clonidine is also helpful in
reduction of withdrawal, but is not as effective as
methadone. Adjunctive prochlorperazine (5-10 mg
PO/IM q 6-8hr prn) for nausea/emesis; dicyclomine
(20 mg PO q6hr.) for stomach cramps/diarrhea;
ibuprofen (600 mg po q6hr prn) for muscle/bone
pain; and methocarbamol (500-750 mg q6hr prn)
can help during the initial days of detoxification.
D. Nicotine Dependence: Sustained release of
bupropion has been approved for smoking
cessation. Up to 50% of patients taking bupropion
will achieve abstinence from tobacco after 12 weeks
of treatment. This rate is twice the rate of placebo.
Success of bupropion is increased by combining
bupropion with a smoking cessation program.
E. Sedative/Hypnotic Withdrawal: Marked
withdrawal symptoms can occur with abrupt
discontinuation of sedative/hypnotic medications.
F. Psychostimulant Abstinence Syndrome:
Discontinuation of psychostimulants such as
amphetamines, methylphenidate, and cocaine can
produce fatigue, depression, hypersomnia, and
irritability. Treatment usually consists of supportive
care. Benzodiazepines can be used to treat
irritability.
Methadone (Dolophine)
Category: Synthetic opioid.
Mechanism: Opioid receptor agonist.
Indications: Detoxification and maintenance treatment of
opioid addiction. Methadone can only be prescribed in a
federally approved treatment center. The drug may be
continued if the patient is hospitalized for another reason.
Preparations: 5, 10, 40 mg tablets; 5 mg/5 mL solution,
10 mg/5 mL solution, 10 mg/mL solution. (PO); 10 mg/mL
solution. (IV, IM)
Dosage:
Detoxification: Short-term use (21 days maximum).
Initial dosage, 10-20 mg po on the first day. Increase
by 5-10 mg per day over the next few days, up to 40
mg per day in a single or divided dosage. Maintain at
this dosage for 2-5 days and then decrease by 5 mg
qod.
Maintenance: Treatment with methadone after 21
days is considered maintenance. A dosage of 60-80
mg is usually effective in preventing relapse.
Half-life: 24-36 hr.
Adverse Drug Reactions:
A. Methadone produces tolerance along with
physiological and psychological dependence.
Tolerance to the euphoric effects may lead to
overdose. Overdose can lead to respiratory and
cardiovascular depression, coma, and death.
B. The most common adverse reactions include
sedation, nausea, emesis, dizziness, sweating,
constipation, euphoria or dysphoria, dry mouth,
urinary retention, and depression.
Drug Interactions:
A. CNS Depressants can potentiate the effects of
alcohol, sedative/hypnotics, other narcotics, general
anesthetics, tricyclic antidepressants.
B. Desipramine may increase desipramine plasma
concentrations.
C. Carbamazepine may lower plasma levels of
methadone.
D. MAOIs: The combination of an MAOI and the
opiates meperidine and fentanyl have led to
fatalities.
Clinical Guidelines
A. Use caution in patients with a history of respiratory
disease, hepatic or renal abnormalities, seizure
disorder, or head injury.
B. Women who conceive while on methadone should
continue taking the drug; however, the newborn will
require medical care for withdrawal symptoms.
Naltrexone (ReVia)
Category: Opioid antagonist.
Mechanism: Antagonist of opioid receptors.
Indications: Alcohol dependence (reduce craving),
opioid dependence (blocks euphoric effects of alcohol).
Preparations: 50 mg tablets.
Long-acting IM preparation is under development
(150-300 mg q 4 weeks).
Dosage:
Alcohol craving: 50 mg/day.
Opioid abuse: Start with 25 mg on first day; then 50
mg/day.
Half-life: 13 hrs (including active metabolite)
Adverse Drug Reactions
A. Naltrexone may precipitate acute opiate withdrawal
in patients who are still using opiates. Nausea is the
most common adverse effect, which is minimized by
starting with 25 mg Qod or administering with food.
Other adverse effects include insomnia, headache,
anxiety, fatigue, dizziness, weight loss, and joint
and muscle pain.
B. Naltrexone may cause hepatocellular injury when
given in excessive dosages. It is contraindicated in
patients with significant liver disease. Liver
enzymes should be monitored.
Drug Interactions
A. Patients who are currently using opioids will
experience withdrawal due to the antagonist effect
of naltrexone. If continued opioid use is suspected,
a naloxone challenge may be used, and the patient
is observed for signs of opiate withdrawal. Patients
should be opioid free for at least 14 days before
initiation of naltrexone.
B. Naltrexone will block the analgesic effects of
opioids, and higher than average doses of
analgesics may be needed for pain relief.
C. Disulfiram and naltrexone should not be combined
because of the hepatotoxic potential of both of
these agents.
Clinical Guidelines
A. Naltrexone decreases the euphoria associated with
alcohol consumption when used in combination with
an alcohol treatment program. It reduces craving,
and there are fewer relapses. Naltrexone also
lowers consumption of alcohol when a patient does
relapse.
B. Naltrexone’s utility in opiate dependent patients is
more controversial. Some heroin dependent
patients will attempt to use high dose of heroin in
order to overcome the Mu receptor blockade. This
can lead to accidental overdose and death by
respiratory depression.
Bupropion (Zyban)
Category: Unicyclic aminoketone antidepressant.
Mechanism: Bupropion may work via alteration of
dopaminergic and noradrenergic neurotransmission.
Indications: Smoking cessation.
Preparations: 150 mg sustained release tablets.
Dosage: 150 mg Qod for several days, then increase
dosage to 150 mg bid
Half-life: 4-21 hr.
Adverse Drug Reactions
A. Most common side effects: Dry mouth, insomnia,
dizziness, and arthralgias.
B. Seizures: Rate of seizures at doses up to 300
mg/day is 0.1%. Bupropion is contraindicated in
patients with history of seizures, head trauma, brain
tumor or who are taking medications that
significantly lower seizure threshold. Avoid use in
patients with anorexia or bulimia, due to possible
electrolyte imbalances leading to seizures.
C. Mania: Bupropion can precipitate mania or rapid
cycling and should be used with caution in patients
with bipolar disorder.
D. Use caution in patients with hepatic, renal, or
cardiac disease.
E. Neuropsychiatric: In depressed patients,
bupropion has been associated with psychosis and
confusion. These symptoms abate with reduction or
discontinuation of bupropion.
F. Bupropion is not recommended during pregnancy
or while breast feeding.
Drug Interactions
A. Enzyme Inducers: Enzyme-inducing agents, such
as carbamazepine, phenobarbital, and phenytoin,
may induce lower plasma bupropion levels.
B. Cimetidine may inhibit the metabolism of bupropion,
leading to higher plasma levels.
Clinical Guidelines: Bupropion is generally well
tolerated. Efficacy compared to nicotine patches or gum
is unknown.
Donepezil (Aricept)
Class: Piperidine.
Mechanism: Reversible selective acetylcholinesterase
inhibitor.
Indications: Mild-to-moderate dementia of the
Alzheimer’s type. Donepezil does not have the potential
for hepatotoxicity associated with tacrine.
Preparations: 5, 10 mg tablets.
Dosage:
Initial Dosage: 5 mg/day for four weeks.
Maintenance Dosage: Increase dose to 10 mg Qod
after 4 weeks if tolerated.
Metabolism: Half-life is 70 hours; hepatic metabolism
through CYP2D6 and 3A4 hepatic isoenzymes, followed
by glucuronidation.
Side-Effect Profile: Most common are nausea, vomiting,
diarrhea, insomnia, muscle cramps, fatigue and anorexia,
which often resolve with continued treatment.
Clinical Guidelines: The 10-mg dose is associated with
a higher incidence of side effects, but may be more
effective. May cause syncope and exacerbate
bradycardia; therefore, beta-blockers should be avoided
or be given in a reduced dosage.
Galantamine (Reminyl)
Class: Tertiary alkaloid.
Indications: Treatment of mild-to-moderate Alzheimer’s
dementia.
Pharmacology
Mechanism of action: Reversible, competitive
acetylcholinesterase inhibitor with subsequent
enhancement of cholinergic function.
Half-life: Approximately 7 hours.
Preparations: 4, 8, and 12 mg tablets; 4 mg/ml oral
solution.
Clinical Guidelines
Dosage and Administration:
The recommended starting dose is 4 mg bid,
increasing to 8 mg twice a day (16 mg/day) after 4
weeks of treatment. A further increase to 12 mg twice
a day (24 mg/day) may be attempted after a minimum
of 4 weeks at the previous dose. The recommended
therapeutic dose for most patients is 16-24 mg/day.
Rivastigmine (Exelon)
Class: Phenyl Carbamate.
Mechanism: Reversible selective acetylcholinesterase
inhibitor.
Indications: Mild-to-moderate dementia of the
Alzheimer’s type. Rivastigmine does not have the
potential for hepatotoxicity associated with tacrine.
Preparations: 1.5, 3, 4.5, 6 mg tablets; 2 mg/mL oral
solution
Dosage:
Initial Dosage: 1.5 mg bid, after 2 weeks increase to
3 mg bid
Maintenance Dosage: 3 mg bid may be effective.
The dose can be increased if necessary to 4.5 mg
bid, and then to 6 mg bid at two week intervals if
required and if tolerated. May be given with food to
reduce GI side effects.
Metabolism: Half-life is 1.5 hours. Rivastigmine is
metabolized and eliminated by the kidneys. Because the
dose is adjusted based on tolerability, adjustments in
renally impaired patients are not always necessary.
Side Effects: Most common are nausea, vomiting,
diarrhea, dizziness, anorexia, headache, abdominal pain,
and sedation. Rivastigmine has more peripheral effects
than donepezil, which may result in more gastrointestinal
side effects.
Tacrine (Cognex)
Class: Acridine
Mechanism: Reversible non-specific cholinesterase
inhibitor (inhibits both acetyl and butyl cholinesterase
increasing occurrence of systemic side effects).
Indications: Mild-to-moderate dementia of Alzheimer’s
type. Tacrine can be hepatotoxic and is infrequently used.
Preparations: 10, 20, 30, 40 mg capsules.
Dosage:
Initial Dosage: 10 mg qid. After four weeks, the dose is
increased to 20 mg qid. Daily dose is raised by 40 mg
increments every four weeks to 120-160 mg/day.
Maintenance Dosage: 120-160 mg/day in divided doses
or qid. Tacrine should be administered at least one hour
before meals as food impairs absorption.
Metabolism: Half-life is 2-4 hours, extensive hepatic
metabolism, principally by CYP 1A2 isoenzyme. Smoking
reduces tacrine levels by induction of the CYP 1A2
isoenzyme. Women develop blood levels by 50% higher
than men.
Side-Effect Profile: Elevation of serum transaminases is
the most frequent side effect (30%). This appears to be
reversible if tacrine is discontinued. Other side effects
include nausea, vomiting, diarrhea, dizziness, agitation,
anorexia, and confusion.
Clinical Guidelines: Serum liver function (ALT/SGPT)
should be monitored every two weeks for the first 4
months of treatment. If elevation is three times normal,
dose should be reduced. Elevations of more than five
times normal, bilirubin above 3 mg/dL, hypersensitivity, or
jaundice require immediate discontinuation.
Psychiatric Side-Effect
Management
I. Indications: Parkinsonian side effects are frequently
encountered during treatment with typical antipsychotic
agents and to a lesser degree with some of the atypical
antipsychotics. Parkinsonian side effects includes
tremor, rigidity, dystonias, and akathisia.
II. Pharmacology
A. Parkinsonian side effects are thought to be
mediated by blockade of nigrostriatal dopamine D2
receptors. They typically occur early after initiation
of treatment with dopamine antagonists.
B. Antiparkinsonian drugs fall into two major
categories:
1. Anticholinergic drugs.
a. Benztropine (Cogentin).
b. Trihexyphenidyl (Artane).
c. Biperiden (Akineton).
d. Procyclidine (Kemadrin).
2. Dopamine agonists.
a. Amantadine (Symmetrel).
III.Clinical Guidelines
A. Anticholinergic agents are frequently required when
treating patients with mid- and high-potency typical
antipsychotics.
B. For patients being treated for the first time with mid-
and high-potency antipsychotics, prophylactic
treatment with an antiparkinsonian is recommended
to prevent unpleasant extrapyramidal side effects.
Prevention of these side effects can improve
compliance with antipsychotic medication. Patients
who have past exposure to antipsychotic agents will
frequently be able to report on the occurrence of
extrapyramidal side effects, and the patient should
receive anticholinergic agents.
IV. Adverse Drug Reactions
A. Anticholinergic agents can cause blurred vision, dry
mouth, constipation, urinary retention, tachycardia
and, less frequently, hyperthermia.
B. Elderly patients are more sensitive to anticholinergic
agents and are at risk for developing anticholinergic
induced delirium.
C. Anticholinergic are contraindicated in patients with
glaucoma, prostatic hypertrophy, myasthenia gravis,
duodenal or pyloric obstruction. Benztropine is the
least sedating anticholinergic agent.
D. Anticholinergic intoxication can occur if drugs with
strong anticholinergic effects are combined.
Confusion, agitation, hallucinations, ataxia,
tachycardia, blurred vision, mydriasis, increased
blood pressure, hyperpyrexia, hot and dry skin,
nausea and vomiting, seizures, coma, and
respiratory arrest can occur.
Benztropine (Cogentin)
Category: Anticholinergic (muscarinic receptor
antagonist).
Indications: Neuroleptic induced extrapyramidal
symptoms.
Preparations: 0.5, 1, 2 mg tablets; 1 mg/mL soln. (IM).
Dosage:
Acute dystonia: 1-2 mg IM (max 6 mg/day).
Chronic Extrapyramidal Symptoms: 1-2 mg PO bid-
tid. Perform trial off benztropine in 4 to 8 weeks to
determine if continued use is necessary. Taper
medication over 2 weeks.
Half-life: 3-6 hours
Side Effects: Drowsiness, dry mouth, blurred vision,
nausea, weakness, confusion, constipation, urinary
retention, sedation, drowsiness, depression, psychosis.
Interactions: Anticholinergics (eg, low-potency
neuroleptics, tricyclics, over-the-counter sleep
preparations); anticholinergic intoxication may develop.
Clinical Guidelines: Avoid using this medication with low
potency neuroleptics because of additive anticholinergic
effects. Benztropine is contraindicated in glaucoma,
prostatic hypertrophy, myasthenia gravis, duodenal or
pyloric obstruction. Benztropine is the most widely used
agent for extrapyramidal symptoms.
Trihexyphenidyl (Artane)
Category: Anticholinergic (muscarinic receptor
antagonist).
Indications: Neuroleptic induced extrapyramidal
symptoms (Extrapyramidal symptoms).
Preparations: 2, 5 mg tablets, 5 mg capsules.
Dosage: Initially 1 mg Qod, then increase to 2 mg bid-qid
(max 15 mg/day). Perform trial off trihexyphenidyl in 4 to
8 weeks to determine if continued use is necessary.
Taper medication over 2 weeks when discontinuing.
Half-life: 4-6 hours
Side Effects: Drowsiness, dry mouth, blurred vision,
nausea, weakness, confusion, constipation, urinary
retention, sedation, drowsiness, depression, psychosis.
May cause restlessness and euphoric symptoms.
Interactions: Anticholinergics (eg, low-potency
neuroleptics, tricyclics, over the counter sleep
preparations) may cause anticholinergic intoxication.
Clinical Guidelines: Avoid this medication with low-
potency neuroleptics (additive anticholinergic effects).
Trihexyphenidyl is contraindicated in glaucoma, prostatic
hypertrophy, myasthenia gravis, and duodenal or pyloric
obstruction.
Biperiden (Akineton)
Category: Anticholinergic (muscarinic receptor
antagonist).
Indications: Neuroleptic induced extrapyramidal
symptoms.
Preparations: 2 mg tablets; 5 mg/mL (IV, IM).
Dosage:
Acute dystonia: 2 mg IM. Repeat in 20 minutes, if
needed.
Chronic extrapyramidal symptoms: 2 mg PO bid-tid
(max 6 mg/day).
Perform trial off biperiden after 4 to 8 weeks to
determine if continued use is necessary. Taper
medication over 2 weeks when discontinuing.
Half-life: 4–6 hours
Side Effects: Drowsiness, dry mouth, blurred vision,
nausea, weakness, confusion, constipation, urinary
retention, sedation, drowsiness, depression, psychosis. IV
form is associated with orthostatic hypotension.
Interactions: Anticholinergics (eg, low-potency
neuroleptics, tricyclics, over-the- counter sleep
preparations) may cause anticholinergic intoxication.
Clinical Guidelines: Avoid using this medication with
low-potency neuroleptics (additive anticholinergic effects).
Biperiden is contraindicated in glaucoma, prostatic
hypertrophy, myasthenia gravis, and duodenal or pyloric
obstruction.
Amantadine (Symmetrel)
Category: Dopamine agonist
Indications: Neuroleptic induced extrapyramidal
symptoms.
Preparations: 100 mg capsules; 50 mg/5 mL syrup.
Dosage:
Initial treatment: 100 mg bid (max 400 mg/day).
Perform trial off amantadine after 4 to 8 weeks to
assess the need for continued use. Taper drug when
discontinuing use.
Half-life: 24 hours, increased in elderly.
Side Effects: Nausea (common), dry mouth, blurred
vision, constipation, anorexia, hypotension, dizziness,
anxiety, tremor, insomnia, irritability, impaired
concentration, psychosis, seizure.
Interactions:
A. Anticholinergics may rarely cause potentiation.
B. CNS stimulants may cause irritability, seizure,
arrhythmia.
C. Thiazides may increase level of amantadine.
D. Sympathomimetics may cause potentiation.
Clinical Guidelines: Amantadine is associated with less
memory impairment than anticholinergics. It is useful
when anticholinergics must be avoided. Amantadine is
less effective than anticholinergics in treatment of acute
dystonias.
Diphenhydramine (Benadryl)
Category: Histamine receptor (H1) antagonist,
muscarinic receptor antagonist
Indications: Neuroleptic-induced extrapyramidal
symptoms (Extrapyramidal symptoms), mild insomnia.
Preparations: 25, 50 mg tablets; 25, 50 mg capsules; 10
mg/mL & 50 mg/mL soln. (IM, IV), 12.5 mg/5 mL elixir
(PO).
Dosage:
Extrapyramidal symptoms: 25-50 mg PO Bid, for
acute Extrapyramidal symptoms 25-50 mg IM or IV.
Half-Life: 1-4 hrs.
Side Effects: Dry mouth, dizziness, drowsiness, tremor,
thickening of bronchial secretions, hypotension,
decreased motor coordination, GI distress.
Interactions.
A. The major concern about concomitant medication
use with diphenhydramine is the additive effect of
other sedatives and other medications with
anticholinergic activity.
B. Medical conditions that are sensitive to
anticholinergic action such as narrow angle
glaucoma and prostatic hypertrophy may worsen.
C. MAOI use can prolong and intensify anticholinergic
effects. Opiate addicts commonly add
antihistamines to enhance the subjective effect of
the illicit drug.
Clinical Guidelines: Diphenhydramine is non-addicting
and available over the counter.
References
DEMENTIA
290.xx Dementia of the Alzheimer's Type, With
Early Onset (also code 331.0 Alzheimer's
disease on Axis III)
.10 Uncomplicated
290.xx Dementia of the Alzheimer's Type, With
Late Onset (also code 331.0 Alzheimer's
disease on Axis III)
.0 Uncomplicated
290.xx Vascular Dementia
.40 Uncomplicated
ALCOHOL-RELATED DISORDERS
COCAINE-RELATED DISORDERS
304.20 Cocaine Dependence
305.60 Cocaine Abuse
OPIOID-RELATED DISORDERS
304.00 Opioid Dependence
305.50 Opioid Abuse
POLYSUBSTANCE-RELATED
DISORDER
304.80 Polysubstance Dependence
DEPRESSIVE DISORDERS
296.xx Major Depressive Disorder
.2x Single Episode
.3x Recurrent
300.4 Dysthymic Disorder
311 Depressive Disorder NOS
BIPOLAR DISORDERS
296.xx Bipolar I Disorder,
.0x Single Manic Episode
.40 Most Recent Episode Hypomanic
.4x Most Recent Episode Manic
.6x Most Recent Episode Mixed
.5x Most Recent Episode
Depressed
.7 Most Recent Episode Unspecified
296.89 Bipolar II Disorder
301.13 Cyclothymic Disorder
296.80 Bipolar Disorder NOS
293.83 Mood Disorder Due to...
[Indicate the General Medical Condition]
ANXIETY DISORDERS
300.01 Panic Disorder Without Agoraphobia
300.21 Panic Disorder With Agoraphobia
300.22 Agoraphobia Without History of Panic
Disorder
300.29 Specific Phobia
300.23 Social Phobia
300.3 Obsessive-Compulsive Disorder
309.81 Posttraumatic Stress Disorder
308.3 Acute Stress Disorder
300.02 Generalized Anxiety Disorder
EATING DISORDERS
307.1 Anorexia Nervosa
307.51 Bulimia Nervosa
307.50 Eating Disorder NOS
ADJUSTMENT DISORDERS
309.xx Adjustment Disorder
.0 With Depressed Mood
.24 With Anxiety
.28 With Mixed Anxiety and Depressed Mood
.3 With Disturbance of Conduct
.4 With Mixed Disturbance of Emotions and
Conduct
.9 Unspecified
PERSONALITY DISORDERS
301.0 Paranoid Personality Disorder
301.20 Schizoid Personality Disorder
301.22 Schizotypal Personality Disorder
301.7 Antisocial Personality Disorder
301.83 Borderline Personality Disorder
301.50 Histrionic Personality Disorder
301.81 Narcissistic Personality Disorder
301.82 Avoidant Personality Disorder
301.6 Dependent Personality Disorder
301.4 Obsessive-Compulsive Personality Disorder
301.9 Personality Disorder NOS