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Transcript
Psychotropic drugs
Prof elham aljammas
Sept 2015
objectives
Identify general pharmacologic strategies
 Discuss antidepressants including indications
for use and side effects
 Describe mood stabilizers including
indications for use and side effects
 Review antipsychotics including how to
choose an antipsychotic and side effects
 Identify anxiolytic classes and indications for
use

Management strategies
-Adjust dosage for optimum benefit,
safety and compliance.
-Use adjunctive and combination
therapies if needed however always
strive for the simplest regimen.
-Keep your therapeutic endpoint in
mind.
Psychotropic drugs
 Treat
mood, cognition, and behavioral
disturbances associated with
psychological disorders
 Most are not used recreationally or
abused
 Benzodiazepines are the exception
General classes of disorders
Mood
 Anxiety
 Psychotic
 Other Disorders
 Attention Deficit Disorder

Depression

Depression is a serious disorder that
afflicts approximately 14 million adults in
the United States each year. The lifetime
prevalence rate of depression in the
United States has been estimated to
include 16 percent of adults (21 percent
of women, 13 percent of men), or more
than 32 million people
Antidepressants
Indications:
 Unipolar and bipolar depression,
 organic mood disorders,
 schizoaffective disorder,
 anxiety disorders including OCD, panic,
social phobia, PTSD,
 premenstrual dysphoric disorder
 and impulsivity associated with
personality disorders.

General guidelines



Antidepressant efficacy is similar so selection
is based on past history of a response, side
effect profile and coexisting medical
conditions.
There is a delay typically of 3-6 weeks after a
therapeutic dose is achieved before
symptoms improve.
If no improvement is seen after a trial of
adequate length (at least 2 months) and
adequate dose, either switch to another
antidepressant or augment with another
agent.
Mood disorders/Antidepressants
MAO Inhibitors
 Tricyclics
 Selective Serotonin
Reuptake Inhibitors
 Dual Action
Antidepressants
 Selective Norepinephrine
Reuptake Inhibitors
 Atypical antidepressant

Mood Stabilizers
(Antimanic
Agents)
LithiumCarbonate
Valproic Acid
Carbamazepine
Lamotragine
Topirimate
MAOI








Use in late 1950s & ended in early 1960s
use ended due to side effect (death)
MAO breaks down many chemicals including
tyramine
Tyramine is present in cheeses, red wines, alcohol,
smoked fish
MAO in liver breaks down tyramine
Causes a hypertensive crisis "cheese syndrome"
increased blood pressure ➔ stroke ➔ death
increased heart rate ➔ heart attack ➔ death
MAOI
Bind irreversibly to monoamine oxidase thereby
preventing inactivation of biogenic amines such as
norepinephrine, dopamine and serotonin leading
to increased synaptic levels.
 Are very effective for depression
 Side effects include orthostatic hypotension,
weight gain, dry mouth, sedation, sexual
dysfunction and sleep disturbance
 Hypertensive crisis can develop when MAOI’s are
taken with tyramine-rich foods or
sympathomimetics.

MAOI


Serotonin Syndrome can develop if take
MAOI with meds that increase serotonin or
have sympathomimetic actions. Serotonin
syndrome sx include abdominal pain,
diarrhea, sweats, tachycardia, HTN,
myoclonus, irritability, delirium. Can lead to
hyperpyrexia, cardiovascular shock and
death.
To avoid need to wait 2 weeks before
switching from an SSRI to an MAOI. The
exception of fluoxetine where need to wait
5 weeks because of long half-life.
SSRI
s
Tricyclic antidepressants
Act as agonists to catecholamines
 No "cheese syndrome"
 Side effects are the major problem
 Cardiotoxic
 Sedative action
 Block acetylcholine system, especially
muscarinic receptors
 blurred vision, dry mouth, urinary retention,
constipation, mental confusion
 Block histamine receptors - sedation

prescaution
Very effective but potentially unacceptable
side effect profile i.e. antihistaminic,
anticholinergic, antiadrenergic
 Lethal in overdose (even a one week
supply can be lethal!)
 Can cause QT lengthening even at a
therapeutic serum level

TCA
Have tertiary amine side chains
 Side chains are prone to cross react with other
types of receptors which leads to more side
effects including antihistaminic (sedation and
weight gain), anticholinergic (dry mouth, dry eyes,
constipation, memory deficits and potentially
delirium), antiadrenergic (orthostatic hypotension,
sedation, sexual dysfunction)
 Act predominantly on serotonin receptors
 Examples:Imipramine, amitriptyline, doxepin,
clomipramine

SSRI












Selectively block re-uptake of 5-HT
Work on DA and NE as well but very little
Eliminate ACh and antihistamine effects
No more effective than MAOIs or tricyclics
Better because there are fewer side effects
On market since late 1980s & early 1990s
Fluoxetine – Prozac
Sertraline - Zoloft
Paroxetine - Paxil
Fluvoxamine - Luvo
Citalopram - Celexa
Escitalopram - Lexapro
SSRI












Selectively block re-uptake of 5-HT
Work on DA and NE as well but very little
Eliminate ACh and antihistamine effects
No more effective than MAOIs or tricyclics
Better because there are fewer side effects
On market since late 1980s & early 1990s
Fluoxetine – Prozac
Sertraline - Zoloft
Paroxetine - Paxil
Fluvoxamine - Luvo
Citalopram - Celexa
Escitalopram - Lexapro
Selective serotonin reuptake
inhibitors





Block the presynaptic serotonin reuptake
Treat both anxiety and depressive
Most common side effects include GI upset,
sexual dysfunction (30%+!), anxiety,
restlessness, nervousness, insomnia, fatigue
or sedation, dizziness
Very little risk of cardiotoxicity in overdose
Can develop a discontinuation syndrome
with agitation, nausea, disequilibrium and
dysphoria
SNRI
Selectively inhibits NE transporter.

Blocks re-uptake.
 Atomoxetine (Strattera)
 Reboxetine (Edronax,Vestra)
 Dual action AD
 Affinity for both 5-HT and NE.
 Block re-uptake for both
 In this sense, like TCAs
 Duloxetine - Cymbalta

Atypical Antidepressants
The atypical antidepressants are a mixed
group of agents that have actions at
several different sites. This group includes
bupropion
, mirtazapine
,nefazodone], and
trazodone

atypical antidepressants
Bupropion (Wellbutrin)
 No effect on either 5-HT or NE
 Effective at blocking DA reuptake
 May be similar action to cocaine
 Lowers seizure threshold
 Venlafaxine (Effexor)
 5-HT, DA and NE reuptake blocker

Drugs for bipolar


Treat the manic phases of Bipolar Disorder
Lithium




Valproic Acid
Carbamazepine/Oxcarbazepine
Lamotragine
Topirimate

Symbyax – Combo of olanzepine and
fluoxetine (Zyprexa & Prozac)
Mood Stabilizers
Indications: Bipolar, cyclothymia,
schizoaffective, impulse control and
intermittent explosive disorders.
 Classes: Lithium, anticonvulsants,
antipsychotics
 Which you select depends on what you
are treating and again the side effect
profile.

lithium
Only medication to reduce suicide rate.
Rate of completed suicide in BAD ~15%
Effective in long-term prophylaxis of both
mania and depressive episodes in 70+% of
BAD I pts
 Factors predicting positive response to
lithium
 Prior long-term response or family member
with good response
 Classic pure mania
 Mania is followed by depression



LITHIUM
Before starting :Get baseline creatinine, TSH
and CBC. In women check a pregnancy testduring the first trimester is associated with
Ebstein’s anomaly 1/1000 (20X greater risk
than the general population)
 Monitoring: Steady state achieved after 5
days- check 12 hours after last dose. Once
stable check q 3 months and TSH and
creatinine q 6 months.
 Goal: blood level between 0.6-1.2mmol /lit

Lithium side effects






Most common are GI distress including reduced
appetite, nausea/vomiting, diarrhea
Thyroid abnormalities
Non significant leukocytosis
Polyuria/polydypsia secondary to ADH
antagonism. In a small number of patients can
cause interstitial renal fibrosis.
Hair loss, acne
Reduces seizure threshold, cognitive slowing,
intention tremor
Lithium toxicity
Mild- levels 1.5-2.0 see vomiting, diarrhea,
ataxia, dizziness, slurred speech,
nystagmus.
 Moderate-2.0-2.5 nausea, vomiting,
anorexia, blurred vision, clonic limb
movements, convulsions, delirium,
syncope
 Severe- >2.5 generalized convulsions,
oliguria and renal failure

Study Questions







Choose the ONE best answer.
12.1 A 55-year-old teacher began to experience changes in mood.
He was losing interest in his work and lacked the desire to play his
daily tennis match. He was preoccupied with feelings of guilt,
worthlessness, and hopelessness. In addition to the psychiatric
symptoms, the patient complained of muscle aches throughout his
body. Physical and laboratory tests were unremarkable. After 6
weeks of therapy with fluoxetine, the patient's symptoms resolved.
However, the patient complains of sexual dysfunction.Which of the
following drugs might be useful in this patient?
A. Fluvoxamine.
B. Sertraline.
C. Citalopram.
D. Mirtazapine.
E. Lithium.

Correct answer = D. Sexual
dysfunction commonly occurs with
TCAs, SSRIs, and SNRIs. Mirtazapine is
largely free from sexual side effects.
A 25-year-old woman has a long history of
depressive symptoms accompanied by body
aches. Physical and laboratory tests are
unremarkable. Which of the following drugs
might be useful in this patient?
 A. Fluoxetine.
 B. Sertraline.
 C. Phenelzine.
 D. Mirtazapine.
 E. Duloxetine.

Correct answer = E. Duloxetine is an
SNRI that can be used for depression
accompanied by neuropathic pain.
MAOs and SSRIs have little activity
against neuropathic pain
A 51-year-old woman with symptoms of
major depression also has narrow-angle
glaucoma. Which of the following
antidepressants should be avoided in this
patient?
 A. Amitriptyline.
 B. Sertraline.
 C. Bupropion.
 D. Mirtazepine.
 E. Fluvoxamine.


Correct answer = A. Because of its
potent antimuscarinic activity,
amitriptyline should not be given to
patients with glaucoma because of the
risk of acute increases in ocular
pressure. The other antidepressants all
lack antagonist activity at the
muscarinic receptor.
A 36-year-old man presents with symptoms of
compulsive behavior. If anything is out of order,
he feels that “work will not be
accomplished effectively or efficiently.―
He
realizes that his behavior is interfering with his
ability to accomplish his daily tasks but cannot
seem to stop himself. Which of the following
drugs would be most helpful to this patient?
 A. Imipramine.
 B. Fluvoxamine.
 C. Amitriptyline.
 D. Tranylcypromine.
 E. Lithium.

Correct answer = B. Selective serotonin
reuptake inhibitors are particularly
effective in treating obsessivecompulsive disorder; flu vox amine is
approved for this condition. The other
drugs are ineffective in the treatment
of obsessive-compulsive disorder.
Neuroleptics
prof Dr Elham Aljammas
23/10/2013
Antipsychotics used to treat
schizophrenia.
Schizophrenia is a severe chronic disorder
 Positive symptoms: hallucinations, and
delusions
 Negative symptoms: amotivation, poverty
of speech, flat affect
 Disorganized symptoms: speech, thought,
and behavior
 Now being used to treat Bipolar as well

Antipsychotics
Indications for use:
 schizophrenia, schizoaffective disorder,
bipolar disorder- for mood stabilization
and/or when psychotic features are
present, delirium,
 psychotic depression,
 dementia,
 trichotillomania, augmenting agent in
treatment resistant anxiety disorders.

Pathways affected by DA in the
Brain
Antagonize dopamine – block a
specific receptor
Typical
Chlorpromazine
Trifluperazine
Thorazine
Haloperidol –
(Haldol)
Atypical
Risperdal - Risperidone
Olanzepine - Zyprexia
Quetiapine - Seroquel
Ziprasidone – Geodon
Aripiprazole – Abilify
Paliperidone – Invega
The Atypical Antipsychotics
agents are serotonindopamine 2 antagonists (SDAs)
 They are considered atypical in the
way they affect dopamine and
serotonin neurotransmission in the
four key dopamine pathways in the
brain.

- atypical
Antipsychotics drugs
(typical)
group
drug
Usual dose
phenothiazines
chlorpromazine
100-1500mg daily
butyrophenones
haloperidol
thioxanthenes
flupentixol
Diphenylbutylpiperidines
Pimozide
5-30mg daily
50-100mg IMI
monthly
5mg IMI orIVI on
need
40-200mg fortnight
Short & long acting
4-30mg daily
Neuroleptics
.
The traditional or typicalneuroleptic drugs
(also called conventional or first-generation
antipsychotics) are competitive inhibitors at
a variety of receptors, but their
antipsychotic effects reflect competitive
blocking of dopamine receptors. These drugs
vary in potency. For example,
chlorpromazine is a low-potency drug, and
fluphenazine is a high-potency agent No one
drug is clinically more effective than another.
Atypical antipsychotic agent
group
drugs
Usual dose
dibenzodiazepine
clozapine
25-900mg daily
Bezisoxazole
Quetiapine -
Risperidone
Seroquel
2-16mg daily
100-200mg/d
thienobenzodiazepin olanzapine
5-20mg daily
Atypical
 atypical
agents are serotonindopamine 2 antagonists (SDAs)
 They are considered atypical in the
way they affect dopamine and
serotonin neurotransmission in the
four key dopamine pathways in the
brain.
Mechanism of action

Dopamine receptor blocking activity in the brain:. D1 and D5 receptors
activate adenylyl cyclase, often exciting neurons, whereas D2, D3 and D4
receptors inhibit adenylyl cyclase, or mediate membrane K+ channel
opening leading to neuronal hyperpolarization. The neuroleptic drugs bind
to these receptors to varying degrees. However, the clinical efficacy of
the typical neuroleptic drugs correlates closely with their relative
ability to block D2 receptors in the mesolimbic system of the
brain. atypical drug clozapine has higher affinity for the D4 receptor
and lower affinity for the D2 receptor, which may partially explain
its minimal ability to cause extrapyramidal side effects (EPS).

Serotonin receptor blocking activity in the brain: Most of the newer
atypical agents appear to exert part of their unique action through
inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors.
(clozapine ,olanzapine,aripiprazole , Quetiapine ).
The undesirable side effects of these agents, however,
are often a result of actions at these other receptors.

Antipsychotic actions: All of the neuroleptic drugs can reduce the
hallucinations and delusions associated with schizophrenia
by blocking dopamine receptors in the mesolimbic system of the brain.
The antipsychotic effects usually take several days to weeks to occur,
suggesting that the therapeutic effects are related to secondary
changes in the corticostriatal pathways.


Extrapyramidal effects: Dystonias (sustained contraction of muscles
leading to twisting distorted postures), parkinson-like symptoms,
akathisia (motor restlessness), and tardive dyskinesia (involuntary
movements of the tongue, lips, neck, trunk, and limbs) occur with
chronic treatment. Blocking of dopamine receptors in the nigrostriatal
pathway probably causes these unwanted movement symptoms. The
atypical neuroleptics exhibit a lower incidence of these symptoms.
Antiemetic effects: With the exceptions of
aripiprazole and thioridazine , most of the
neuroleptic drugs have antiemetic effects that are
mediated by blocking D2-dopaminergic receptors
of the chemoreceptor trigger zone of the medulla.
 Antimuscarinic effects: Some of the neuroleptics,
particularly thioridazine, chlorpromazine, clozapine,
and olanzapine ,produce anticholinergic effects,
including
blurred vision dry mouth (exception: clozapine
increase salivation), confusion, and inhibition of
gastrointestinal and urinary tract smooth muscle,
leading to constipation and urinary retention. This
anticholinergic property may actually assist in
reducing the risk of EPS with these agents.

Important side effects to be
considered when choosing
antipsychotic drugs
◦ 1-Extrapyramidial side effects:

Atypical antipsychotic has less
extrapyramidal effect.
2-hyperprolactinaemia:
Lead to
menstrual disturbances,increased risk of
malignancy,increased galactorrhea,& increased
osteoporosis.
Prolactine sparingis aripiprazole
 3-sedationIncreased sedation with high affinity
to histamine& muscarinic receptors
CPZ,olanzapine,clozapine
Helpful in acute state
4-weight gain:
Histamine & 5HT R block
(>olanzapine)less with
resperidone,amisulpride,&aripipraz
5.Type 11 DM
>clozapine &olanzapine
Should be monitored by Bd sugar,lipid
profile& weight.
6-CV& cerbrovascular events ,
through their effect on the
lipid profile ,Wt,& insulin
resistance. Some produce prolonge QT
interval.
olanzapine& resperidone
7-postural hypotension

8-sexual dysfunction

9-photosensitivity
10-agranulocytosis
11-constipation
12-reduction of fit threshold

Other effects: Blockade of -adrenergic receptors
causes orthostatic hypotension and lightheadedness. The neuroleptics also alter
temperature-regulating mechanisms and can
produce poikilothermia (body temperature varies
with the environment). In the pituitary,
neuroleptics block D2 receptors, leading to an
increase in prolactin release. Atypical neuroleptics
are less likely to produce prolactin elevations.
Sedation occurs with those drugs that are potent
antagonists of the H1-histamine receptor, including
chlorpromazine, olanzapine, quetiapine, and
clozapine. Sexual dysfunction may also occur with
the antipsychotics due to various receptor-binding
characteristics.
Therapeutic uses
Treatment of schizophrenia:
 The neuroleptics are considered to be the only efficacious
treatment for schizophrenia.
 Prevention of severe nausea and vomiting: The older neuroleptics
(most commonly prochlorperazine) are useful in the treatment
of drug-induced nausea


Other uses: The neuroleptic drugs can be used as tranquilizers to
manage agitated and disruptive behavior secondary to other
disorders.
 Neuroleptics are used in combination with narcotic analgesics
for treatment of chronic pain with severe anxiety
 . Chlorpromazine is used to treat intractable hiccups.
 Promethazine, this agent is used in treating pruritus .

Pimozide is primarily indicated for
treatment of the motor and phonic tics of
Tourette's disorder. risperidone and
haloperidol are also commonly prescribed
for this tic disorder.
 Also, risperidone is now approved for the
management of disruptive behavior and
irritability secondary to autism

Antipsychotic adverse effect
Tardive Dyskinesia (TD)-involuntary muscle
movements that may not resolve with drug
discontinuation- risk approx. 5% per year
 Neuroleptic Malignant Syndrome (NMS):
Characterized by severe muscle rigidity,
fever, altered mental status, autonomic
instability, elevated WBC, CPK and lfts.
Potentially fatal.
 Extrapyramidal side effects (EPS): Acute
dystonia, Parkinson syndrome, Akathisia

Adverse effects
 . Parkinson-like symptoms of
bradykinesia, rigidity, and tremor usually
occur within weeks to months of
initiating treatment. Clozapine can
produce bone marrow suppression,
seizures, and cardiovascular side effects.
The risk of severe agranulocytosis
necessitates frequent monitoring of
white-blood-cell counts
 . The
neuroleptics depress the
hypothalamus, affecting
thermoregulation, and causing
amenorrhea, galactorrhea,
gynecomastia, infertility, and impotence.
Significant weight gain is often a reason
for noncompliance. It is also
recommended that glucose and lipid
profiles be monitored in patients taking
antipsychotics
The choice of medication &dose
:depend on
1-sevirety of the problems.
 2-degree of sedation required.
 3-side effect profile.
 4-preferance of individual clinician.

Study Questions







Choose the ONE best answer.
13.1 An adolescent male is newly diagnosed
with schizophrenia. Which of the following
neuroleptic agents may improve his apathy
and blunted affect?
A. Chlorpromazine.
B. Fluphenazine.
C. Haloperidol.
D. Risperidone.
E. Thioridazine
Correct answer = D. Risperidone is the
only neuroleptic on the list that has
some benefit in improving the negative
symptoms of schizophrenia. All the
agents have the potential to diminish
the hallucinations and delusional
thought processes.
Which one of the following neuroleptics
has been shown to be a partial agonist at
the D2 receptor?
 A. Aripiprazole.
 B. Clozapine.
 C. Haloperidol.
 D. Risperidone.
 E. Thioridazine.


Correct answer = A. Aripiprazole is the
agent that acts as a partial agonist at D2
receptors. Theoretically, the drug would
enhance action at these receptors when
there is a low concentration of dopamine
and would block the actions of high
concentrations of dopamine. All the other
drugs are only antagonistic at D2
receptors, with haloperidol being
particularly potent.






A 21-year-old male has recently begun pimozide
therapy for Tourette's disorder. He is brought to the
emergency department by his parents. They
describe that he has been having “differentappearing tics―
than before, such as prolonged
contraction of the facial muscles. While being
examined, he experiences opisthotonus (spasm of
the body where the head and heels are bent
backward and the body is bowed forward. A type of
extrapyramidal effect). Which of the following drugs
would be beneficial in reducing these symptoms?
A. Benztropine.
B. Bromocriptine.
C. Lithium.
D. Prochlorperazine.
E. Risperidone
Correct answer = A.The patient is
experiencing extrapyramidal
symptoms due to pimozide, and a
muscarinic antagonist such as
benztropine would be effective in
reducing the symptoms.The other
drugs would have no effect or, in the
case of prochlorperazine, might
increase the symptoms.
A 28-year-old woman with schizoid
affective disorder and difficulty sleeping
would be most benefited by which of the
following drugs?
 A. Aripiprazole.
 B. Chlorpromazine.
 C. Haloperidol.
 D. Risperidone.
 E. Ziprasidone.

Correct answer = B. Chlorpromazine has
significant sedative activity as well as
antipsychotic properties. Of the
choices, it is the drug most likely to
alleviate this patient's major
complaints, including her insomnia
Anxiolytic
Prof. Dr Elham Aljammas
Anxiolytic
Treat anxiety disorders
 Generalized Anxiety Disorder
 Panic Disorder
 PTSD
 OCD
 Social Anxiety Disorder (SAD)

Anxiolytic
Used to treat many diagnoses including
panic disorder,
 generalized Anxiety disorder,
 substance-related disorders and their
withdrawal,
 insomnias and parasomnias.
In anxiety disorders often use anxiolytics in
combination with SSRIS or SNRIs for
treatment.

Benzodiazepines
Used to treat insomnia, parasomnias and
anxiety disorders.
 Often used for CNS depressant withdrawal
protocols ex. ETOH withdrawal.
 Side effects/cons
 Somnolence
 Cognitive deficits
 Amnesia
 Disinhibition
 Tolerance
 Dependence

Dose Equivalency
(mg)
Drug
Alprazolam (Xanax)
0.5
Peak Blood
Level
(hours)
Elimination HalfLife1 (hours)
1-2
12-15
Rapid oral absorption
2-4
15-40
Active metabolites; erratic
bioavailability from IM
injection
1-4
18-50
Can have layering effect
1-2
20-80
Active metabolites; erratic
bioavailability from IM
injection
1-2
40-100
Active metabolites with long
half-lives
1-6
10-20
No active metabolites
2-4
10-20
No active metabolites
2-3
10-40
Slow oral absorption
Comments
10.0
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
0.25
5.0
Diazepam (Valium)
30.0
Flurazepam (Dalmane)
Lorazepam (Ativan)
Oxazepam (Serax)
Temazepam (Restoril)
1.0
15.0
30.0
0.25
Triazolam (Halcion)
1
2-3
Rapid onset; short duration of
action
Monitor for efficacy and tolerance and adjust
as indicated.
If the patient does not improve step back,
rethink your diagnosis and treatment plan!
Keep an eye on drug-drug interactions
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Benzodiazepines
Facilitate GABA neurotransmission
Bind to a particular site on the GABA receptor
Xanax, Ativan, Valium, Serax, Librium
Beta-Blockers
Antagonize NE by blocking Beta receptor subtype
SSRIs
PTSD, OCD, SAD, and to some degree GAD
Others
Buspar
Non-sedating
Does not interact with alcohol
Not highly effective
ADD
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Methylphenidate – Ritalin
DA reuptake inhibitor
So slowly it enters the brain that it is not addictive like
cocaine even though they have the same mechanism
Concerta (Immediate release combined with time release)
Adderal (mixed amphetamine salts)
Has extended release
Modafinil – Provigil
Vyvanse
An amphetamine pro-drug
Less abusable
Straterra
Mixing Med.
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Although classified as a certain type of drug most
psych meds used for many different disorders.
Antipsychotics in Bipolar Disorder
Abilify
Zyprexa
Mood stabilizers in alcoholism
Topiramate
Prescribing a medication for a disorder when it is
known to work, but there is no formal FDA
indication is called “off-label prescribing”
It’s perfectly legal and quite common
Thank You