Transcript Psychopharmacology

Psychopharmacology
Greg Matthew Teo (MD080087)
ASMPH 2013 YL8
Outline
I. Basic Biologic Principles
II. Psychosis and Schizophrenic
Disorders
III.Mood Disorders
IV.Anxiety Disorders
I. BASIC BIOLOGIC PRINCIPLES
Neurotransmitter – chemical signals
that flow between neurons
• The molecule is synthesized in the neuron.
• The molecule is present in the presynaptic
neuron and is released on depolarization in
physiologically significant amounts.
• When administered exogenously as a drug, the
exogenous molecule mimics the effects of the
endogenous neurotransmitter.
• A mechanism in the neurons or the synaptic cleft
acts to remove or deactivate the
neurotransmitter.
II. PSYCHOSIS AND SCHIZOPHRENIC
DISORDERS
Pathophysiology: Dopamine
Hypothesis
• Dopaminergic hyperactivity linked to severity of
POSITIVE psychotic symptoms
• Proposed mechanisms:
• Too much release of dopamine
• Too many dopamine receptors
• Hypersensitivity of dopamine receptors
• No specified dopamine tract although
MESOCORTICAL and MESOLIMBIC tracts are
most often implicated
4 Dopaminergic Pathways
Dopaminergic Pathways in
PSYCHOSIS
• Mesocortical Dopaminergic Pathway
• Involves the prefrontal cortex
• Predominance of D1 receptors
• HYPOACTIVITY results to negative symptoms
• Mesolimbic Dopaminergic Pathway
• Involves the limbic system
• Predominance of D2 receptors
• HYPERACTIVITY results to positive symptoms
Other hypotheses for Schizophrenia
• Serotonin excess causes both positive and
negative symptoms in schizophrenia
• Neuronal degeneration within the
norepinephrine reward neural system can cause
ANHEDONIA
• Loss of inhibitory GABAergic neurons can lead to
hyperactivity of dopaminergic neurons
A. TYPICAL ANTIPSYCHOTICS
(DOPAMINE RECEPTOR ANTAGONISTS)
Class
Examples
Potency
Aliphatic
Chlorpromazine
(Thorazine)
Low potency
Piperazine
Fluphenazine (Permitil)
Thioridazine (Mellaril)
High potency
Low-potency
THIOXANTHENES
Thiothixene (Navane)
High-potency
DIHYDROINDOLE
Molindone (Moban)
High-potency
BUTYROPHENONES
Haloperidol (Haldol)
High potency
PHENOTHIAZINES
• Low-potency drugs – given in doses of several
hundred milligrams per day; produce MORE
WEIGHT GAIN and SEDATION
• High-potency drugs – less than 10 mg per day;
more likely to cause EXTRAPYRAMIDAL SYMPTOMS
Typical Antipsychotics
• Mechanism of action for antipsychotic activity:
high-affinity antagonism of DOPAMINE D2
receptors
• Also block noradrenergic, cholinergic, and
histaminergic receptors
• 1st mainstay treatment of schizophrenia during
the 1950s-1980s
• No longer the mainstay of the treatment of
schizophrenia with the advent of ATYPICAL
ANTIPSYCHOTICS
• Therapeutic Effects
on Schizophrenia:
• Reduce both acute
psychotic
symptoms and
prevent future
exacerbations
• Most dramatic
effects against
POSITIVE
SYMPTOMS
• May worsen
negative symptoms
• Indications
• Acute psychotic episodes in
schizophrenia and
schizoaffective disorder
• Maintenance treatment in
schizophrenia and
schizoaffective disorders
• Mania
• Depression with psychotic
symptoms
• Delusional disorder
• Borderline personality disorder
• Substance-induced psychotic
disorder
• Delirium and dementia
• Mental disorders due to a
medical condition
• Childhood schizophrenia
• Pervasive developmental
disorder
• Tourette's syndrome
• Huntington's disease
Side Effects:
• Neurological
• Acute extrapyramidal syndromes
• Akathisia
• Acute dystonia
• Drug-induced parkinsonism
• Neuroleptic malignant syndrome
• Chronic extrapyramidal syndromes
• Tardive dyskinesia and dystonia
• Perioral tremor
• Can lower the seizure threshold – Molindone is
the least epileptogenic
Side Effects:
• Orthostatic (Postural) Hypotension
• Cardiac – low-potency drugs cause prolongation of
QT and PR intervals, blunting of T waves and ST
depression
• Endocrine – breast enlargement, galactorrhea,
amenorrhea, inhibited orgasm in women and
impotence in men
• Peripheral Anticholinergic Effects
• dry mouth and nose, blurred vision, constipation,
urinary retention, mydriasis, CONSTIPATION
• WEIGHT GAIN not as severe as with atypicals
B. ATYPICAL ANTIPSYCHOTICS
(SEROTONIN-DOPAMINE
ANTAGONISTS)
Mechanism of Action
• Higher ratio of serotonin type 2 (5HT2A) to D2
receptor blockade  more specific for
mesolimbic than striatal dopamine system 
reduced risk for EPS and tardive dyskinesia
• Examples:
• Risperidone (Risperdal)
• Olanzapine (Zyprexa)
• Quetiapine (Seroquel)
• Clozapine (Clozaril)
• Ziprasidone (Geodon)
Indications
• Schizophrenia and Schizoaffective Disorder
• Proven efficacy for treatment of positive
symptoms and clearly superior than DRAs for
treatment of negative symptoms
• Fewer relapses and less frequent
hospitalizations than DRAs
• Acute Mania
• Maintenance Treatment for Bipolar Disorder –
Olanzapine
• Augment antidepressants in acute management
of Major Depression
Risperidone (Risperdal)
• Dosage: 1-2 mg at night which can then
be raised to 4 mg per day
• Side effects:
• Extrapyramidal effects are dosage
dependent
• Weight gain, anxiety, nausea and
vomiting, rhinitis, erectile
dysfunction, orgasmic dysfunction
and increased pigmentation
• Only SDA currently available in depot
formulation
• 25, 50 or 75 mg IM every 2 weeks
Olanzapine (Zyprexa)
• Dosages: starting daily dose of 5-10
mg raised to 10 mg a day
• Side effects:
• More frequent weight gain than
other atypical antipsychotics
which plateaus after about 10
months and is not dose-related
• Constipation, somnolence, dry
mouth, dizziness, dyspepsia,
increased appetite, akathisia,
tremor
Quetiapine (Seroquel)
• Side effects:
• Most common: somnolence,
postural hypotension, and
dizziness
• SDA to least likely cause
extrapyramidal side effects,
regardless of dose
• Dosages:
• 400 mg/day for Schizophrenia
• 800 mg/day for mania
• 300 mg/day for bipolar depression
• 25-300 mg at night for insomnia
Ziprasidone (Geodon)
• Also considered a serotoninnorepeinephrine reuptake
inhibitor (SNRI)
• Side effects:
• No significant effects outside
the CNS
• Almost no weight gain and no
prolactin elevation
• BUT can cause QT
prolongation thus
contraindicated in patients
with arrythmias
Clozapine (Clozaril)
• Not considered a first-line
agent because of its side
effects and need for weekly
blood tests
• Can cause agranulocytosis –
0.73% risk during the 1st year
• Good for suicidality
Aripiprazole (Abilify)
• Potent 5-HT2A antagonist but
unlike other SDAs it is a partial
D2 agonist
• Competes with D2 receptors
for endogenous dopamine
 functional reduction of
dopamine activity
• Usually nonsedating and has
not been found to pose an
increased risk of weight gain
and diabetes
C. PHASES OF TREATMENT
Acute Psychosis
• lasts from 4-8 weeks
• Typically associated with severe agitation
• Goal: alleviate most severe psychotic symptoms
• Give antipsychotics and benzodiazepines
• Single IM injection of haloperidol (Haldol),
fluphenazine (Prolixin, Permitil), olanzapine
(Zyprexa), or ziprasidone (Geodon) 
calming without excess sedation
Stabilization and Maintenance
Phase
• Goal: prevent relapse and to assist patient in
improving their level of functioning
• 16-23% of patients receiving treatment will
relapse within a year
• 53-72% of patients without medications will
relapse within a year
• Generally recommended that multiepisode
patients receive maintenance treatment for at
least 5 years
III. MOOD DISORDERS
A. PHARMACOTHERAPY FOR MAJOR
DEPRESSION
Monoamine hypothesis of
Depression
• depression is related
to a deficiency in the
amount or function
of cortical and limbic
serotonin (5-HT),
norepinephrine (NE),
and dopamine (DA).
Serotonin – Raphe
Nuclei
Noradrenaline – locus
ceruleus
Acute Phase of Treatment
• Lasts a minimum of 6-12 weeks
• Goals: induce remission of symptoms and
achieve a full return to the patient’s baseline
level of functioning
• Antidepressant medications can be used as an
initial treatment modality by patients with mild,
moderate or severe MDD
Acute Phase of Treatment
• Clinical Features that may suggest that
medications are the preferred treatment:
• History of prior positive response to
antidepressant medications
• Presence of moderate to severe symptoms
• Significant sleep or appetite disturbances
• Agitation
• Patient preference
• Anticipation of the need for maintenance
therapy
Choosing an Antidepressant
Medication
• No replicable or robust
findings to establish a clinically
meaningful difference
• For most patients, the
effectiveness of
antidepressant medications is
generally comparable between
and within classes
• Antidepressant medications,
however, do differ in their
potential to cause particular
side effects
• Optimal for most patients:
SSRIs, SNRIs, mirtazapine,
bupropion
Continuation Phase
• To reduce the risk of relapse, patients who have
been treated successfully with antidepressant
medications in the acute phase should continue
treatment with these agents for 4-9 months.
• Depression-focused psychotherapy is
recommended.
• Patients who respond to an acute course of ECT,
continuation pharmacotherapy with
combination of lithium and nortriptyline has
the best available evidence for efficacy.
Maintenance Phase
• Antidepressant medication that produced
symptom remission during the acute and
continuation phase should be continued at a full
therapeutic dose.
• Indicated for patients who have had 3 or more
major depressive episodes or who have chronic
major depressive disorder.
Fluoxetine (Prozac)
Sertraline (Zoloft)
Paroxetine (Paxil)
Fluvoxamine (Luvox)
Citalopram (Celexa)
Escitalopram (Lexapro)
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRI)
Pharmacodynamics
• MOA: 5-HT reuptake inhibition
• Citalopram and Escitalopram
• Most selective with very little inhibition of
norepinephrine or dopamine reuptake and very low
affinities for H1, GABA or benzodiazepine receptors
• Fluoxetine
• Binds to 5-HT2C; Weakly inhibits norepinephrine
reuptake
• Sertraline
• Weakly inhibits norepinephrine and dopamine
reuptake
• Paroxetine
• Has significant anticholinergic activity at higher
dosages
Indications
• Depression
• Anxiety Disorders
• Obsessive-Compulsive Disorder
• Panic Disorder
• Social Anxiety Disorder
• Post-Traumatic Stress Disorder
• Generalized Anxiety Disorder
• Bulimia Nervosa
• Off-label Uses: Premature ejaculation,
Paraphilias, Autism
Side Effects
• Weight gain
• Sexual Dysfunction: most common AE associated
with long-term treatment
• Gastrointestinal: nausea, diarrhea, anorexia,
vomiting, flatulence, dyspepsia
• Sertraline and Fluvoxamine produce the most
intense GI symptoms
• Paroxetine, however, frequently produces
constipation.
Side Effects
• CNS
• Anxiety – seen during the first few weeks of
fluoxetine; seen less frequent with paroxetine and
escitalopram
• Insomnia – most commonly seen with Fluoxetine
• Emotional Blunting
• Yawning
• Seizures – 0.1-0.2% incidence in SSRI treated
patients
• Extrapyramidal symptoms
Side Effects
• Hematologic: functional impairment of platelet
aggregations  easy bruising and excessive or
prolonged bleeding
• Endocrine: can acutely decrease glucose
concentrations
• SEROTONIN SYNDROME: due to concurrent
administration of SSRI with a MAOI, Ltryptophan, or lithum
Serotonin Syndrome
• Signs arranged as condition worsens:
• Diarrhea
• Restlessness
• Extreme agitation, hyperreflexia and autonomic
instability with possible rapid fluctuations in vital signs
• Myoclonus, seizures, hyperthermia, uncontrollable
shivering and rigidity
• Delirium, coma, status epilepticus, cardivascular
collapse and death
• Treatment:
• Remove offending agents
• Nitroglycerine, cyproheptadine, methysergide
(Samsert), cooling blankets, Chlorpromazine,
Dantrolene, benzodiazepines, anticonvulsants,
mechanical ventilation, and paralyzing agents
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Desvenlafaxine (Pristiq)
Milnacipran
Sibutramine (Meridia)
SELECTIVE SEROTONIN-NOREPINEPHRINE
REUPTAKE INHIBITORS (SNRI)
Venlafaxine (Effexor)
• Indications:
• Depression, Generalized Anxiety Disorder, Social
Anxiety Disorder, Panic Disorder
• May be beneficial in ADHD, OCD, Agoraphobia,
and Depression w/ Cocaine dependence
• Adverse Effects:
• Sweating is more common than with SSRIs
• May cause MYDRIASIS – need to monitor patients
with narrow-angle glaucoma
• Nausea, somnolence, dry mouth, dizziness,
nervousness, constipation, asthenia, anxiety,
anorexia, blurred vision, abnormal ejaculation or
orgasm, erectile disturbance, impotence
Duloxetine
• Indications: Depression,
GAD, Neuropathic pain
associated with diabetes
and stress urinary
incontinence
• Adverse Effects:
• Nausea was the most
common side effect that
lead to treatment
discontinuation in clinical
trials.
Mirtazapine (Remeron)
SEROTONIN-NOREPINEPHRINE
MODULATOR
Mirtazapine (Remeron)
• MOA:
• Antagonism of central presynaptic
α2-adrenergic receptors  causes
increased firing of norepinephrine
and serotonin neurons
• Blockade of postsynaptic serotonin
5-HT2 and 5-HT3 receptors
• Indications
• HIGHLY SEDATING and INCREASES
APPETITE makes it a reasonable
choice for depressed patients
melancholic features such as longstanding insomnia, weight loss and
agitation
Buproprion (Wellbutrin; Zyban)
NOREPINEPHRINE-DOPAMINE REUPTAKE
INHIBITOR
Bupropion (Wellbutrin)
• Does not act on the serotonin system
 little risk of sexual dysfunction or
sedation and with modest weight loss
during acute and long-term treatment
• No withrawal syndrome linked to
discontinuation
• Only medication approved by FDA for
prevention of seasonal depressive
episodes of patients with seasonal
affective disorder (SAD)
• Brand name, Zyban, is also indicated
for smoking cessation
Bupropion (Wellbutrin)
• Adverse Reactions:
• Exerts indirect sympathomimetic
activity  restlessness, agitation,
irritability, positive inotropic
effect on myocardium
TRICYCLIC AND TETRACYCLIC
ANTIDEPRESSANTS
Tricyclics and Tetracyclics
• MOA: block the transporter site for
norepinephrine and serotonin  increase
synaptic concentrations of these
neurotransmitters
• Indications same as SSRIs
• How do they differ from SNRIs?
• TCAs are nonselective since they also affect
muscarinic, adrenergic and histaminergic
receptors  MORE SIDE EFFECTS
Tricyclics and Tetracyclics
• Each drug differs in its affinity for each
transporter.
• Clopipramine (Anafranil) – most serotonin
selective
• Desipramine (Norpramin, Pertofane) – most
norepinephrine selective
• Doxepin (Adapin, Sinequan) – most
antihistaminergic activity
Tricyclics and Tetracyclics
• More likely to cause CONSTIPATION, sedation,
dry mouth, or lightheadedness than the SSRIs
• Less likely to cause sexual dysfunction, significant
long-term weight gain and sleep disturbances
than the SSRIs.
Use limited to
treatmentresistant cases due
to risk of
developing
tyramine induced
hypertensive crisis
and consequent
need for a
restrictive diet.
MONOAMINE OXIDASE INHIBITORS
(MAOI)
Never achieved
widespread use in
treatment of MDD
because they were
too sedating at
therapeutic doses.
Trazodone (Desyrel)
Nefazodone (Serzone)
SEROTONIN MODULATORS
Causes PRIAPISM
in 1 of 10,000 men
due to α1adrenergic
antagonism.
B. PHARMACOTHERAPY FOR BIPOLAR
DISORDER
FDA-Approved Medications for
Treatment of Bipolar Disorder
Agent
Mania
Maintenance
Aripiprazole (Abilify)
Yes (2004)
No
Carbamazepine XR (Equetro)
Yes (2004)
No
Divalproex (Depakote)
Yes (1996)
No
Lamotrigine (Lamictal)
No
Yes (2003)
Lithium (Lithobid)
Yes (1970)
Yes (1974)
Olanzapine (Zyprexa)
Yes (2000)
Yes (2004)
Risperidone (Risperdal)
Yes (2003)
No
Quetiapine (Seroquel)
Yes (2004)
No
Ziprasidone (Geodon)
Yes (2004)
No
Lithium (Eskalith,
Lithobid, Lithonate)
• Mechanism for moodstabilizing effects of lithium
still unknown
• Indications:
• Acute mania in Bipolar
Disorder
• Augmentation of
antidepressants in MDD
and antipsychotics in
Schizoaffective and
Schizophrenia Disorders
Lithium (Eskalith,
Lithobid, Lithonate)
• Acute Manic Episodes in Bipolar
Disorder
• Blood-brain-barrier permits
only slow passage of lithium
 onset of antimanic action
can be slow (1-3 weeks)
• supplemented in the early
phases of treatment by
atypical antipsychotics,
mood-stabilizing
anticonvulsants, or highpotency benzodiazepines
Lithium (Eskalith,
Lithobid, Lithonate)
• Maintenance treatment with Lithium
• markedly decreases the frequency, the severity, and the
duration of manic and depressive episodes in persons
with bipolar I disorder
• provides relatively more effective prophylaxis for mania
than for depression
• indicated after the second episode of bipolar I disorder
depression or mania and should be considered after the
first episode for adolescents or for persons who have a
family history of bipolar I disorder
• reduces the incidence of suicide in patients with bipolar
I disorder sixfold or sevenfold.
• Lithium is also effective treatment for persons with
severe cyclothymic disorder.
Lithium Toxicity
Mild to Moderate Toxicity (lithium level = 1.5 to 2.0 mEq/L)
Gastrointestinal Vomiting, Abdominal pain, Dryness of mouth
Neurologic
Ataxia, Dizziness, Slurred speech, Nystagmus, Lethargy or
excitement, Muscle weakness
Moderate to severe intoxication (lithium level = 2.0 to 2.5 mEq/L)
GI
Anorexia, Persistent nausea and vomiting
Neurologic
Blurred vision, Muscle fasciculations, Clonic limb movements
Hyperactive deep tendon reflexes, Choreoathetoid
movements
Convulsions, Delirium, Syncope, Electroencephalographic
changes, Stupor, Coma, Circulatory failure (lowered BP,
cardiac arrhythmias, and conduction abnormalities)
Severe lithium intoxication (lithium level >2.5 mEq/L)
Generalized convulsions
Oliguria and renal failure
Death
Lamotrigine (Lamictal)
• antiepileptic drug used as adjunctive therapy for
general and partial seizures in adults and
pediatric patients
• shown to keep patients euthymic longer and was
particularly effective in preventing depressive
episodes
• no significant metabolic or neurologic effects,
and does not require laboratory testing of
plasma concentrations BUT has no acute
antimanic effects
Lamotrigine (Lamictal)
• MOA:
• blockade of voltage-sensitive sodium channels
 modulate release of glutamate and
aspartate, and slight effect on calcium
channels.
• Modestly increases plasma serotonin
concentrations, possibly through inhibition of
serotonin reuptake, and is a weak inhibitor of
serotonin 5-HT3 receptors.
Lamotrigine
• most common adverse effects are mild:
dizziness, ataxia, somnolence, headache,
diplopia, blurred vision, nausea, joint or back
pain
• Important AE: RASH which is common and
occasionally very severe.
• 8% of patients develop a benign
maculopapular rash during the first 4 months
of treatment
• drug should be discontinued if a rash develops
Carbamazepine
• first used to treat partial- and generalized-onset epilepsy and
trigeminal neuralgia
• been used for decades as a first-line agent for acute and
maintenance treatment for bipolar I disorder OUTSIDE THE
UNITED STATES
• Anticonvulsant MOA:
• Prolongs inactive state of voltage-dependent sodium
channels  reduces voltage-dependent calcium channel
activation and, therefore, synaptic transmission
• reduction of currents through N-methyl-D-aspartate
(NMDA) glutamate-receptor channels
• competitive antagonism of adenosine A1 receptors
• potentiation of central nervous system (CNS) catecholamine
neurotransmission.
• MOOD STABILIZING MOA UNKNOWN
Valproate, Divalproex
• MOA poorly understood.
• Postulated mechanisms include
• enhancement of γ-aminobutyric acid
(GABA) activity, modulation of voltagesensitive sodium channels, and action on
extrahypothalamic neuropeptides.
• Antimanic response elicited at higher
therapeutic
Valproate, Divalproex
• Psychiatric Indications:
• Schizophrenia and Schizoaffective Disorder
• Valproate may accelerate response to antipsychotics
• Valproate alone is ineffective for treatment of psychotic symptoms
• Bipolar I Disorder
• Acute Mania
• 2/3 of patients with mania usually respond within 1 to 4 days
after achieving valproate serum concentrations above 50
µg/mL. short-term antimanic effects of valproate can be
augmented with addition of lithium (Eskalith), carbamazepine
(Tegretol), or dopamine receptor antagonists (DRAs).
• Mixed Episodes
• Acute Bipolar Depression
• effect is far less pronounced than for treatment of manic
episodes.
• Among depressive symptoms, valproate is more effective for
treatment of agitation than dysphoria.
IV. ANXIETY DISORDERS
A. SEDATIVE-HYPNOTICS
• Sedative (anxiolytic) agent - reduces anxiety and
exerts a calming effect. The degree of central
nervous system depression caused by a sedative
should be the minimum consistent with
therapeutic efficacy.
• Hypnotic drug - produce drowsiness and
encourage the onset and maintenance of a state
of sleep
• involve more pronounced depression of the
central nervous system than sedation
Subclasses
• Benzodiazepines
• Barbiturates
• Newer Hypnotics
• Melatonin receptor agonist
• 5-HT-receptor agonist
Benzodiazepines
• Mechanism of action
• enhance GABA's effects
allosterically without
directly activating GABAA
receptors or opening the
associated chloride
channels
• Increases frequency of
channel-opening events
 enhancement in
chloride ion conductance
Benzodiazepines
Quickest onset of action
Shortest-acting (plasma
half lives of < 30 hours)
Longest-acting (plasma half
lives of 30 to > 100 hours)
Diazepam (Valium)
Lorazepam (Ativan)
Alprazolam (Xanax)
Oxazepam (Serax)
Diazepam
Terazepam (Restoril)
Chlordiazepoxide
Estazolam
Clonazepam (Klonopin)
Triazolam (Halcion)
Estazolam (Prosom)
Alprazolam
Clorazepate
Triazolam – shortest halflife (2-3 hours)
Flurazepam (Dalmane) –
longest half-life
Prazepam (Centrax)
Quazepam (Doral)
Halazepam (Paxipam)
Psychiatric Indications of
Benzodiazepines
• Insomnia
• Flurazepam – minor cognitive impairment on
the day after its administration
• Triazolam – mild rebound anxiety and
anterograde amnesia
• Quazepam – daytime impairment when used
for a long time
• Temazolam
• Estazolam – rapid onset of sleep and a
hypnotic effecto for 6-8 hours
Psychiatric Indications of
Benzodiazepines
• Generalized Anxiety Disorder
• Panic Disorder – Alprazolam and clonazepam used in
conjunction with SSRIs  tapered after 3-4 weeks
when benefits of SSRIs emerge
• Social Phobia – clonazepam
• PTSD and OCD
• Anxiety with Depression – alprazolam
• Bipolar I disorder – clonazepam, lorazepam and
alprazolam
• Alcohol Withdrawal – chlordiazepoxide (Librium)
• Substance-Induced or Psychotic-Induced Agitation
Adverse Effects of Benzodiazepenes
• Most common: DROWSINESS, residual daytime
sedation
• Ataxia (< 2%)
• Dizziness (< 1%)
• Teratogenic
• Impairment of respiration in patients with COPD
and sleep apnea
• Alprazolam can can exert a direct appetite
stimulant effect and cause weight gain.
Newer hypnotics - Zolpidem, Zaleplon,
Eszocpiclone
• Indicated for insomnia
• Zolpidem 10 mg QID may be used in
Parkinson’s Disease
• Mechanism of action:
• Selective binding of certain units of
GABAA receptor  selective sedative
effects and relative lack of muscle
relaxant and anticonvulsive effects
• Adverse Effects:
• Zolpidem – Anterograde amnesia,
Dizziness, drowsiness, dyspepsia, or
diarrhea, hallucinations and
behavioral changes
• Eszopiclone in elderly patients - Pain,
dry mouth and unpleasant taste
Barbiturates
• High abuse and addiction potential
• narrow therapeutic range with low therapeutic
index and unfavorable side effects
• Indications:
• Methohexital (Brevital) – anesthetic agent for
ECT (0.7-1.2 mg/kg) and can be used to abort
prolonged seizures in ECT or to limit post-ictal
agitation; brief duration of action: 5-7 minutes
• Phenobarbital (Solfoton, Luminal) – for
generalized tonic-clonic and simple partial
seizures; 10-20 mg/kg IV for status epilepticus
Barbiturates
• Mechanism of action:
• increase the duration of the GABAgated chloride channel openings 
high chloride-ion conductance
• barbiturates may also be GABAmimetic binding to sites different
than those of benzodiazepines 
directly activating chloride channels
• Barbiturares can depress the
actions of the excitatory
neurotransmitter glutamic acid via
binding to the AMPA receptor.
• nonsynaptic membrane effects in
parallel with their effects on GABA
and glutamate
Buspirone
• Demonstrated efficacy only in the treatment of GAD
• Mechanism of action: UNCLEAR – proposed
mechanisms are presynaptic and postsynaptic 5-HT1A
agonist with some effect on D2 receptors
• Adverse effects:
• Headache, nausea, dizziness, and rarely insomnia
• No weight gain, sexual dysfunction, sleep
disturbance, or discontinuation syndrome
• No sedation or cognitive and psychomotor
impairment
Ramelteon (Rozerem)
• For the treatment of INSOMNIA characterized by
difficulty with sleep onset
• Mechanism of Action: targets the melatonin
MT1 and MT2 receptors in the suprachiasmatic
nucleus (SCN)
• Dosage: 8 mg within 30 minutes before going to
bed
• Adverse Events: somnolence, dizziness, and
fatigue
indicate the presence of a primary psychiatric or medical illness that should be evaluated. Long-term use of hy
is an irrational and dangerous medical practice.
Table 22–3 Dosages of Drugs Used Commonly for Sedation and Hypnosis.
Hypnosis
Sedation
Drug
Dosage (at Bedtime)
Drug
Dosage
Alprazolam
0.25–0.5 mg 2–3 times daily Chloral hydrate 500–1000 mg
Buspirone
5–10 mg 2–3 times daily
Chlordiazepoxide 10–20 mg 2–3 times daily
Estazolam
0.5–2 mg
Eszopiclone
1–3 mg
Clorazepate
5–7.5 mg twice daily
Lorazepam
2–4 mg
Diazepam
5 mg twice daily
Quazepam
7.5–15 mg
Halazepam
20–40 mg 3–4 times daily
Secobarbital
100–200 mg
Lorazepam
1–2 mg once or twice daily
Temazepam
7.5–30 mg
Oxazepam
15–30 mg 3–4 times daily
Triazolam
0.125–0.5 mg
Phenobarbital
15–30 mg 2–3 times daily
Zaleplon
5–20 mg
Zolpidem
5–10 mg
OTHER THERAPEUTIC USES
References:
• American Psychiatric Association. 2010. Practice
Guideline for the Treatment of Patients with
Major Depressive Disorder, 3rd ed
• Katzung BG, Masters SB, Trevor AJ. 2009. Basic &
Clinical Pharmacology, 11th Edition. McGraw-Hill
• Sadock BJ and Sadock VA. 2007. Kaplan &
Sadock's Synopsis of Psychiatry: Behavioral
Sciences/Clinical Psychiatry, 10th Edition.
Lippincott Williams & Wilkins