PsychopharmacologyGreg Matthew Teo (MD080087)ASMPH 2013 YL8

OutlineI. Basic Biologic PrinciplesII. Psychosis and Schizophrenic

DisordersIII.Mood DisordersIV.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

PHENOTHIAZINES

Aliphatic Chlorpromazine (Thorazine)

Low potency

Piperazine Fluphenazine (Permitil)Thioridazine (Mellaril)

High potencyLow-potency

THIOXANTHENES Thiothixene (Navane) High-potency

DIHYDROINDOLE Molindone (Moban) High-potency

BUTYROPHENONES Haloperidol (Haldol) High potency

• 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 serotonin-norepeinephrine 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.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRI)

Fluoxetine (Prozac)Sertraline (Zoloft)Paroxetine (Paxil)Fluvoxamine (Luvox)Citalopram (Celexa)Escitalopram (Lexapro)

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, L-tryptophan, 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

SELECTIVE SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRI)

Venlafaxine (Effexor)Duloxetine (Cymbalta)Desvenlafaxine (Pristiq)MilnacipranSibutramine (Meridia)

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.

SEROTONIN-NOREPINEPHRINE MODULATOR

Mirtazapine (Remeron)

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 long-standing insomnia, weight loss and agitation

NOREPINEPHRINE-DOPAMINE REUPTAKE INHIBITOR

Buproprion (Wellbutrin; Zyban)

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.

MONOAMINE OXIDASE INHIBITORS (MAOI)

Use limited to treatment-resistant cases due to risk of developing tyramine induced hypertensive crisis and consequent need for a restrictive diet.

SEROTONIN MODULATORS

Trazodone (Desyrel)Nefazodone (Serzone)

Never achieved widespread use in treatment of MDD because they were too sedating at therapeutic doses.

Causes PRIAPISM in 1 of 10,000 men due to α1-adrenergic 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 mood-stabilizing 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 high-potency 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 ToxicityMild 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 movementsHyperactive deep tendon reflexes, Choreoathetoid movementsConvulsions, 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 voltage-sensitive 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

BenzodiazepinesQuickest onset of action Shortest-acting (plasma

half lives of < 30 hours)Longest-acting (plasma half lives of 30 to > 100 hours)

Diazepam (Valium) Oxazepam (Serax) Diazepam

Lorazepam (Ativan) Terazepam (Restoril) Chlordiazepoxide

Alprazolam (Xanax) Estazolam Clonazepam (Klonopin)

Triazolam (Halcion) Alprazolam Clorazepate

Estazolam (Prosom) Triazolam – shortest half-life (2-3 hours)

Flurazepam (Dalmane) – longest half-lifePrazepam (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 GABA-

gated chloride channel openings high chloride-ion conductance

• barbiturates may also be GABA-mimetic 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

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