Pharmacotherapy of Depression

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					Pharmacotherapy of Major
  Psychiatric Disorders
 Part I: Antidepressants & Anxiolytics

                         Mimi Israël M.D.
                         August, 2004
          Depression: Facts
• Top 5 causes of disability in the world,
  leading cause by 2020
• Affects ~20% of Canadians
• Chronic and recurrent illness
• Increased vulnerability to cardiovascular
  disease; 4-5 x increased mortality post MI
• Poorer outcome to treatment; cardiovascular
  disease, stroke
       Antidepressants Classes
• Selective Serotonin Reuptake Inhibitors (SSRI)
   – Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine
     (Paxil) Sertraline (Zoloft), Citalopram (Celexa)
• Tricyclics (TCA)
   – Desipramine (Norpramin), Imipramine (Tofranil),
     Amitriptyline (Elavil), Nortriptyline (Aventyl),
     Clomipramine (Anafranil), Doxepin (Sinequan),
     Trimipramine (Surmontil), Amoxapine (Asendin),
     Maprotiline (Ludiomil)
• Monoamine Oxidase Inhibitors (MAOI)
   – Phenelzine (Nardil), Tranylcypromine (Parnate),
     Moclobamide (Manerix)
         Antidepressants Classes

• Serotonin antagonist/re-uptake inhibitors (SARI)
  – Trazodone (Desyrel)
• Serotonin-Noradrenaline re-uptake inhibitor
  (SNRI) –Venlafaxine (Effexor)
• Noradrenaline-Dopamine re-uptake inhibitors
  (NDRI) - Bupropion (Wellbutrin)
• Noradrenergic and specific serotonergic re-
  uptake inhibitors (NaSSA) - Mirtazapine (Remeron)
         How do they work?
• All increase neurotransmission of serotonin
  (5-HT) and/or norepinephrine (NE)
 Model of Neurotransmitter Specificity

      NA          BOTH              5-HT

•Motivation   •Mood            •Impulsivity
•Energy       •Sleep           •Suicidality
•Interest     •Aches & Pains   •Appetite
•Attention    •Anxiety
            Serotonergic agents
5-HT2 receptor         5-HT3 receptor
  stimulation            stimulation
• Agitation            • Nausea
• Insomnia             • Diarrhea
• Sexual dysfunction   • Headache
• Satiation
             Newer theories
• Drug therapy may act on specific
  transcription factors and target genes
  regulating Neuroprotection AND Neuronal
    Efficacy & Onset of action
Compared to others
• Does the drug work better?
• Does the drug work faster?
• Does the drug have a predictable onset of
 Single vs. Dual Action Antidepressants
Single action       Dual action
• Mostly NE         • Both NE & 5-HT
   – Desipramine       –   Clomipramine
   – Bupropion         –   Other TCAs
   – Reboxetine        –   Mirtazapine
• Mostly 5-HT          –   MAOIs
   – SSRI’s            –   Venlafaxine
   Dual-action Antidepressants
• Potential benefits
  –   More rapid antidepressant effect?
  –   Severe and or inpatient depression?
  –   Retarded and /or melancholic depression?
  –   Treatment resistant depression?
• Melancholic; nonreactive mood, worse in
  the morning, extreme agitation/ retardation
• Atypical; reactive mood, overeating,
  oversleeping, rejection sensitivity
• Psychotic; hallucinations, delusions
• Other: Bipolar, Anxious, Seasonal, Post-
Treatment guidelines: Symptom profile…
• Atypical
   – SSRIs, Bupropion
   – Other options: Venlafaxine, MAOIs
   – Avoid: TCAs
• Anxious/agitated
   – Mirtazapine, SSRIs, Venlafaxine, MAOIs
   – Least preferred: Bupropion
Treatment guidelines: Symptom profile
• Severe/ Psychotic
  – Venlafaxine (high doses), Mirtazapine
  – Second line: TCAs, MAOIs
  – Least preferred: Bupropion
           Treatment Guidelines:
• Panic disorder
   – SSRIs
   – Other options: Venlafaxine, Mirtazapine, TCAs,
   – Avoid: Bupropion
   – SSRIs
   – Other options: Venlafaxine, Mirtazapine, MAOIs
  Treatment Guidelines: Comorbidity…

• Generalized Anxiety Disorder
  – SSRIs, Venlafaxine,
  – Other options: TCAs, Mirtazapine
• Social Phobia
  – SSRIs, Venlafaxine, MAOIs
  – Avoid: TCAs
  Treatment Guidelines: Comorbidity

• Obsessive-Compulsive Disorder
  – SSRIs
  – Other options: Clomipramine, TCAs
• Bulimia/Binge Eating
  – SSRIs (some)
  – Other options: Venlafaxine, TCAs
  – Avoid: Bupropion, Mirtazapine
        Adverse effects & Toxicity
• Issues
  –   Potential switch to mania or hypomania
  –   Common side effects
  –   Potentially serious side effects
  –   Safety in overdose
       SSRIs: Adverse effects
• Less toxicity in overdose
• Moderate risk of switch to mania (~3%)
• Gastrointestinal
  – Nausea
  – Constipation
  – Diarrhea, loose stools
         SSRIs: Adverse effects
• Central nervous system
  –   Insomnia, somnolence
  –   Blunting, apathy, lethargy
  –   Anxiety, restlessness
  –   Dizziness, headaches, tremors, anorexia
• Other
  – Weight loss/weight gain
  – Sexual dysfunction
  – Sweating, SIADH
          Sexual Dysfunction
• Frequent         • Less frequent
  – Clomipramine      – Meclobemide
  – MAOIs             – Mirtazapine
  – SSRIs             – Bupropion
• Moderate
  – Venlafaxine
  – TCAs
     Management of Sexual Dysfunction

•   Wait for tolerance to develop
•   Reduce dose
•   Change dose schedule
•   Switch antidepressants
•   Augment
    – Amantadine, Bupropion, Buspirone, Cyproheptadine, Ginko
      Biloba, Mirtazapine, Sildenafil, Yohimbine,
      Antidepressant Withdrawal
• Higher risk: MAOI, TCA, Paroxetine,
• Medium risk: Fluvoxamine
• Lower risk: Bupropion, Citalopram,
  Fluoxetine, Mirtazapine, Sertraline
       Antidepressant Withdrawal
• Can occur despite tapering
• Can last several weeks
• Common symptoms
  – Dizziness, headache, paresthesias
  – Nausea
  – Irritability, lowered mood, lethargy, insomnia,
    vivid dreams
      Antidepressant Withdrawal
• Higher risk: MAOI, TCA, Paroxetine,
• Medium risk: Fluvoxamine
• Lower risk: Bupropion, Citalopram,
  Fluoxetine, Mirtazapine, Sertraline
            Special Populations
• Geriatric
   – Higher & more variable drug concentrations, more
     sensitive to side effects, may respond better to double
• Adolescents/Children
   – Different side effect, efficacy and metabolic profile
   – Antidepressants and suicidality
• Pregnancy/Lactation
   – Incidence of depression 10-16%, no reported
     malformations with SSRI, ?withdrawal in infants
   – Risk/benefits
              Medically Ill
• Cardiac
  – TCAs
• Hypertension
  – Venlafaxine
• Diabetes/Obesity
  – TCA, some SSRIs, Mirtazapine
                Medically Ill
• Seizure disorder
  – Bupropion
• GI
  – SSRIs
• Bleeding disorders
  – SSRIs
• Dementia, cognitive deficits
  – TCA
               Depression Treatment Phases

                                  REMISSION     RECOVERY

Normalcy                             RELAPSE    RECURRENCE



             Phases   ACUTE      CONTINUATION   MAINTANANCE
 Evaluating Treatment Response
• Week 1: Side effects
• Week 2: Good sign if minimal response
• Week 4: If non-response check
  – Diagnosis, (including comorbid substance
  – Compliance
  – Dose
  – Drug-drug interactions
Evaluating Treatment Response

• Week 6-8: If non-response
  – Treatment failure, revise strategy
• Week 8-10: If partial response
  – Suboptimal treatment response, revise
  Continuation and Maintenance
• Continue medications for at least 6 months
  after remission
  – Relapse rate in first 6 months
       • Off medications 35-60%
       • On medications 10-25%
• Consider longer (more than 2 years) if
  –   3 or more lifetime episodes
  –   Frequent episodes (2 or more in 5 years)
  –   Chronic episodes
  –   Older age
  Refractory Depression: Definition

• Inadequate response to two trials of
  different antidepressants at therapeutic
  doses for a sufficient amount of time.
Refractory Depression: Strategies
• Optimisation
  – Factors: Partial response, medication well
  – Strategy: Dose augmentation
 Refractory Depression: Strategies*
• Augmentation
  – Factors: Partial response, medication well
  – Strategy: Add a non-antidepressant medication
     •   Lithium
     •   Thyroxine (T3)
     •   Atypical antipsychotics
     •   Others: Stimulants, Pindolol, Buspirone, Mood
         stabilisers (Lamotrigine, Valproate…), Estradiol
 Refractory Depression: Strategies*
• Association
  – Strategy: Combining antidepressants with different
    mechanisms of action
     •   SSRIs (5-HT) + Bupropion (NA/DA)
     •   SSRIs + Meclobemide (NA/DA)
     •   SSRIs + Desipramine (NA)
     •   Mirtazapine (5-HT/NA) + SSRI or Bupropion or Venlafaxine
     •   Venlafaxine (5-HT/NA) + Bupropion or TCA or SSRI
  – Caution: Drug-drug interactions, serotonin syndrome
 Refractory Depression: Strategies*

• Substitution
     • Factors: No therapeutic response, intolerable
       adverse effects
     • Strategy: Same class or different class
        –   TCA→ TCA 10 à 30% success rate
        –   SSRI → SSRI 48% success rate
        –   SSRI → TCA, Venlafaxine, Mirtazapine
        –   * → IMAO (complete washout required)
     • Caution: Drug-drug interactions, serotonin
        Serotonin Syndrome*
• Confusion, agitation, coma.
• Hypereflexia, rigidity, tremors,
• Autonomic hyperactivity
  – Diaphoresis, pyrexia, tachycardia, nausea
• 25 years old, off work for 18 months, presents to
  ER after hitting partner for the first time
• On Venlafaxine 300mg for 1 year, seeing
  psychologist for 6 months
• Labile mood, irritability, anxious, cries easily,
  unmotivated, anhedonic, hopeless
• Decreased appetite, no weight loss
• Angry and impulsive, suicidal on 3 occasions
  (thought of slashing wrists), no attempts, no
• No alcohol in 2 years (used to abuse), occasional
  pot, family history of alcoholism
Pharmacotherapy of Anxiety
          Anxiety Disorders
• Panic disorder; more expensive to general
  medical system than any other psychiatric
• Use up general & specialty resources
• Panic disorder patients go undiagnosed 98%
  of the time in ER
• Physical symptoms
  – Agitation, restlessness, feeling “keyed up” (on
    edge), exaggerated startle response
  – Chest pain, tachypnea, dysphagia, muscle tension,
    difficulty falling or staying asleep, fatigue
• Behavioral symptoms
  – Avoidance
  – Rituals
  – Addictive behaviors; with others, with substances
        Cognition by Diagnosis…
• Social phobia
  – Worry about scrutiny, negative evaluation,
    embarrassment, humiliation
• Panic disorder
  – Worry about dying, going crazy, losing control
• Agoraphobia
  – Worry about being in a situation that might trigger a
    panic attack and from which escape might be
          Cognition by Diagnosis
• Generalized anxiety disorder (GAD)
  – Worry about ordinary things (family, finances, work, illness)
  – Doubt “What if…”
  – Anticipation that things will go wrong
• Obsessive compulsive disorder (OCD)
  – Worry involving magical thinking (Dirt, illness, doubt,
    aggression, order, religion, sex)
  – Pathological doubt
  – Responsability
      Depression versus Anxiety
   Depression         Both             GAD
•Depressed      •Motor tension   •Autonomic
mood            •Agitation       hyperactivity
•Anhedonia      •Fatigue         •Vigilance
•Weight         •Poor            •Scanning
gain/loss       concentration
•Guilt          •Insomnia
• Benzodiazepines
• Azaspirones
  – Buspirone
• Antidepressants
  – SSRIs, TCAs, MAOIs, Novel agents
• Beta-blockers
• Other
  – i.e. Mood Stabilizers
• Advantages
  – Rapid onset of action
  – Treat insomnia
  – Rapid dose adjustment & P.R.N. Dosing
• Disadvantages
  –   Abuse potential
  –   Withdrawal (seizures, rebound anxiety)
  –   Potentiate alcohol
  –   Side effects; memory impairment, ataxia, lack
      of coordination, sedation, sexual dysfunction
• Advantages
  – Treat co-morbid disorders
  – No dependence
  – Do not potentiate alcohol
• Disadvantages
  – Delayed onset of action
  – Side effects; excitation, GI symptoms, sexual
•   5-HT1A partial agonist
•   As effective as bzds in treating GAD
•   Not effective in panic disorder
•   Not preferred by patients who have taken
• Initial effect within 1-2 weeks
• Full effect require 4-6 weeks
• No sedation,ataxia, or cognitive
• No dependency
• Does not potentiate alcohol
          Antidepressants …
• SSRI/Venlafaxine
  – Effective in Panic disorder, OCD, Social
    phobia, GAD, PTSD
• Bupropion
  – Not effective in Panic disorder
• Mirtazapine
  – Effective in GAD and Panic disorder
          Antidepressants …
• TCAs
  – Effective in GAD Panic disorder and PTSD
  – Not effective in Social phobia
  – Clomipramine effective in OCD
  – Effective in Panic disorder, Social phobia,
  – Effective in Panic disorder
 Other Classes: Anticonvulsants
• Controlled studies
     • Lamotrigine; PTSD
     • Gabapentin; Social phobia
     • Valproic acid; Panic disorder
• Augmentation therapy: Panic disorder,
  – Valproate, Gabapentin, Lamotrigine
   Other Classes: Neuroleptics
• Augmentation for OCD, PTSD
  – Risperidone
  – Olanzapine
         Treatment Guidelines

Anxiety category     First line agent

Situational          Benzodiazepines

Persistent anxiety   Buspirone

Panic disorder       Antidepressant
       Treatment principles…

• Psychoeducation is essential
  – Patients are frightened and difficult to reassure
  – Patients resist the idea that symptoms may be
    linked to a mental illness
Problems with Pharmacotherapy*
• Somatic anxiety symptoms are frequently
  viewed as side effects of medications
• Side effects can also mimic the symptoms
  of the illness
• Many antidepressants initially cause
• Taking medication is perceived as a loss of
       Clinical guidelines*…
• Recognize signs & symptoms suggestive of
  an underlying anxiety disorder
• Conduct appropriate but limited medical
• Explain the diagnosis to the patient
• Discuss specific treatment options
         Clinical guidelines
• Consider comorbidity when choosing first
  line agent
• Start low, go slow, aim high
• Continue effective treatment for 12-24
  months, only consider stopping when life
  situation is stable
• Discontinue meds slowly (4-6 months)
• Inform patients not to stop abruptly
      What to tell patients*…
• Avoid caffeine
• Avoid excess alcohol and nicotine
• Exercise moderately to relieve tension and
  improve sleep
• Monitor over-the-counter medications
    What not to tell patients*…
• “There is nothing wrong with you”
• “The problem is in your head”
• “Your tests are normal, it’s just stress”
Pharmacotherapy of Major
  Psychiatric Disorders
Part II: Mood Stabilisers & Antipsychotics
    Unipolar versus Bipolar? …
                  Unipolar         Bipolar

Age of onset      Anytime          Before age 25*

Gender             in women        equal

Substance abuse       -               

Cycling            Longer less      Shorter
                   frequent         more frequent

                          *Psychosis in adolescence
       Unipolar versus Bipolar?
                              Unipolar    Bipolar

Family History                Unipolar    Bipolar

Personality                      -           *BPD
Seasonal pattern                 -          

Postpartum                       -          
Response to antidepressants     Improve   Hypomania
 Factors in treatment selection…
• State of the patient
  – Acute, asymptomatic, hypomanic, manic,
    depressed, mixed, psychotic, course of illness
• Presence of substance abuse
• Co-morbid psychiatric disorders
  – ADHD, anxiety disorders, personality disorders
  Factors in treatment selection
• Co-morbid medical disorders
  – Psoriasis, acne, PCO, renal, hepatic, cardiac,
• Concomitant medications
• Pregnancy
• Family history of drug response
           Organic Mania*
• What medications that can induce mania?

• What medical conditions can cause mania?
          Lithium: Efficacy
• Possibly less effective in rapid cycling,
  mixed states, co-morbid substance abuse
  and secondary mania
• Mania-depression-euthymia course may be
  predictive of response
• Possesses antidepressant properties
• Risk of relapse with rapid discontinuation
• Side effects common (~ 75% of patients)
  – Renal, cognitive, hypothyroid,
    hypoparathyroidism, weight gain, GI, tremor,
• Renal excretion; narrow therapeutic range
  0.8-1.1 mmols/l
• Drug interactions which can lead to toxicity
  e.g., diuretics, NSAID, tetracycline
 Lithium: Baseline interventions
• Medical history
  – Renal, thyroid, cardiac, dermatologic
• Laboratory investigations
  – creatinine, BUN, TSH
• EKG (if indicated)
• Pregnancy test (if indicated)
    Lithium: Contraindications
• Significant contraindications
  – Impaired renal function
  – Cardiac arrhythmia
  – Other causes of fluid imbalances
• Relative contraindications
  – First-trimester pregnancy teratogenicity
    (Epstein’s anomaly)
  – Severe psoriasis or acne
              Lithium: Follow-up
• Check lithium levels if;
   –   Change in medical or psychiatric status
   –   Change in diet, salt intake, climate or exercise level
   –   Starting new medications
   –   Suspect lithium toxicity
• Monitor
   – Thyroid function
   – Renal function & Calcium
      Valproic Acid: Efficacy
• Effective in acute mania, rapid cycling,
  mixed states, co-morbid substance abuse
  and secondary mania
• A depression-mania course may be
  predictive of response
 Valproic Acid: Adverse Effects
• Dose dependent GI complaints, appetite and
  weight gain
• Sedation, tremor
• Hair loss, osteoporosis, polycystic ovarian
• Uncommon or rare
  – Coagulopathy/thrombocytopenia, agranulocytosis
• Teratogenicity (neural tube defect)
Valproic acid: Baseline interventions

• Medical history
  – Hepatic, hematological, bleeding abnormalities,
    menstrual irregularities
• Baseline CBC and liver function tests
  – Benign hepatic transaminase elevation
Bipolar Disorder: Other treatments…
• Benzodiazepines
  – Effective in mania, bipolar depression
  – Consider as initial treatment for
     • Pregnant women, manic delirium with severe
       hyperthermia, catatonia, medical conditions that
       preclude other treatments
• Calcium channel blockers, Thyroid
  hormone, Omega-3 fatty acids
 Bipolar Disorder: Other treatments
New anticonvulsants (third generation)
• Lamotrigine
   – Rash
   – Valproic acid inhibits its metabolism
• Topiramate
   – Common: weight loss, somnolence, dizzyness,
     cognitive disturbance
   – Severe: oligohydrosis & hyperthermia; acute myopia
     (secondary angle closure glaucoma)
         Bipolar Depression
• First line; Lithium
• Second line; Lamotrigine
  – Marked suicidality
  – Severe psychosis
• If antidepressants required
  – Use with a mood stabilizer
  – Use SSRIs or Bupropion if necessary
  – Avoid TCAs
             Efficacy by Phase…
  Drug          Acute mania Acute Depression Prophylaxis

Lithium                  A+                 A                     A+

Valproic acid            A+                  D                     A-

Carbamazepine            A                   D                     B-

Antidepressants          F (worsen mania)    A                     ? (may induce
                                                                   rapid cycling)

  A = Double blind placebo controlled trials with adequate samples
  B = Double blind comparator trials with adequate samples
  C = Open trials with adequate samples
  D = Uncontrolled observation or controlled studies with ambiguous results
  E = No published evidence         F= Available evidence negative
               Efficacy by Phase
 Drug           Acute mania Acute Depression Prophylaxis

Lamotrigine             F                    A                  A+ (for depression)
Topiramate              D                   D                   E

Gabapentin              F                   D                    E

A = Double blind placebo controlled trials with adequate samples
B = Double blind comparator trials with adequate samples
C = Open trials with adequate samples
D = Uncontrolled observation or controlled studies with ambiguous results
E = No published evidence         F= Available evidence negative
              Efficacy by Phase..
 Drug          Acute mania Acute Depression Prophylaxis

Risperidone             A                  A                    E

Olanzapine              A+                 D                    E

Quetiapine              A                  E                    E

Omega-3                  E                   E                  D

A = Double blind placebo controlled trials with adequate samples
B = Double blind comparator trials with adequate samples
C = Open trials with adequate samples
D = Uncontrolled observation or controlled studies with ambiguous results
E = No published evidence         F= Available evidence negative
• Acute Mania or Mixed Episode
  – Taper mood elevating effects drugs
  – Choose category A evidence drugs (mood
    stabilizer or Atypical antipsychotic)
  – Use combination if severe
• Prophylaxis
  – Maintain what worked in the acute phase
  * Polypharmacy may be necessary for those with
    frequent relapses (i.e. 1 or 2 mood stabilizers +
    antipsychotic +/- antidepressant)
Pharmacotherapy of Psychotic
New Onset Psychosis Differential
• Psychotic Disorders
   –   Schizophrenia & schizophreniform disorder
   –   Delusional disorder
   –   Schizoaffective disorder
   –   Brief psychotic disorder
• Affective
   – Mood disorder with psychotic features (bipolar or unipolar)
• Organic
   – Substance-induced psychosis
   – Mental Retardation
   – Psychotic disorder due to a medical condition (i.e. Delirium…)
        Schizophrenia: Symptoms
•   Positive
    –   Hallucinations, delusions, disorganized
        thinking, bizarre or catatonic behavior
    –   Aggression
•   Negative
    –   Affective flattening, poverty of thought,
        Schizophrenia: Symptoms
•   Affective
    –   Depression, Anxiety
    –   Suicidality
•   Cognitive
    –   Information processing, abstract thinking,
        problem solving
          Points to remember
• Prognosis is affected by early intervention
• Positive symptoms respond well
• Negative symptoms respond only slightly
• First episode patients are more sensitive to
• Rapid high dose treatment is almost never
            Treatment Guidelines

• Antipsychotic medication is the cornerstone of
   – Canadian guidelines; second-generation for first
   – Aim for therapeutic response without EPSE
   – “Start low, go slow”
   – First generation drugs also have role
• Psychosocial interventions should be combined
  with pharmacotherapy
 Antipsychotics: Adverse Effects…
• Extrapyramidal side effects (EPSE)
  – Dystonia, Parkinsonism, Akathisia
  – Tardive dyskinesia, Rabbit syndrome
• EPSE management
  – Adjust dosage
  – Switch to a second-generation agent
  – Add anticholinergic agents (e.g. benztropine,
    procyclidine )
Antipsychotics: Adverse Effects..
• Galactorrhea
• Gynecomastia
• Menstrual changes
• Sexual dysfunction/Infertility
Antipsychotics: Adverse Effects
• Neuroleptic malignant syndrome (NMS)
  – Acute, life threatening
  – Rigidity, mutism, hyperthermia, delirium,
    autonomic instability
  – High CPK and leukocytosis
   Today’s theory of antipsychotic
       mechanism of action
• DA antagonism necessary but not sufficient
• Sustained D2 occupancy not necessary to
  achieve antipsychotic efficacy (fast-off
  – Antipsychotics with higher k-off values are
    better able to decrease their occupancy in
    response to increased dopamine surges required
    for task related activities
   Today’s theory of antipsychotic
       mechanism of action

• Other systems (5-HT, GABA, Glutamate,
  – No evidence of primary antipsychotic action
  – May influence through modulating DA activity
  – May play a role in other clinical dimensions
    (i.e. affect, cognition)
   Second generation: Advantages…

• Efficacy (symptom relief, relapse rates)
   – Equal or greater efficacy
   – Superior efficacy in treatment-refractory
     (mainly clozapine)
• Tolerability (side effects, safety, ease of
   – Fewer EPSE
   – Less likely to  PRL
   – Probable ↓ tardive dyskinesia
 Second generation: Advantages
• Functioning (activities of daily living, quality of
   – Probable superiority; negative symptoms
   – Possible superiority; cognitive dysfunction
   – Possible superiority; mood symptoms
• Acceptability (factors that affect compliance)
   – Adverse effects (i.e. weight gain)
   – Safety/impact of monitoring (Clozaril)
Comparing second generation agents
• Clozapine
  – Blood monitoring (agranulocytosis), weight gain,
    diabetes, dose-related risk of seizures, sedation,
• Risperidone
  – EPS, increased prolactin, hypotension
• Olanzepine
  – Weight gain, diabetes, somnolence, hypotension
• Quetiapine
  – Somnolence, hypotension
   First generation: Advantages
• Availability in long-acting form
  – Non-compliant or high risk patients
• Cost containment
         Refractory Psychosis
• Persistent positive and negative symptoms
  with deficits in social and occupational
  functioning despite treatment
  – 30-60% unresponsive or partially responsive to
    first-generation antipsychotics
• Lack of response to two trials of at least 6
  weeks each of antipsychotic medication
  – Including at least one second-generation agent
  Refractory psychosis: Options
• Clozapine
  – For refractory
  – For severe EPSE or TD, even while receiving a
    second-generation agent
• Mood stabilizers
  – Lithium, Valproic acid, Carbamazepine,
  Refractory psychosis: Options
• Antidepressants
  – Also as adjunct to treat comorbidity
• Benzodiazepines
  – Acute agitation