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					Pharmacotherapy in
Psychiatry
Depression

Schizophrenia

Bipolar   disorders
Contents

   Schizophrenia and antipsychotics
   Depression and antidepressants
   Bipolar disorders and mood stabilizers
Schizophrenia and
antipsychotics
Schizophrenia

   Characterized by psychosis,
    hallucinations, delusions, cognitive
    defects, occupational and social
    dysfunction
   Chronic psychotic illness
    Episodic exacerbations and remissions
     with residual symptoms
    Complete remission is not common
Schizophrenia

   Epidemiology
    Lifetime prevalence is 1% in United
     States
    Onset in late teens or early 20s in males;
     sometime later in females
    Suicide rate comparable to depressive
     illness (approx 10%)
Schizophrenia

   Etiology
    Exact etiology unknown
        Genetic predisposition
        Intrauterine, birth or postnatal complications

        Viral CNS infections

        Environmental stressors (biochemical or social)

    No evidence of association with poor
     parenting
Schizophrenia

   Pathophysiology
    No consistent neuropathology or
     biomarkers for schizophrenia
       ? Increased dopamine in mesolimbic
        pathways causes delusions and hallucinations
       ? Dopamine deficiency in mesocortical and
        nigrostriatal pathways causes negative
        symptoms (apathy, withdrawal)
       Hallocinogens produce effect through action
        on 5-HT2 receptors
Schizophrenia

   Positive symptoms          Negative symptoms
     Hallucinations             Social withdrawal
     Delusions                  Emotional
     Disordered thinking         withdrawal
     Disorganized speech        Lack of motivation
     Combativeness              Poverty of speech
     Agitation                  Blunted affect
     Paranoia                   Poor insight
                                 Poor judgement
                                 Poor self-care
Schizophrenia

   Antipsychotics
    Typical / Conventional antipsychotics
    Atypical antipsychotics
Typical / conventional
antipsychotics
   Chlorpromazine (Largactil®)
   Flupenthixol (Fluanxol®)
   Haloperidol (Serenace®, Haldol®)
   Pericyazine (Neulactil®)
   Pimozide (Orap®, Orap Forte®)
   Sulpiride (Dogmatil®)
   Thioridazine (Melleril®)
   Trifluoperazine (Stelazine®)
   Thiothixene (Navane®)
Typical / conventional
antipsychotics
   Refers to agents introduced in US before
    1990
   Also known as
     “Dopamine receptor antagonists”
          Pharmacologic activity at blocking central dopamine
           receptors (esp. D2 receptors)
     “Neuroleptics”
          Due to tendency to cause neurologic Adverse effects
     “Major tranquilizers”
          Inappropriate as these agents (esp. high potency) can
           improve psychosis without sedating or making patients
           tranquil
Typical / conventional
antipsychotics
Dopamine receptors in various tracks
Track           Origin         Innervations   Function        Antipsychotic
                                                              effect
Mesolimbic      Midbrain,      Limbic         Emotional and   Hallucinations,
                Ventral        structure,     intellectual    deulsions,
                tegmental      nucleus                        disordered
                               accumbens                      cognition
Mesocortical    Ventral        Frontal
                tegmental      cortex
Nigrostriatal   Substantia     Basal ganglia Extrapyramidal   Motor
                nigra                        system           symptomatology
                                             movement
Tubero-         Hypothalamus   Pituitary      Regulate        Plasma
infundubular                   gland          endocrine       prolactin levels
                                              functions
Typical / conventional
antipsychotics
   Mechanism of action
    Blocks receptors for dopamine,
     acetylcholine, histamine and
     norepinephrine
    Current theory suggests dopamine2 (D2)
     receptors suppresses psychotic symptoms
       All typical antipsychotics block D2 receptors
       Close correlation between clinical potency and
        potency as D2 receptor antagonists
Typical / conventional
antipsychotics
   Properties
     Effective in reducing positive symptoms during
      acute episodes and in preventing their
      reoccurrence
     Less effective in treating negative symptoms
          Some concern that they may exacerbate negative
           symptoms by causing akinesia
     Higher incidence of EPS / sedation /
      anticholinergic Adverse effects
Typical / conventional
antipsychotics
   Potency
    All have same ability to relieve symptoms
     of psychosis
    Differ from one another in terms of
     potency
         i.e. size of dose to achieve a given response
    When administered in therapeutically
     equivalent doses, all drugs elicit
     equivalent antipsychotic response
Typical / conventional
antipsychotics
   Low potency
    Chlorpromazine, thioridazine
   Medium potency
    Perphenazine
   High potency
    Trifluoperazine, thiothixene, fluphenazine,
     haloperidol, pimozide
Typical / conventional
antipsychotics
Potency    Drug              Equiv   EPS        Sedation   Anticholinergic s/e
                             oral
                             dose
                             (mg)
Low        Chlorpromazine 100        Moderate   High       Moderate
           Pericyazine       NA      Low        High       Low
           Thioridazine      100     Low        High       High
Moderate   Perphenazine      10      Moderate   Moderate   Low
High       Trifluoperazine   5       High       Low        Low
           Thiotheixene      2       High       Low        Low
           Fluphenazine      2       High       Low        Low
           Haloperidol       2       High       Low        Low
           Pimozide          0.5     High       Moderate   Moderate
           Sulpiride         200     Low        Moderate   Low
Typical / conventional
antipsychotics
Comparison of representative antipsychotics
Drug              Advantages              Disadvantages
Chlorpromazine    Generic, inexpensive    Many adverse effects
                                          (esp. autonomic)
Thioridazine      Slight EPS, generic     Cardiotoxicity (QT
                                          prolongation)
Fluphenazine      Generic, depot          (?) increased tardive
                  available               dyskinesia
Thiothixene       (?) decreased tardive   Uncertain
                  dyskinesia
Haloperidol       Generic, injection and Prominent EPS
                  depot A/V, few
                  autonomic s/e
Typical / conventional
antipsychotics
Receptor blockade and Adverse effects
Receptor type          Consequence of blockade
D2 dopaminergic        Extrapyramidal symptoms; prolactin
                       release
H1 histaminergic       Sedation
Muscarinic cholinergic Dry mouth, blurred vision, urinary
                       retention, constipation, tachycardia
Alpha1-adrenergic      Orthostatic hypotension; reflex
                       tachycardia
5-HT2 serotonergic     Weight gain
Typical / conventional
antipsychotics
   Adverse effects
     Extrapyramidal symptoms (EPS)
          Early reactions – can be managed with drugs
              Acute dystonia
              Parkinsonism
              Akathisia
          Late reaction – drug treatment unsatisfactory
              Tardive dyskinesia (TD)
          Early reactions occur less frequently with low potency
           drugs
          Risk of TD is equal with all agents
Typical / conventional
antipsychotics
   Adverse effects
     Acute dystonia
           Develops within a few hours to 5 days after first dose
           Muscle spasm of tongue, face, neck and back
           Oculogyric crisis (involuntary upward deviation of eyeballs)
           Opisthotonus (tetanic spasm of back muscles, causing trunk
            to arch forward, while head and lower limbs are thrust
            backwards)
           Laryngeal dystonia can impair respiration
           Management
                 Anticholinergics (Benztropine, diphenhydramine IM/IV)
                 Lower or split dosing
                 Switch agent
                 Add scheduled benztropine / diphenhydramine with
                  antipsychotic
Typical / conventional
antipsychotics
   Adverse effects
     Parkinsonism (neuroleptic induced)
          Occurs within first month of therapy
          Bradykinesia, mask-like facies, drooling, tremor,
           rigidity, shuffling gait, cogwheeling, stooped posture
          Shares same symptoms with Parkinson’s disease
          Management
              Centrally acting anticholinergics (scheduled benztropine
               / diphenhydramine / benzhexol with antipsychotics) and
               amantadine
              Avoid levodopa as it may counteract antipsychotic
               effects
              Switch to atypical antipsychotics for severe symptoms
Typical / conventional
antipsychotics
   Adverse effects
     Akathisia
          Develop within first 2 months of therapy
          Compulsive, restless movement
          Symptoms of anxiety, agitation
          Management
              Beta blockers (propranolol)
              Benzodiazepines (e.g. lorazepam)
              Anticholinergics (e.g. benztropine, benzhexol)
              Reduce antipsychotic dosage or switch to low potency
               agent
Typical / conventional
antipsychotics
   Adverse effects
    Tardive dyskinesia (TD)
        Develops months to years after therapy
        Involuntary choreoathetoid (twisting, writhing,
         worm-like) movements of tongue and face
        Can interfere with chewing, swallowing and
         speaking
        Symptoms are usually irreversible
Typical / conventional
antipsychotics
   Adverse effects
     Tardive dyskinesia (TD)
          Management
             Some manufacturers suggest drug withdrawal at earliest
              signs of TD (fine vermicular movements of tongue) may
              halt its full development
             Gradual drug withdrawal (to avoid dyskinesia)
             Use lowest effective dose
             Atypical antypsychotic for mild TD
             Clozapine for severe, distressing TD
             Inconsistent results with
                  Diazepam, clonazepam, valproate
                  Propranolol, clonidine
                  Vitamin E
Typical / conventional
antipsychotics
   Other Adverse effects
     Neuroleptic malignant syndrome (NMS)
          Rare but serious reaction, 0.2% of patients on
           neuroleptics
          High fever, autonomic instability, mental status
           changes, leaden rigidity, elevated CK, WBC,
           myoglobinuria
          Management
              Discontinue antipsychotic
              Paracetamol for hyperthermia
              IV fluids for hydration
              Benzodiazepines for anxiety
              Dantrolene for rigidity and hyperthermia
              Bromocriptine for CNS toxicity
Typical / conventional
antipsychotics
   Other Adverse effects
    Neuroleptic malignant syndrome (NMS)
          After symptom resolution
             Some suggest to wait for at least 2 weeks before
              resuming
             Use lowest effective dose
             Avoid high potency agents
             Consider atypical antipsychotics
                 However, NMS has been reported from
                  patients taking clozapine, risperidone,
                  olanzapine and quetiapine
Typical / conventional
antipsychotics
   Other Adverse effects
     Prolactinemia
          D2 receptor blockade decreases dopamine inhibition of
           prolactin
          Results in galactorrhea, amenorrhea, loss of libido
              Managed with bromocriptine
     Sedation
          Administer once daily at bedtime
     Seizures
          Haloperidol has a lower risk of seizures
          Anticonvulsants (beware or possible interaction with
           antipsychotic)
Atypical antipsychotics

   Refers to newer agents
   Also known as
    “Serotonin-dopamine antagonists”
          Postsynaptic effects at 5-HT2A and D2
           receptors
Atypical antipsychotics

   Amisulpiride (Solian®)
   Quetiapine (Seroquel®)
   Ziprasidone (Zeldox®)
   Risperidone (Risperdal®)
   Olanzapine (Zyprexa®)
   Clozapine (Clozaril®)
   Aripiprazole (Abilify®)
Atypical antipsychotics

   Mechanism of action
     Similar blocking effect on D2 receptors
     Seem to be a little more selective, targeting the
      intended pathway to a larger degree than the
      others
     Also block or partially block serotonin receptors
      (particularly 5HT2A, C and 5HT1A receptors)
     Aripiprazole: dopamine partial agonist (novel
      mechanism)
Atypical antipsychotics

   Properties
    Available evidence to show advantage for
     some (clozapine, risperidone, olanzapine)
     but not all atypicals when compared with
     typicals
    At least as effective as typicals for
     positive symptoms
    May be more efficacious for negative and
     cognitive symptoms (still under debate)
Atypical antipsychotics

   Properties
    Less frequently associated with EPS
    More risk of weight gain, new onset
     diabetes, hyperlipidemia
    Novel agents, more expensive
Atypical antipsychotics

   Potency
    All atypical antipsychotics are equally
     effective at therapeutic doses
       Except clozapine
       Most effective antipsychotic

       For resistant schizophrenia

       2nd line due to life-threatening side effect
Atypical antipsychotics
Relative receptor-binding of atypical antipsychotics
Drug            D1    D2     5-HT2 1       M1     H1
Clozapine       ++    ++     +++     +++ +++ +
Risperidone     -     +++ +++        +++ -         +
Olanzapine      ++    ++     +++     ++     +++ ++
Quetiapine      -     +      ++      +++ +         +
Ziprasidone     +/-   ++     +++     ++     -      +
Aripiprazole    +     +++ ++         ++     -      +
Atypical antipsychotics
Comparison of representative atypical antipsychotics
Drug           Advantages                       Disadvantages
Clozapine      For treatment-resistant cases,   Risk of fatal agranulocytosis
               little EPS
Risperidone    Broad efficacy, little or no EPS EPS and hypotension at high
               at low doses                     doses
Olanzapine     Effective with positive and      Weight gain
               negative symptoms, little or
               no EPS
Quetiapine     Similar to risperidone, maybe    Dose adjustment with associated
               less weight gain                 hypotension, bd dosing
Ziprasidone    Perhaps less weight gain than    QT prolongation
               clozapine, Inj A/V
Aripiprazole   Less weight gain, novel          Uncertain
               mechanism potential
Atypical antipsychotics
Relative incidence of Adverse effects

Drugs          Sedatio   EPS    Anticholinergic   Orthostasis   Seizure   Prolactin   Weight
               n                                                          elevation   gain


Clozapine      ++++      +      ++++              ++++          ++++      0           ++++

Risperidone    +++       +      ++                +++           ++        0 to        ++
                                                                          ++++


Olanzapine     +++       +      +++               ++            ++        +           +++

Quetiapine     +++       +      ++                ++            ++        0           ++

Ziprasidone    ++        +      ++                ++            ++        0           +

Aripiprazole   ++        +      ++                ++            ++        0           +
Atypical antipsychotics
   1st line atypical antipsychotics
     All atypicals except clozapine
     NICE recommendations
          Atypical antipsychotics considered when choosing 1st
           line treatment of newly diagnosed schizophrenia
          Treatment option of choice for managing acute
           schizophrenic episode
          Considered when suffering unacceptable Adverse
           effects from a conventional antipsychotic
          Changing to an atypical not necessary if typical
           controls symptoms adequately and no unacceptable
           Adverse effects
Atypical antipsychotics
   2nd line atypical antipsychotic
     Clozapine
          Most effective antipsychotic for reducing symptoms
           and preventing relapse
          Use of clozapine effectively reduce suicide risk
          1% risk of potentially fatal agranulocytosis
              Acute pronounced leukopenia with great reduction in
               number of neutrophil
     NICE recommendations
          Clozapine should be introduced if schizophrenia is
           inadequately controlled despite sequential use of 2 or
           more antipsychotic (one of which should be an atypical)
           each for at least 6-8 weeks)
Atypical antipsychotics
   Clozapine
     BNF 52 (September 2006)
          Leucocyte and differential blood count normal before
           starting
          Monitor counts Q week for 18 weeks, then at least Q 2
           weeks after 1 year
          At least Q 4 weeks after count stable for 1 year (for 4
           more weeks after discontinuation)
          If leucocyte count < 3000/mm3, or if ANC <
           1500/mm3, discontinue immediately and refer to
           hematologist
          Patient should report immediately symptoms of
           infection, esp. flu-like illness (fever, sore throat)
Atypical antipsychotics
   Clozapine
     Rare cases of myocarditis and cardiomyopathy
          Fatal
          Most commonly in first 2 months
          CSM recommendations
             Physical exam and medical history before starting
             Persistent tachycardia esp. in first 2 weeks should
              prompt observation for cardiomyopathy
             If myocarditis or cardiomyopathy, stop clozapine
             Inform patients for unexplained fatigue, dyspnea,
              tachypnea, chest pain, paipitation and ask them to
              report these signs and symptoms immediately
Atypical antipsychotics

   Clozapine
    Contraindication
        History of clozapine-induced agranulocytosis
        Bone marrow suppression

        On myelosuppressive drugs

    Caution
        Seizure disorders
        Diabetes
Antipsychotic oral-dispersible
and solution preparations
   Oral-dispersible preps available for
      2 atypicals
            Risperidone (Risperdal Quicklet®)
            Olanzapine (Zyprexa Zydis®)
      Carefully peel off packing, allow tablet to dissolve on tongue and
       swallow
      Do not break the tablet
      Some may be dispersed in fluids (consult manufacturer literature)
   Solutions available for
      1 typical
            Haloperidol (Haldol® drops)
      1 atypical
            Risperidone (Risperdal® solution)
      Very concentrated, avoid from contact with skin (dermatitis)
Antipsychotic injections

   Available for
    2 typicals
        Chlorpromazine (Largactil®)
        Haloperidol (Haldol®)

    2 atypicals
        Olanzapine (Zyprexa®)
        Ziprasidone (Zeldox®)

    Useful for acutely agitated patients
Antipsychotic depot injections
   Available for
     4 typicals
          Haloperidol decanoate (Haldol Decanoate®)
          Fluphenazine decanoate (Modecate®)
          Flupenthixol (Fluanxol®)
          Zuclopenthixol (Clopixol Depot®)
     1 atypical
          Risperidone (Risperdal Consta®)
     Used for chronic illness and history of
      noncompliance
     Trial of oral meds first to assess tolerability
Non-antipsychotic agents
   Benzodiazepines
     Useful in some studies for anxiety, agitation,
      global impairment and psychosis
     Schizophrenic patients are prone to BZD abuse
     Limit use to short trials (2-4 weeks) for
      management of severe agitation and anxiety
   Lithium
     Limited role in schizophrenia monotherapy
     Improve psychosis, depression, excitement, and
      irritability when used with antipsychotic in some
      studies
Non-antipsychotic agents
   Carbamazepine
     Weak support when used alone and with antipsychotic
     Alters metabolism of antipsychotic
     NOT to be used with clozapine (risk of agranulocytosis)
   Valproate
     Concurrent administration with risperidone and olanzapine
      resulted in early psychotic improvement in recent
      investigation
   Propranolol
     Research showed improvement in chronic aggression
     Treat aggression or enhance antipsychotic response
     Reasonable trial  240mg/day
Antipsychotics in
schizophrenia
   Selection of typical antipsychotics
     Equally efficacious
     Chosen by side effect profile
   Atypical antipsychotics may be appropriate if
     Adverse effect is a particular concern
     Additional benefits for negative and cognitive
      symptoms required
   Clozapine
     2nd line treatment when other agents are
      ineffective or not tolerated
Antipsychotics in
schizophrenia
   Depot antipsychotic preparations
     Useful for noncompliant patients with poor
      insight
   Antidepressents and mood stabilisers
     In schizoaffective disorders
     Patients with secondary mood symptoms or
      aggressivity
   Differentiate between adverse effects and
    signs of disease progression
     E.g. Parkinsonism vs. psychotic hysteria,
      Akathisia vs. exacerbation of psychosis
Antipsychotics in
schizophrenia
   Oral administration
      Divided daily doses at initial phase
      Once daily at bedtime when stabilized
            Promoting sleep and reducing daytime sedation
      Smallest effective dose employed
   Oral-dispersible and solution preparations
      For unreliable patients
   Injections
      Usually deltoid or gluteal muscle (or according to manufacturer)
   Depot injections
      At intervals of 1 to 4 weeks
      Generally not more than 2-3ml oily injection at one site
      Correct injection technique (z-track) and injection site rotation
Antipsychotics in
schizophrenia
   Treatment response
     First 7 days
          Decreased agitation, hostility, combativeness, anxiety,
           tension and aggression
          Normalization of sleep and eating habits
     First 2-3 weeks
          Increased socialization, improvement in self-care
     6-8 weeks
          Improvement in formal thought disorder
Antipsychotics in
schizophrenia
   Acute phase
     Initiate therapy
     Titrate as tolerated to average effective dose
   Stabilization phase
     Dose titration within the therapeutic range
   Maintenance phase
     Therapy should be continued for at least 12 months after
      remission of 1st episode
     Good treatment responders should be treated for at least
      5 years
     Continuous lifetime maintenance required in the majority
      of patients to prevent relapse
           Lowest effective and tolerable dose
Depression and
antidepressants
Depression
   Depressed mood and/or decrease in interest in
    things that used to give pleasure
   Sadness severe enough or persistent enough to
    interfere with function
   DSM-IV:
     Major depressive disorder / major depression
     Dysthymia
           Depression for most of the day, more days than not
     Depressive disorder not otherwise specified
     Depressive disorder due to a general physical condition
     Substance-induced depressive disorder
Depression

   Epidemiology
    Life prevalence 3-17%
    Onset in late 20s
    Highest in
       25-44 years
       Elderly in community

    Female vs male = 2:1
       Female 10-25% lifetime risk
       Male 5-12% lifetime risk
Depression
   Epidemiology
     4th most common reason to visit family physician
     Most common in elderly and difficult to diagnose
     Coexists with dementia or delirium frequently
     Recurrence rate of major depression
          After single episode = 50%
          After second episode = 70%
          After third episode = 90%
     Approx 10-15% of patients with major
      depressive or bipolar disorder complete suicide
Depression
   Signs and symptoms
     Depressed mood
     Sleep (insomnia or hypersomnia)
     Loss of interest (including libido)
     Guilt
     Energy loss
     Concentration loss
     Appetite (loss or gain)
     Psychomotor (agitation or retardation)
     Suicide (ideation)
Depression

   Etiology
     Etiology unknown
          Uncertain with heredity
          History of child abuse or other major life stresses
          Changes in neurotransmitter/neurohormone levels
              Cholinergic, noradrenergic/dopaminergic and
               serotonergic neurotransmission
              Deregulation with hypothalamic-pituitary-adrenal axis,
               hypothalamic-pituitary-thyroid axis and growth hormone
          Life stresses (e.g. Separation and losses)
Depression

   Pathophysiology
    Exact course unknown
         Changes in receptor-neurotransmitter
          relationship in limbic system
            Serotonin, norepinephrine, sometimes dopamine
         Increased pump uptake of neurotransmitter
            Reabsorption into neuron
            Destroyed by monoamine oxidase in mitochondria
            Lack of neurotransmitters
Antidepressants
   Tricyclic and related antidepressants (TCA)
     E.g. amitriptyline, imipramine, doxepin,
      mianserin, trazodone
   Monoamine-oxidase inhibitors (MAOI)
     E.g. moclobemide, phenelzine, isocarboxazid,
      tranylcypromine
   Selective serotonin reuptake inhibitors (SSRI)
     E.g. fluoxetine, paroxetine, sertraline, citalopram
   Other antidepressants
     E.g. mirtazapine, venlafaxine, duloxetine,
      flupentixol
Tricyclic and related
antidepressants (TCA)
   Amitriptyline (Saroten®)
   Clomipramine (Anafranil®)
   Dothiepin (a.k.a. dosulepin, Prothiaden®)
   Doxepin (Sinequan®)
   Imipramine (Tofranil®)
   Mianserin (Tolvon®)
   Nortriptyline (Nortrilen®)
   Trazodone (Trittico®)
   Trimipramine (Surmontil®)
Tricyclic and related
antidepressants (TCA)
   Mechanism of action
     Blocks neuronal uptake or norepinephrine and
      serotonin
     Initial response develops in 1-3 weeks
     Maximal response develops in 1-2 months
     Older tricyclics
          Marked anticholinergic Adverse effects
          Risk of cardiotoxicity
     Tricyclic-related drugs (e.g. trazodone)
          Fewer anticholinergic Adverse effects
          Sedation, dizziness, priapism (persistent penile erection
           accompanied by pain and tenderness)
Tricyclic and related
antidepressants (TCA)
   Properties
     Inexpensive, generic
     Some with off-label use, e.g.
          Neuropathy with amitriptyline
          Refractory skin diseases with doxepin
     Very dangerous in overdose
          Life threatening
          Lethal dose only 8 times average daily dose
          Acutely depressed patients should not be given more
           than 1-week TCA supply at one time
Tricyclic and related
antidepressants (TCA)
   Adverse effects
     Orthostatic hypotension
           Reduced by moving slowly when assuming upright posture
           Sit or lie down if symptoms (dizziness, lightheadedness)
            occur
           Divided doses and slow titration
     Anticholinergic effects
           Dry mouth, blurred vision, photophobia, constipation, urinary
            retention, tachycardia
           Tolerance may develop as treatment persists
           Divided doses and slow titration
     Sedation
           Dose at bedtime
Tricyclic and related
antidepressants (TCA)
   Adverse effects
     Cardiac toxicity
           Arrhythmias and heart block
           ECG recommended before initiation
           Do not use in heart block
     Seizures
           Lowered seizure threshold
     Hypomania (mild mania)
           Elevated mood
           Patient should be evaluated to determine dose reduction or
            bipolar disorder
     Diaphoresis
           Paradoxical effect
Tricyclic and related
antidepressants (TCA)
   Drug interactions
    CNS depressants
        Narcotics, benzodiazepines
        Additive CNS depression

    Anticholinergics
          Additive anticholinergic effects
    P450 enzyme inducers/inhibitors
Monoamine-oxidase inhibitors
(MAOI)
   Moclobemide (Aurorix®)
   Not registered in Hong Kong
    Phenelzine
    Isocarboxazid
    Tranylcypromine
Monoamine-oxidase inhibitors
(MAOI)
   Mechanism of action
    Inhibit both MAO-A and MAO-B
         Phenelzine, tranylcypromine
    Selective & reversible inhibitor of MAO-A
         Moclobemide
Monoamine-oxidase inhibitors
(MAOI)
   Properties
    Useful in atypical depression (somnolence
     and weight gain), refractory disorders
     and certain types of anxiety disorders
    Less prescribed than tricyclics, SSRIs and
     other antidepressants
          Danger of dietary and drug interactions
Monoamine-oxidase inhibitors
(MAOI)
   Properties
    Drug interactions
        Other antidepressants should not be started
         for 2 weeks after MAOI has been stopped (3
         weeks for clomipramine or imipramine)
        MAOI should not be started for 7-14 days
         after a tricyclic or related antidepressant (3
         weeks for clomipramine or imipramine)
        MAOI should not be started for at least 2
         weeks after a previous MAOI
Monoamine-oxidase inhibitors
(MAOI)
   Adverse effects
    Hypertensive crisis
          Severe occipital headache, photophobia,
           palpitation, sharply increased in BP due to
           additive effect between MAOI and adrenergic
           stimulants
             Tyramine-rich food e.g. cheese, wine,
              smoked/aged/picked meat or fish, alcohol
             Amphetamins
             Pseudoephedrine
Monoamine-oxidase inhibitors
(MAOI)
   Adverse effects
    Orthostatic hypotension
    Insomnia
    Weight gain
    Sexual dysfunction
Selective serotonin reuptake
inhibitors (SSRI)
   Fluoxetine (Prozac®)
   Fluvoxamine (Faverin®)
   Paroxetine (Seroxat®)
   Sertraline (Zoloft®)
   Citalopram (Cipram®)
   Escitalopram (Lexapro®)
Selective serotonin reuptake
inhibitors (SSRI)
   Mechanism of action
    Inhibits reuptake of serotonin (5-HT)
     presynaptic uptake
    Increases availability of serotonin at
     synapses
Selective serotonin reuptake
inhibitors (SSRI)
   Properties
    Overdose less likely to be fatal
    Less anticholinergic side effects
    But more GI side effects
    Seems to be better tolerated
Selective serotonin reuptake
inhibitors (SSRI)
   Properties
     Fluoxetine
          Most stimulating SSRI
          Indicated for premenstrual dysphoric disorder (PMDD)
           (as Sarafem®)
          Long half-life, ensure 5 week washout before MAOI (2
           week for other SSRI)
     Some SSRIs also indicated for
          Obsessive-compulsive disorder (OCD)
          Panic disorder
          Eating disorders
          Social phobia
          Post traumatic stress disorder (PTSD)
Selective serotonin reuptake
inhibitors (SSRI)
   Adverse effects
    Headache
    GI
        Nausea, diarrhoea, loss of appetite
        Titrate dose to minimize side effect
        May be taken with food

    Anticholinergic Adverse effects
        Fever than TCA
        Tend to see more with paroxetine
Selective serotonin reuptake
inhibitors (SSRI)
   Adverse effects
    Somnolence or insomnia
          Dose in morning for insomnia
    Increase in anxiety, agitation, akathisia
     early in treatment (esp. fluoxetine)
    Agitation or nervousness
    Sexual dysfunction
Selective serotonin reuptake
inhibitors (SSRI)
   Adverse effects
     Serotonergic syndrome
          Rare but potentially fatal interaction between 2 or
           more drugs that enhance serotonin
          Anxiety, shivering, diaphoresis, tremor, hyperflexia,
           autonomic instability (BP, pulse)
          Fatal if malignant hyperthermia
          Management
              Mild: resolve in 24-48 hours after discontinuing
               offending agent
              Severe: 5-HT antagonist, cyproheptidine, propranolol,
               methysergide, dantrolene (hyperthermia)
Serotonin norepinephrine
reuptake inhibitor (SNRI)
   Duloxetine (Cymbalta®)
   Venlafaxine (Efexor®, Efexor XR®)
   Mechanism of action
    Inhibits norepinephrine and serotonin
     reuptake
    Potentiates neurotransmitter activity in
     the CNS
Serotonin norepinephrine
reuptake inhibitor (SNRI)
   Duloxetine (Cymbalta®)
   Properties and Adverse effects
    More potent than venlafaxine
    Also indicated for diabetic neuropathy
    Insomnia, nausea, headache
Serotonin norepinephrine
reuptake inhibitor (SNRI)
   Venlafaxine (Efexor®, Efexor XR®)
   Properties and Adverse effects
    Also for anxiety disorders
    Lacks sedative and anticholinergic effects
     predominant with TCAs
    Nausea, dizziness, sexual dysfunction,
     hypertension (when > 300mg/day)
Mixed serotonin
norepinephrine effects
   Mirtazapine (Mirtazon®, Remeron®,
    Remeron SolTab®)
   Mechanism of action
    Presynaptic α2-antagonist
    Increases central noradrenergic and
     serotonergic neurotransmission
Mixed serotonin
norepinephrine effects
   Mirtazapine (Mirtazon®, Remeron®,
    Remeron SolTab®)
   Properties and Adverse effects
    Fewer anticholinergic effects
    Marked sedation during initial treatment
    Stimulating as dose increases
    Increased appetite and weight gain
    Constipation, dry mouth
Norepinephrine dopamine
reuptake inhibitor (NDRI)
   Bupropion (Wellbutrin SR®)
   Mechanism of action
    Inhibits weakly the neuronal uptake of
     dopamine, norepinephrine and serotonin
    Does not inhibit monoamine oxidase
Norepinephrine dopamine
reuptake inhibitor (NDRI)
   Bupropion (Wellbutrin SR®)
   Properties and side effects
    GI side effects, confusion, dizziness,
     headache, insomnia, tremor
    Seizure risk at high doses
    Minimal risk of sexual dysfunction
    Also licensed for smoking cessation
     (Zyban®)
Other antidepressants

   Flupenthixol (Fluanxol®)
    Typical antipsychotic
    Antidepressant effect at low doses
        Antipsychotic dose: 3-9mg twice daily
        Antidepressant dose: 1-3mg daily

    Combined with another antidepressant as
     Deanxit®
        Flupenthixol 0.5mg + melitracen 10mg
        For depression and anxiety
Non-antidepressants
   Anxiolytics
   Antipsychotics
     Use may mask the true diagnosis
     Used with caution
     But are still useful adjuncts in agitated patients
   Lithium and thyroid
     To potentiate effect of antidepressants in
      refractory cases
          Lithium: plasma level 0.4-0.8mEq/L
          Thyroid supplement: 25mcg/day
Antidepressants in depression

   Choice of agents
    All are equally efficacious for depression
    Selection based on
        Side effect profile
        Potential drug interaction

    Response failure to an antidepressant
     does not predict response to another
     drug class or another drug within class
Antidepressants in depression

   Geriatrics
     Reduce initial dose by half
     Gradual dose titration
          Risk of dizziness and syncope
          Hyponatremia
   Pediatrics
     Decrease initial dose by half
     Recent evidence links SSRIs with suicide in
      adolescents
Antidepressants in depression
   Treatment response
     Weeks 1-2
          Physical responses
             Improvement in appetite and sleep
     Weeks 3-4
          Energy and cognitive responses
             Improvement in energy
             Improvement in guilt, concentration
     Weeks 5-6
          Emotional responses
             Improvement in mood
Antidepressants in depression
   Continuation therapy
     To prevent relapse
     4-9 months after complete remission of
      symptoms
     At therapeutic doses
   Lifelong maintenance therapy
     Recommended by some investigators for
      patients at greater risk or reoccurrence
          < 40 years with ≥ 2 prior episodes
          Any age with ≥ 3 prior episodes
Bipolar disorders and mood
stabilizers
Bipolar disorders
   Cyclic disorder with recurrent fluctuations in
    mood, energy and behaviour, “mood swings”
   Episodes of mania and/or hypomania, and
    major depression that cause marked
    impairment and/or hospitalization
   Devastating long term illness
     Deterioration in functioning
     Suicidal ideation
     Substance abuse
     Noncompliance to meds
Bipolar disorders
   DSM-IV:
     Bipolar I disorder
           ≥1 manic or mixed episode
     Bipolar II disorder
           Recurrent major depressive episodes with hypomanic
            episodes
     Bipolar disorder not otherwise specified
     Cyclothymic disorder
           Both hypomanic and depressive episodes not meeting criteria
            for a major depressive epidose
           Mood symptoms have persisted for 2 years without > 2
            months of remission at a time
     Bipolar disorder due to their general physical condition
     Substance-induced bipolar disorder
Bipolar disorders

   Epidemiology
    Prevelance 1-2%
    Male = female
    Average age of onset 20 to 30
    10-15% rate of suicide
Bipolar disorders

   Epidemiology
    5-15% of adults diagnosed with major
     depressive disorder eventually meet
     criteria for bipolar I disorders
    60-70% of manic or hypomanic episodes
     occur immediately before or after major
     depressive episode
    Period of euthymia (normal mood)
Bipolar disorders

   Etiology
    Exact cause unknown
        Genetic predisposition
        Life stressors

        Can occur with several physical disorders

        As adverse effects of many drugs

        As part of several mental disorders
Bipolar disorders

   Pathophysiology
    Neurotransmitters known to be involved
       Serotonin
       Norepinephrine

       Dopamine

    Brain structures most involved
         MRI findings suggests abnormalities in
          prefrontal cortical areas, striatum, and
          amygdala predate illness onset
Bipolar disorders
   Signs and symptoms
   Mania                                Hypomania
     Distractability                      Distinct period of
     Insomnia                              persistently elevated,
     Grandiosity or inflated self-         expansive, or irritable
      esteem                                mood
     Flight of ideas or                   Lasting throughout at least
      subjective experience that            4 days
      thoughts are racing                        < 1 week for mania
     Agitation or increase in             Different from usual non-
      goal-directed activity                depressed mood
     Speech pressured/more                But not severe enough to
      talkative than usual                  cause marked impairment
                                            in social or occupational
     Taking risks                          functioning
Bipolar disorders
   Signs and symptoms
   Mixed episode                    Rapid cyclers
     Simultaneous                     > 4 major depressive or
      occurrence of manic and           manic episodes (manic,
      depressive symptoms               mixed or hypomanic for
      nearly every day for aat          12 months)
      least 1 week                     Frequent and severe
     Poorer prognosis                  episodes of depression
     More seen in younger             Poorer prognosis
      and older patients               Often require
     Less likely to respond to         combination therapies
      mood stabilizer
      monotherapy
Mood stabilizers

   Lithium
   Anticonvulsants
    Valproate
    Carbamazepine
    Lamotrigine
   Antipsychotics, antidepressants and
    others
Lithium

   Mechanism of action
     Not fully understood
          Mood-stabilizing effect has been postulated to
           reduction of catecholamine neurotransmitter
           concentration
          Possibly related to Na-K-ATPase to improve membrane
           transport of Na ion
          Alternative postulate that Li may decrease cyclic AMP
           concentrations, which would decrease sensitivity of
           hormonal-sensitive adenylcyclase receptors
Lithium
   Properties
     Manic episode
          Approved for manic episodes and maintenance therapy
          About 70% patients show at least partial reduction of
           mania
          Full effect takes 1-2 weeks
     Depressive episode
          As adjunct to antidepressant for refractory patients
          Onset 4-6 weeks
     Long term use reduces suicide risk and mortality
     Narrow therapeutic index
Lithium

   Dosing
    Start with low divided doses to minimize
     Adverse effects
    Gradual titration
    Adjusted to achieve serum lithium
       Acute manic episode: 1.0-1.5 mmol/L
       Maintenance: 0.6-1.2 mmol/L
Lithium
   Adverse effects                      Late Adverse effects
     Early, dose related                  Psoriasis / acne
      Adverse effects                       exacerbation
           GI distress                    Nephrogenic diabetes
           Sedation, weight gain           insipidus
           Muscle weakness                Hypothyroidism
           Polyuria, polydipsia           Cardiac
           Impaired cognitive                   T-wave flattening or
            funciton                              inversion
           Tremor                               Bradycardia
     Tolerance may develop                      AV block
     Management                           Leukocytosis
           Take with meal
           Beta blocker for tremor
Lithium

   Adverse effects
     Nephrogenic diabetes insipidus (DI)
          Reduced renal response to aldosterone (ADH)
          Low osmolality polyuria
             > 3L urine output per day
             Urine specific gravity < 1.005
          Management
             Lowest effective dose
             Adequate hydration
             Once-daily bedtime dose
             Thiazides (lithium dose to 50%) or amiloride
Lithium
Lithium toxicity (serum level > 1.5-2.5 mmol/L)
Mild toxicity       Moderate toxicity Severe toxicity
(< 1.6 mmol/L) (< 2.5 mmol/L) (> 2.5 mmol/L)
Apathy              Blurred vision    Cardiovascular
Irritability        Confusion         collapse
Lethargy            Drowsiness        Coma
Muscle weakness Progressing           Seizure
Nausea              tremor
                    Slurred speech
                    Unsteady gait
Lithium

   Toxicity
    Discontinue lithium
    NaCl infusion, rehydration, electrolyte
    Monitor lithium level q3h
    Electrolyte panel, renal function labs
    Hemodialysis if patient not clearing
     lithium well or lithium level > 3 mmol/L
    Supportive care
Lithium

   Interactions
    Numerous drug interactions!
    Dietary sodium, soda, coffee, tea,
     caffeine  lithium clearance
    Acute mania  lithium clearance
Lithium

   Formulation
     Regular release tablets
          As lithium carbonate 250mg and 400mg (e.g.
           Camcolit®)
          More adverse effects due to higher peak levels
          More convenient for small dose increments
     Sustained release tablets
          As lithium sulphate 660mg (e.g. Lithiofor®)
          Fewer Adverse effects
          More expensive
Anticonvulsants

   Carbamazepine (Tegretol®, Tegretol
    CR®)
   Lamotrigine (Lamictal®)
   Valproate (Epilim EC®, Epilim Chrono®)
Carbamazepine

   Properties
     Approved for acute mania and mixed episodes in
      bipolar I disorder
          As Equetro® extended-release capsules
     Preferred when response to lithium is poor
          Rapid cyclers
          Mixed mania episodes
     Not recommended as monotherapy for bipolar
      depression
     P450 enzyme inducer
Carbamazepine

   Adverse effects
    Weight gain
    Neurotoxicity
        Diplopia, drowsiness, blurred vision, vertigo
        Transient and reversible with dose reduction

    Mild elevation of liver enzymes
    Hypersensitivity rash
          Uncommon
Carbamazepine

   Adverse effects
     Hematologic effects
          Rare: agranulocytosis, blood dyscrasia
          Discontinue when
              Fever, sore throat, rash, mouth ulcers, bruising or
               bleeding
     Syndrome of inappropriate antidiuretic hormine
      (SIADH)
     Cardiac conduction abnormalities (sometimes
      arrhythmia)
Lamotrigine

   Properties
     Approved for maintenance of bipolar I disorder
          To delay the time to occurrence of mood episodes
           (depression, mania, hypomania, mixed episodes)
     Significant antidepressant effect without increase
      in cycling
     May not be effective for severe mania
     Significant drug interactions with other
      anticonvulsants
Lamotrigine
Dosing of lamotrigine in bipolar disorders
               Weeks 1-2    Weeks 3-4        Week 5         Maintenance
                                                            dose
Lamotrigine    25mg qd      50mg qd          100mg qd       200mg/day
monotherapy
Lamotrigine    25mg qod     25mg qd          50mg qd        100mg/day
added to
valproate
Lamotrigine    50mg qd      100mg/day        200mg/day for Increase up
added to                    in divided       1 week, then    to
enzyme                      doses            300mg/day for 400mg/day
inducers w/o                                 1 week (both in
valproate                                    divided doses )
Lamotrigine

   Adverse effects
    Skin rash
        Stevens-Johnson’s Syndrome, toxic epidermal
         necrosis, hypersensitivity syndrome
        Consider withdrawal if rash or signs of
         hypersensitivity occur
            Increased risk of serious skin reactions with
                Concomitant use of valproate
                Initial lamotrigine doses higher than
                 recommended dose
                Dose escalation more rapid than recommended
Lamotrigine

   Adverse effects
    GI
          Abdominal pain, indigestion, nausea, vomiting
    Asthenia, pain
    Ataxia, dizziness, headache, somnolence
Valproate
   Properties
     Approved for treatment of mania in bipolar
      disorder
          As divalproex sodium (Depakote® and Depakote® ER)
             Delayed release (Depakote®): manic episode
             Extended release (Depakote® ER): acute mania and
              mixed episodes
     Preferred when response to lithium is poor
          Substance abusers
          Rapid cyclers
          Mixed mania episodes
     P450 enzyme inhibitor
Valproate

   Adverse effects
    GI: anorexia, indigestion, nausea,
     vomiting, heartburn, diarrhoea
          Decrease dose, antacid or H2-antagonist
    Irreversible but rare hepatotoxicyt
    Weight gain, increased appetite
          Decrease dose, monitor weight
Valproate

   Adverse effects
    Neutropenia and thrombocytopenia
    Sedation, tremor
        Decrease dose
        Beta blocker for tremor

    Menstrual disturbances and polycystic
     ovaries is posssible
    Transient alopecia
Other anticonvulsants

   Oxcarbazepine (Trileptal®)
   Topiramate (Topamax®)
    No FDA approval
    Tested in some clinical studies
    Less used than carbamazepine,
     lamotrigine and valproate
Other drugs for bipolar
diseases
   Antipsychotics
    Effective as adjunctive treatment of acute
     mania
    Should be used when patient is psychotic
    Novel ones preferred
    Monotherapy may be used in acute
     nonpsychotic mania, but effectiveness of
     mood stabilization in maintenance phase
     not well established
Other drugs for bipolar
diseases
   Antipsychotics
     Olanzapine
     Risperidone
          FDA approval: acute mania, mixed episodes,
           maintenance
     Aripiprazole
     Ziprasidone
          FDA approval: acute mania, mixed episodes
     Quetiapine
          FDA approval: acute mania, depressed phase
Other drugs for bipolar
diseases
   Antidepressants
     May improve acute depression in short term
     Ineffective for long term
     Monotherapy (TCAs in particular) can precipitate
      manic episodes or rapid cycling
     May be used as adjunct with mood stabilizers if
      patient has a history of refractory depression
      and manic episodes that are relatively
      responsive
Other drugs for bipolar
diseases
   Benzodiazepines
    As adjunct to treat acute agitation,
     anxiety and insomnia
    For severely ill patients
    Short term use only
Mood stabilizers in bipolar
disorders
   Acute manic or mixed episode
     Mild to moderate
          1) Stabilize with lithium / valproate / antipsycotic (e.g.
           olanzapine, quetiapine, risperidone)
              Alternative anticonvulsant: carbamazepine, lamotrigine
               or oxcabazepine
          2) If inadequate response, adjunctive benzodiazepines
           for anxiety or insomnia
          3) If still inadequate response, consider two-drug
           therapy
              Lithium + anticonvulsant / antipsychotic
              Anticonvulsant + anticonvulsant / antipsychotic
Mood stabilizers in bipolar
disorders
   Acute manic or mixed episode
    Moderate to severe
         1) Stabilize with lithium / valproate PLUS
          antipsychotic for short term adjunctive
          treatment (e.g. olanzapine, quetiapine,
          risperidone)
            Alternative anticonvulsant: carbamazepine,
             lamotrigine or oxcabazepine
         2) If inadequate response, adjunctive
          benzodiazepines for anxiety or insomnia
            Lorazepam recommended for catatonia
Mood stabilizers in bipolar
disorders
   Acute manic or mixed episode
     Moderate to severe
          3) If still inadequate response, consider 2-drug therapy
              Lithium + anticonvulsant / antipsychotic
              Anticonvulsant + anticonvulsant / antipsychotic
          4) If still inadequate response, electroconvulsive
           therapy or add clozapine for refractory illness
          5) If still inadequate response, consider adjunctive
           therapies
              α2-adrenergic agonist, calcium channel blockers
               (nimodipine, verapamil), newer anticonvulsants (e.g.
               gabapentin, topiramate)
Mood stabilizers in bipolar
disorders
   Depressive episode
    Mild to moderate
         Stabilize with lithium or lamotrigine
            Alternative anticonvulsant: carbamazepine,
             oxcabazepine or valproate
Mood stabilizers in bipolar
disorders
   Depressive episode
    Moderate to severe
         1) Stabilize with 2-drug therapy
            Lithium / lamotrigine PLUS antidepressant
            Lithium PLUS lamotrigine
                 Alternative anticonvulsant: carbamazepine,
                  oxcabazepine or valproate
         2) If inadequate response, short-term
          adjunctive atypical antipsychotic if needed
Mood stabilizers in bipolar
disorders
   Depressive episode
     Moderate to severe
          3) If still inadequate response, consider 3-drug therapy
              Lithium + anticonvulsant + antipsychotic
              Lamotrigine + anticonvulsant + antidepressant
          4) If still inadequate response, electroconvulsive
           therapy (ECT) for refractory illness and depression with
           psychosis or catatonia
          5) If still inadequate response, consider adjunctive
           therapies
              α2-adrenergic agonist, calcium channel blockers
               (nimodipine, verapamil), newer anticonvulsants (e.g.
               gabapentin, topiramate)
Mood stabilizers in bipolar
disorders
   Initial therapy
     If first line agent(s) not effective for 2-4 weeks, add a
      second agent to augment mood stabilization
   Maintenance therapy
     Maintain with a mood stabilizer for both bipolar I and II
      disorders for 6-month continuation phase
           First line: lithium or valproate
           Alternative: carbamazepine, lamotrigine, oxcabazepine
     Taper off adjunctive therapy and discontinue
     Patient with only 1 manic episode should continue
      maintenance therapy for 12 months
           Gradually taper off over several months (usually 6 months
            after complete remission)
Mood stabilizers in bipolar
disorders
   Lifelong prophylaxis
     Consider with mood stabilizers for
          Patients after 2 manic episodes
          After 1 severe episode
          Strong family history of bipolar disorder
          Frequent episodes (> 1 per year)
          Rapid onset of manic apisodes
          Bipolar II
          After 3 hypomanic episodes
          Patients who become hypomanic with antidepressants
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