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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.

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pharmacotherapy in psychiatry

Pharmacotherapy in Psychiatry

Depression

Schizophrenia

Bipolar disorders

contents
Contents
  • Schizophrenia and antipsychotics
  • Depression and antidepressants
  • Bipolar disorders and mood stabilizers
schizophrenia
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
schizophrenia1
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%)
schizophrenia2
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
schizophrenia3
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
schizophrenia4
Positive symptoms

Hallucinations

Delusions

Disordered thinking

Disorganized speech

Combativeness

Agitation

Paranoia

Negative symptoms

Social withdrawal

Emotional withdrawal

Lack of motivation

Poverty of speech

Blunted affect

Poor insight

Poor judgement

Poor self-care

Schizophrenia
schizophrenia5
Schizophrenia
  • Antipsychotics
    • Typical / Conventional antipsychotics
    • Atypical antipsychotics
typical conventional 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 antipsychotics1
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 antipsychotics3
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 antipsychotics4
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 antipsychotics5
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 antipsychotics6
Typical / conventional antipsychotics
  • Low potency
    • Chlorpromazine, thioridazine
  • Medium potency
    • Perphenazine
  • High potency
    • Trifluoperazine, thiothixene, fluphenazine, haloperidol, pimozide
typical conventional antipsychotics10
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 antipsychotics11
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 antipsychotics12
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 antipsychotics13
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 antipsychotics14
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 antipsychotics15
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 antipsychotics16
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 antipsychotics17
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 antipsychotics18
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
Atypical antipsychotics
  • Refers to newer agents
  • Also known as
    • “Serotonin-dopamine antagonists”
      • Postsynaptic effects at 5-HT2A and D2 receptors
atypical antipsychotics1
Atypical antipsychotics
  • Amisulpiride (Solian®)
  • Quetiapine (Seroquel®)
  • Ziprasidone (Zeldox®)
  • Risperidone (Risperdal®)
  • Olanzapine (Zyprexa®)
  • Clozapine (Clozaril®)
  • Aripiprazole (Abilify®)
atypical antipsychotics2
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 antipsychotics3
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 antipsychotics4
Atypical antipsychotics
  • Properties
    • Less frequently associated with EPS
    • More risk of weight gain, new onset diabetes, hyperlipidemia
    • Novel agents, more expensive
atypical antipsychotics5
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 antipsychotics9
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 antipsychotics10
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 antipsychotics11
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 antipsychotics12
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 antipsychotics13
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
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
Antipsychotic injections
  • Available for
    • 2 typicals
      • Chlorpromazine (Largactil®)
      • Haloperidol (Haldol®)
    • 2 atypicals
      • Olanzapine (Zyprexa®)
      • Ziprasidone (Zeldox®)
    • Useful for acutely agitated patients
antipsychotic depot injections
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
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 agents1
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
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 schizophrenia1
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 schizophrenia2
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 schizophrenia3
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 schizophrenia4
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
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
depression1
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
depression2
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
depression3
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)
depression4
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)
depression5
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
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
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 tca1
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 tca2
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 tca3
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 tca4
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 tca5
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
Monoamine-oxidase inhibitors (MAOI)
  • Moclobemide (Aurorix®)
  • Not registered in Hong Kong
    • Phenelzine
    • Isocarboxazid
    • Tranylcypromine
monoamine oxidase inhibitors maoi1
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 maoi2
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 maoi3
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 maoi4
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 maoi5
Monoamine-oxidase inhibitors (MAOI)
  • Adverse effects
    • Orthostatic hypotension
    • Insomnia
    • Weight gain
    • Sexual dysfunction
selective serotonin reuptake inhibitors ssri
Selective serotonin reuptake inhibitors (SSRI)
  • Fluoxetine (Prozac®)
  • Fluvoxamine (Faverin®)
  • Paroxetine (Seroxat®)
  • Sertraline (Zoloft®)
  • Citalopram (Cipram®)
  • Escitalopram (Lexapro®)
selective serotonin reuptake inhibitors ssri1
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 ssri2
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 ssri3
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 ssri4
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 ssri5
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 ssri6
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
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 snri1
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 snri2
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
Mixed serotonin norepinephrine effects
  • Mirtazapine (Mirtazon®, Remeron®, Remeron SolTab®)
  • Mechanism of action
    • Presynaptic α2-antagonist
    • Increases central noradrenergic and serotonergic neurotransmission
mixed serotonin norepinephrine effects1
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
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 ndri1
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
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
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
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 depression1
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 depression2
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 depression3
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
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 disorders1
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 disorders2
Bipolar disorders
  • Epidemiology
    • Prevelance 1-2%
    • Male = female
    • Average age of onset 20 to 30
    • 10-15% rate of suicide
bipolar disorders3
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 disorders4
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 disorders5
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 disorders6
Signs and symptoms

Mania

Distractability

Insomnia

Grandiosity or inflated self-esteem

Flight of ideas or subjective experience that thoughts are racing

Agitation or increase in goal-directed activity

Speech pressured/more talkative than usual

Taking risks

Hypomania

Distinct period of persistently elevated, expansive, or irritable mood

Lasting throughout at least 4 days

< 1 week for mania

Different from usual non-depressed mood

But not severe enough to cause marked impairment in social or occupational functioning

Bipolar disorders
bipolar disorders7
Signs and symptoms

Mixed episode

Simultaneous occurrence of manic and depressive symptoms nearly every day for aat least 1 week

Poorer prognosis

More seen in younger and older patients

Less likely to respond to mood stabilizer monotherapy

Rapid cyclers

> 4 major depressive or manic episodes (manic, mixed or hypomanic for 12 months)

Frequent and severe episodes of depression

Poorer prognosis

Often require combination therapies

Bipolar disorders
mood stabilizers
Mood stabilizers
  • Lithium
  • Anticonvulsants
    • Valproate
    • Carbamazepine
    • Lamotrigine
  • Antipsychotics, antidepressants and others
lithium
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
lithium1
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
lithium2
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
lithium3
Adverse effects

Early, dose related Adverse effects

GI distress

Sedation, weight gain

Muscle weakness

Polyuria, polydipsia

Impaired cognitive funciton

Tremor

Tolerance may develop

Management

Take with meal

Beta blocker for tremor

Late Adverse effects

Psoriasis / acne exacerbation

Nephrogenic diabetes insipidus

Hypothyroidism

Cardiac

T-wave flattening or inversion

Bradycardia

AV block

Leukocytosis

Lithium
lithium4
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
lithium6
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
lithium7
Lithium
  • Interactions
    • Numerous drug interactions!
    • Dietary sodium, soda, coffee, tea, caffeine  lithium clearance
    • Acute mania  lithium clearance
lithium8
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
Anticonvulsants
  • Carbamazepine (Tegretol®, Tegretol CR®)
  • Lamotrigine (Lamictal®)
  • Valproate (Epilim EC®, Epilim Chrono®)
carbamazepine
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
carbamazepine1
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
carbamazepine2
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
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
lamotrigine2
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
lamotrigine3
Lamotrigine
  • Adverse effects
    • GI
      • Abdominal pain, indigestion, nausea, vomiting
    • Asthenia, pain
    • Ataxia, dizziness, headache, somnolence
valproate
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
valproate1
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
valproate2
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
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
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 diseases1
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 diseases2
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 diseases3
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
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 disorders1
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 disorders2
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 disorders3
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 disorders4
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 disorders5
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 disorders6
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 disorders7
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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