Drugs Used in Psychiatry

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Drugs Used in Psychiatry

• Dr Noel Kennedy Clinical
  Lecturer and Consultant Psychiatrist

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Schizophrenia

• Positive symptoms
• - delusions
• - hallucinations
• Negative symptoms
• - apathy
• - avolition

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Schizophrenia Diagnosis (Schneider, 1959)

• Hallucinations
• - third person
• - running commentary
• - thought echo
• Thought interference or Somatic passivity
• Delusional perception
• (also bizarre delusions DSM-IV, one month
  duration0

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Schizophrenia - Epidemiology

• 1 prevalence, higher cities, ethnic minorities
• MgtF, late teens to early 20s
• Two peaks in onset
• - early onset, male, developmental delay,
  drugs
• - late mid-life, female, preserved
  personality
• Interst in substance abuse, prenatal viral
  exposure
• Poor outcome - gt80 relapse, majortiy impaired

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Schizophrenia Aetiology

• Genetic
• - First degree relative 10
• - Twin studies MZDZ 484, Adoption studies
• Neurochemical
• - D2 blockade (amphetamines, animal models,
  receptor occupancy)
• - Serotonin blockade (?5HT2 block, LSD,.5HT
  impact on dopamine )
• - Glutamate (NMDA antagonists e.g.
  ketamine)

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Antipsychotics- Classification
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Typical antipsychotics D2 Antagonism
Mesolimbic (Antipsychotic)
HPA (? PRL)
Basal Ganglia (EPSE, Parkinsonism)
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Typical Antipsychotics

• High potency Clean (Likely EPSE)
• - Butyrophenones (e.g. haloperidol)
• - Piperazine (e.g. trifluoperazine)
• Low potency Dirty (anticholinergic,
  antiadrenergic)
• - Aliphatic (e.g. chlorpromazine)
• - Thioxanthene (Zuclopenthixol)

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Extrapyramidal Side Effects

• Acute Dystonia (Young men, early, first episode)
• Parkinsonism (cog-wheeling, rigidity,
  bradykinesia)
• Akathesia (uncontrollable restlessness, suicide
  risk)
• Tardive Dyskinesia (long-term tx, female,
  elderly)
• Neuroleptic Malignant Syndrome

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Neuroleptic Malignant Syndrome (NMS)

• Early in tx (lt4 weeks) MgtF, 20
  mortality,mid-life
• Clinical
• - muscle rigidity
• - pyrexia
• - delirium
• - pyrexia
• - ??CPK, ?K ?Neutorophils, Myoglobinurea
• Treatment
• - respiratory support
• - bromocriptine/dantrolene

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Antipsychotics Other Side Effects

• Anticholinergic (low potency)
• - blurred vision, constipation, confusion, wt
  gain
• Antiadrenergic (low potency)
• - postural hypotension, sexual
• ? Seizure threshold
• Weight gain (low potency, clozapine, olanzapine)
• Neutropenia/Agranulocytosis (clozapine)
• Diabetes/Impaired GTT (clozapine, olanzapine)
• Cholestatic jaundice (chlorpromazine)
• ECG change, QT prolongation (low effect)

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Atypical Antipsychotics

• Definitions
• - Less EPSE
• - Mesolimbic specific or 5HT2/D2 antagonism
• Clinical Potency
• - As effective as typicals in positive
  symptoms
• - Some more effective (clozapinegtolanzapine/
  sulpiridegtrest Davis et al.)
• - May have more effect on negative symptoms
  

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Atypical Antipsychotics

• Sulpiride/Amisulpiride
• - D2 blockade mesolimbic specific, ?PRL
  antidepressant
• Risperidone
• - 5HT2/D2 blockade, EPSE high doses, little
  sedation, wt gain
• Olanzapine
• - 5HT2/D2 blockade, significant weight gain
  (9), sedation
• Quetiapine
• - D2/5HT2/ blockade, sedative, few other
  s/e, ?potency
• Clozapine
• - treatment resistant scz, multiple
  receptors, agranulocytosis

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Clozapine

• Most effective treatment for treatment resistant
  schizophrenia (30 6 weeks, 70 1 year kane et
  al, 1988)
• Multiple receptor occupancy
• (D1, D2, D4, D5, 5HT2, 5HT3, adrenergic,
  muscarinic)
• Many side effects including agranulocytosis
  (2-3)
• May lead to reduction in suicide

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Clozapine Important Side Effects

• Neutropenia
• - Weekly blood monitoring (18 weeks), 2-4
  weeks afterwards
• Seizures
• - Mainly myoclonic, dose related, valproate
• Myocarditis/Cardiomyopathy
• - 1 in 10,000-20,000
• Pulmonary embolism
• - 1 in 5,000, effect on antiphospholipid
  antibodies
• Diabetes and weight gain
• - 1/3rd within 5 years of treatment

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Clozapine Other Side Effects

• Sedation (early)
• Hypersalivation (hyoscine)
• Hypertension/hypotension
• Tachycardia (early)
• Constipation
• Fever

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Antipsychotics and Diabetes

• Especially clozapine and olanzapine (30-40
  diabetes long-term)
• Usually early in treatment
• Needs regular monitoring
• (Baseline HBA1C, OGTT, then 3-6 monthly)

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Depression Treatment Symptoms

• At least two of (gt2 weeks)
• - persistent low mood (DMV)
• - anhedonia
• - poor energy
• At least two of
• - sleep disturbance
• - appetite disturbance/weight loss
• - impaired libido
• - guilt cognitions
• - poor concentration
• - futility feelings/suicidal ideation
• - social withdrawal

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Depression - Epidemiology

• 6-9 prevalence, higher women (FM 21)
• Late 20s throughout life
• Higher rates cities, low social class
• Poor outcome high levels of disability
• - 10 chronicity
• - 10 unnatural death
• - 70 long-term recurence
• - 50 of time symptomatic over 10 years

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Depression and subsyndromal symptoms over 10-year
follow-up (Kennedy et al, 2004)
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Theories of Depression

• Monoamine Theory
• - Deficits of monamines 5HT/Nad
• - Most antidepressants increase monoamines
• Neuroendocrine (HPA axis)
• - Hypercortisolaemia/loss of circadian
  rthymn
• - Failure of DST (60)
• - Failure to supress CRH

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Antidepressants Classes

• Monoamine oxidase inhibitors (MAOI)
  - ?stores Nad/5HT by
  inhibiting MAO-A
• Tricyclic antidepressants (TCA)
  inhibits 5HT/Nad neuronal
  reuptake
• Selective serotonin reuptake inhibitor (SSRI)
  inhibits 5HT neuronal reuptake
• Others
• - venlafaxine - Nad/5HT reuptake/receptor
  inhibition
• - mirtazepine - alpha 2, 5HT2 receptor
  inhibition
• - reboxetine Nad reuptake inhibitor

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Management of Depression General Principles

• Antidepressants only effective (70)
• Partial response a problem (40)
• Length of treatment important (4-8 weeks)
• Not all antidepressants are equal (meta-analysis)
  
• Consider symptoms
• Consider side efffects
• Length of continuation/maintenance treatment

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Consider Symptoms and Side Effects
NE
5HT
Mood Sleep Loss of pleasure
Attention Drive Appetite
Obsessions Anxiety Cognitions
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Selective Serotonin Reuptake Inhibitors (SSRI)

• First line treatment
• Effective in anxiety
• Safe, flat dose response
• - Escitalopram - ? More efffective than
  citalopram
• - Fluoxetine long t1/2, potent inhibition
  CYP
• - Paroxetine short t1/2, discontinuation
• - Sertraline mild CYP inhibition

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Selective Serotonin Reuptake Inhibitors (SSRI)

• Common adverse effects
• - nausea, vomiting, abdo pain, diarrhoea
• - sweating
• - headache
• - agitation, insomnia, tremor
• - hyponatraemia (SIADH) elderly, female,
• - discontinuation syndrome (paroxetine)
• - sexual dysfunction

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Tricyclic Antidepressants (TCA)

• Probably more effective than SSRI
• S/E Anti chol, anti adren, anti hist action
• Cardiotoxic OD, QT prolongation
• Weight gain long-term
• Doses prescribed too low
• - Amitriptyline sedation, anti chol, ?BP
  postural
• - Clomipramine similar s/e, 5HT anxiety/OCD
• - Loferpramine less cardiotoxic, sedative
• - Nortriptyline less s/e, elderly

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Monoamine Oxidase Inhibitors (MAOI)

• Mode of Action
• - Block MAO A (Nad/5HT) and B (Dop/TYP)
• - Avoid tyramine containing substances- ??BP
• Clinical Potency
• - Best for atypical or resistant depression
• - Withdrawal 2 weeks, withdrawal effects,
  5HT syndroms
• - Mocclobemide Reversible MAO A inh
• - Phenelzine/tranylcypromine
  irreversible inh, non selective

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Monoamine Oxidase Inhibitors (MAOI)

• NB Lots of S/E MCQ answer yes
• - anti cholinergic/anti adrenergic/anti
  histamine
• - paraesthesia
• - headache
• - hepatotoxicity
• - leucopenia
• - hypertensive crises (9)
• - sexual dysfunction

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Other Antidepressants

• Venlafaxine
• - 5HT/Nad reuptake inhibitor like clomipramine
  
• - meta-analysis higher proportion recovery
• - linear dose response
• - s/e discontinuation, short t1/2, BP, SSRI
  like
• Mirtazepine
• - ?2 antagonist, wt gain, sedation
• Reboxetine
• - selective Nad antagonist
• Duloxetine
• - 5ht/Nad reuptake inhibitor

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Electroconvulsive Therapy

• Most effective in TRD (80-85 response)
• Well tolerated (6-12 treatments)
• Best severe, agitated, elderly, depression
• ?Nad/5HT transmission, Da, PRL oxyticin release,
  ?plasma cortisol, ?BBB permiability
• Adverse effects
• headache, muscle stiffness, memory, GA

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Refractory Depression Definitions

• Failure to respond fully to gt1 or several
  antidepressants (10-30)
• Chronic duration lt2 years (10)
• - least likely to be effectively treated
• Partial response also a problem (gt40)

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Management of TRD

• Outrule medical cause/medications
  (e.g.
  diabetes, hypothyroidism, Cushings syndrome,
  dementia)
• Investigate precipitants of depression
• (e.g. bereavement, marital or family
  dysharmony, social factors)
• Consider comorbidity or misdiagnosis
• (e.g. anxiety disorders, substance abuse,
  dementia)

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Management of TRD

• Psychoeducational
• - self-help books
• Pharmacological
• - optimise antidepressant treatment
• - switch class of antidepressant
• - augment antidepressant
• Psychological
• - CBT/interpersonal psychotherapy prevents
  early relapse
• -

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Management of TRD Augmentation

• First low dose lithium
  
  
• 50 response within 1 week
• Second low dose atypical antipsychotics
• Third Triiodothronine (T3), lamotrigine,
  tryptophan
• Fourth Combine antidepressants
  

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?
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Anxiety Disorders

• Types
• - Generalized Anxiety Disorder
• - Social phobia
• - Agoraphobia
• - Obsessive Compulsive Disorder
• Treatment
• - Exposure therapy
• - SSRIs and Clomipramine, Benzos (lt2
  weeks)

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Bipolar Affective Disorder - Epidemiology

• 0.8 prevalence, women later onset (FM 1.21)
• Onset early 20s, 50 mania,
• Higher rates cities, ?higher social class
• Strongly genetic (20 first degree relative)
• Very high proportion recur (gt90)
• Women more depression BPIIgtBPI

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Management of BAD Acute

• Treatment of mania
• - Antipsychotics or benzodiazepines
• - (semi)sodium valproate/lithium
• Treatment of bipolar depression
• - Lithium treatment of choice
• - Lamotrigine
• - Antidepressants risk of inducing
  mania/rapid cycling

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Management of BAD Maintenance

• Moderate dose lithium (0.8-1.2 meq/l)
  
  
• (60-70), prevents mania and depression
• ValproategtCambamazepine
• Better for mania than depression
• Lamotrigine
• Better for depression than mania
• Atypical antipsychotics recent data
  

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Lithium

• Acute and maintenance (depressiongtmania)
• Mode of action
• - salt, not metabolised, 2/3 excreted by 24
  hrs, Avoid NSAID ACE Inh
• - G proteins, Na/K ATP ase, cAMP
• Side effects
• - Immediate dry or metallic taste,
  diarrhoea, tremor
• - Nephrogenic diabetes insipitus
  polydipsia/polyurea (ADH resistance)
• - Later Nephropathy (5), Hypothyroidism
  (3 pa), weight gain/oed
• - Toxicity (.2.0 meq/l) coarse tremor,
  confusion, ataxia, coma

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Other Mood Stabilizers

• All are anticonvulsants and act on Na channels
  and GABA
• Valproate
• - Acute mania, maintenance, rapid cycling
• - S/E sedation, weight gain, hair loss,
  hepatic failure, leucopenia, terato
• thrombocytopaenia, highly plasma protein
  bound, displacement
• Cambamezipine
• - Acutr mania, rapid cycling, agression S/E
  leucopenia (10) agran, sed
• apl anaemia, enzyme inducer OCP, rash
  Stevens-Johnson syndrome
• - Lamotrigine
• - Bipolar dsepression S/E rash, headache,
  nausea, ataxia