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Drugs Used in Psychiatry

Drugs Used in Psychiatry. Dr Noel Kennedy Clinical Lecturer and Consultant Psychiatrist. Schizophrenia. Positive symptoms - delusions - hallucinations Negative symptoms - apathy - avolition. Schizophrenia – Diagnosis (Schneider, 1959). Hallucinations

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Drugs Used in Psychiatry

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  1. Drugs Used in Psychiatry Dr Noel Kennedy Clinical Lecturer and Consultant Psychiatrist

  2. Schizophrenia • Positive symptoms - delusions - hallucinations • Negative symptoms - apathy - avolition

  3. 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

  4. Schizophrenia - Epidemiology • 1% prevalence, higher cities, ethnic minorities • M>F, 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 - >80% relapse, majortiy impaired

  5. Schizophrenia Aetiology • Genetic - First degree relative 10% - Twin studies MZ:DZ 48:4, 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)

  6. Antipsychotics- Classification

  7. Typical antipsychotics D2 Antagonism HPA (↑PRL) Mesolimbic (Antipsychotic) Basal Ganglia (EPSE, Parkinsonism)

  8. 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)

  9. 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

  10. Neuroleptic Malignant Syndrome (NMS) • Early in tx (<4 weeks) M>F, 20% mortality,mid-life • Clinical - muscle rigidity - pyrexia - delirium - pyrexia - ↑↑CPK, ↑K ↓Neutorophils, Myoglobinurea • Treatment - respiratory support - bromocriptine/dantrolene

  11. 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)

  12. Atypical Antipsychotics • Definitions - Less EPSE - Mesolimbic specific or 5HT2/D2 antagonism • Clinical Potency - As effective as typicals in positive symptoms - Some more effective (clozapine>olanzapine/sulpiride>rest Davis et al.) - May have more effect on negative symptoms

  13. 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

  14. 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

  15. 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

  16. Clozapine Other Side Effects • Sedation (early) • Hypersalivation (hyoscine) • Hypertension/hypotension • Tachycardia (early) • Constipation • Fever

  17. 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)

  18. Depression Treatment: Symptoms • At least two of (>2 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

  19. Depression - Epidemiology • 6-9% prevalence, higher women (F:M 2:1) • 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

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

  21. 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

  22. 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

  23. 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

  24. Consider Symptoms and Side Effects NE 5HT Attention Drive Appetite Mood Sleep Loss of pleasure Obsessions Anxiety Cognitions

  25. 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

  26. 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

  27. 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, ↓BPpostural - Clomipramine – similar s/e, 5HT anxiety/OCD - Loferpramine – less cardiotoxic, sedative - Nortriptyline – less s/e, elderly

  28. 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

  29. 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

  30. 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

  31. 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

  32. Refractory Depression: Definitions • Failure to respond fully to >1 or several antidepressants (10-30%) • Chronic duration <2 years (10%) - least likely to be effectively treated • Partial response also a problem (>40%)

  33. Management of TRD • Outrule medical cause/medications (e.g. diabetes, hypothyroidism, Cushing’s 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)

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

  35. 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

  36. ↑

  37. Anxiety Disorders Types - Generalized Anxiety Disorder - Social phobia - Agoraphobia - Obsessive Compulsive Disorder Treatment - Exposure therapy - SSRIs and Clomipramine, Benzos (<2 weeks)

  38. Bipolar Affective Disorder - Epidemiology • 0.8% prevalence, women later onset (F:M 1.2:1) • Onset early 20s, 50% mania, • Higher rates cities, ?higher social class • Strongly genetic (20% first degree relative) • Very high proportion recur (>90%) • Women more depression BPII>BPI

  39. 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

  40. Management of BAD: Maintenance • Moderate dose lithium (0.8-1.2 meq/l) (60-70%), prevents mania and depression • Valproate>Cambamazepine • Better for mania than depression • Lamotrigine • Better for depression than mania • Atypical antipsychotics – recent data

  41. Lithium • Acute and maintenance (depression>mania) • 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

  42. 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

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