Pharmacotherapy in Psychiatry

1. Pharmacotherapy in Psychiatry Depression Schizophrenia Bipolar disorders

2. Contents • Schizophrenia and antipsychotics • Depression and antidepressants • Bipolar disorders and mood stabilizers

3. Schizophrenia and antipsychotics

4. 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

5. 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%)

6. 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

7. 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

8. 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

9. Schizophrenia • Antipsychotics • Typical / Conventional antipsychotics • Atypical antipsychotics

10. Typical / conventional antipsychotics • Chlorpromazine (Largactil®) • Flupenthixol (Fluanxol®) • Haloperidol (Serenace®, Haldol®) • Pericyazine (Neulactil®) • Pimozide (Orap®, Orap Forte®) • Sulpiride (Dogmatil®) • Thioridazine (Melleril®) • Trifluoperazine (Stelazine®) • Thiothixene (Navane®)

11. 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

12. Typical / conventional antipsychotics

13. 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

14. 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

15. 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

16. Typical / conventional antipsychotics • Low potency • Chlorpromazine, thioridazine • Medium potency • Perphenazine • High potency • Trifluoperazine, thiothixene, fluphenazine, haloperidol, pimozide

17. Typical / conventional antipsychotics

18. Typical / conventional antipsychotics

19. Typical / conventional antipsychotics

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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)

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

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

31. 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)

32. 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)

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

34. 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

35. Atypical antipsychotics

36. Atypical antipsychotics

37. Atypical antipsychotics

38. 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

39. 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)

40. 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)

41. 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

42. Atypical antipsychotics • Clozapine • Contraindication • History of clozapine-induced agranulocytosis • Bone marrow suppression • On myelosuppressive drugs • Caution • Seizure disorders • Diabetes

43. 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)

44. Antipsychotic injections • Available for • 2 typicals • Chlorpromazine (Largactil®) • Haloperidol (Haldol®) • 2 atypicals • Olanzapine (Zyprexa®) • Ziprasidone (Zeldox®) • Useful for acutely agitated patients

45. 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

46. 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

47. 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

48. 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

49. 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

50. 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