Psychopharmacology

1. Psychopharmacology Agustin Magat

2. Identifying Data • R.R. • 34/M • College graduate • Unemployed • Roman Catholic • American • Currently residing in Q.C. • Chief Complaint: “This is a call center I guess”

3. History of Present Illness • 13 mos PTA • Living in the house with a NYPD police officer • Underwent police training (2/3) • Was kicked out of the house due to unknown reason • Became homeless and wandered in the streets

4. History of Present Illness • 13 mos PTA • Sleeps in bus and subway stations • Mother contacted him and gave assistance to help him return to the Philippines • Withdraws from friends and family. • Denied 2 job applications

5. History of Present Illness • 13 mos PTA • No changes in mood and appetite • Seems to drink lots of carbonated beverages to help him “stay awake”

6. History of Present Illness • 11 mos PTA • Patient was given a condominium unit with monthly allowance • Described as “anti-social” – doesn’t go to social gatherings; finds a reason • Walks from ayala heights to UP to look for internet shops everyday

7. History of Present Illness • 11 mos PTA • Sometimes talks about conspiracy about NPA and terrorists • Claimed that he once reported an accident to the NYPD and believed that it was connected to the conspiracy theory

8. History of Present Illness • 3 weeks PTA • Mom visited the patient • Claimed that he is a NYPD officer • Talks about his music and claims that he can make 36000 dollars annually • More irritable and hostile to the people disturbing him • Became more paranoid even to the maintenance staff of the condominium

9. Family History • Older of 2 children • Mother: a Filipino military doctor • Father: an American businessman, widower, with three kids • The family resided in a U.S. military base for around 5 years due to the mother’s work but later on transferred to Manhattan when the mother opted for private practice

10. Personal History • Early Childhood • born via CS in SLMC to a 38 yo G1P1 • Described as a quiet and shy child but with a lot of friends • Middle Childhood • Parents separated; the father left the family for another woman • Patient was said to be very sad and asked “Who is going to leave next?”

11. In grade school, his mother brought him to school in a flashy MB but he told her to drop him off a block away from school so as not to make other kids feel bad • Described as a smart child; class topnotcher • Late childhood • Patient was around 15 when the mother opted to bring the family back to the Philippines • All U.S. properties were disposed and the mother decided to have the family stay here for good

12. Patient entered the Ateneo but had to repeat 1 year. He was unhappy. He was also bullied due to his poor Tagalog and his different appearance. • Patient was frustrated with school because his classmates cheated. • To appease the patient, he was allowed annual visits to U.S. friends

13. Adulthood • Took up 1st year in ADMU but was kicked out because of missed classes • Brother says patient went out with the “wrong crowd” • Transferred to AMA Computer College, stayed for a sem but later on quit since he did not believe in the school • Transferred again to Angelicum College where he finished Communication Arts

14. Worked as a radio DJ for several months • Became a call center agent but quit because he did not like lying about being a Texan • Went to the US and had odd jobs including being a piano teacher • Was still partially supported by the mother financially

15. Came back to the Philippines to work in his mother’s English school but the venture did not go well • 4 years PTA – patient worked in a US airport for 1 ½ years, his longest job • Met a black Jamaican American woman who did not gain the mother’s approval; they eventually broke up

16. 2 years PTA – patient tried joining the NYPD and lived with a police officer • Was eventually kicked out, due to unknown reasons • Became homeless for 2-3 days before coming back to the Phils.

17. Physical Examination • Essentially normal

18. Mental Status Examination The patient is an adult Filipino-looking male, appropriate for chronological age. He was unkempt and was wearing a green checkered oversized polo which was half-buttoned and oversized soiled pants with torn ends. He had no footwear and had dirty toenails. He spoke softly but his mood was anxious. He did not understand why some boys took him to the unit. His speech was clear and normoproductive but with occasional tangentiality. He gave a paper which he claimed contained his internet research; it contained paragraphs without any common thought or idea. He denied any hallucinations but claimed he was a NYPD officer. He manifested poor judgment, poor abstract thinking, and poor insight.

19. Assessment • Axis I: T/C Schizophrenia, Paranoid type R/O Substance Induced Psychosis • Axis II: Defer • Axis III: None • Axis IV: Work-related stressors, relational stressors • Axis V: GAF 21-30

20. Salient Features • 34/M • (+) delusions of grandeur – NYPD officer, music composer • Negative symptoms – affective flattening • Social/occupational dysfunction – cannot hold jobs, a “recluse” • Duration: >6 months • Tangentiality, loose assocations, poor judgment, poor abstract thinking, and poor insight

21. Plan • Establish therapeutic alliance for supportive psychotherapy • Diagnostics: CBC, BUN, Creatinine, ALT, TSH, UA, CXR, ECG, UDS (All substances + MDMA) • Therapeutics: • Aripiprazole 10 mg tab 1 tab in the morning • Clonazepam 2 mg/tab 1 tablet twice daily • Olanzapine 10 mg/IM as needed for agitation • Suicide, Homicide, Escape, Assault Precaution

22. Results: Diagnostics • CBC, UA, TFTs, CXR, ECG: normal • Urine Drug Screen: none detected (methamphetamine, cannabinoids, benzodiazepines, barbiturates, opiates, cocaine, ecstasy)

23. LFTs

24. Schizophrenia • Disruptive psychopathology in: cognition, emotion, perception, behavior. • Diagnosis is based entirely on the psychiatric history and mental status examination

25. Schizophrenia • Equally prevalent in men and women·       • According to onset: earlier in men • Men • Peak age of onset: 10-25 years old • Most likely to be impaired

26. Schizophrenia • Etiologies • Retroviral Infection • Active viral infection • Virus-activated immunopathology • Autoimmune pathology • Maternal infection • Genetic

27. Schizophrenia • Dopamine Hypothesis • Increased dopaminergic activity

28. Schizophrenia • DSM-IV-TR Diagnostic Criteria for Schizophrenia(From American Psychiatric Association DSM-IV-TR) · • Characteristic symptoms: Two (or more) of the following, each present for a significant portion of time during a 1-month period • Delusions   • Hallucinations • Disorganized speech • Grossly disorganized or catatonic behavior • Negative symptoms, i.e., affective flattening, alogia, or avolition· • Social/occupational dysfunction: major areas of functioning like work, interpersonal relations, or self-care are markedly low • Duration: at least 6 months. • Schizoaffective and mood disorder are ruled out·  • Substance/general medical condition exclusion: The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.

29. Treatment • Mainstay of treatment: antipsychotic medications • Psychotherapy, behavioral skills therapy, family-oriented therapy, CBT, etc. – can augment clinical improvement • More benefit is derived from a combination of antipsychotic drugs ad psychosocial treatment

30. Hospitalization • Indications • Diagnostic purposes • Stabilization of medications • Patient safety e.g. against suicidal/homicidal ideations • Grossly disorganized/inappropriate behavior • Inability to take care of basic needs e.g. food, clothing, shelter • Primary goal: establish an effective association between patient and community support system

31. Principles of Pharmacologic Treatment • Define the target symptom to be treated • If (+) previous drug use: • Successful: use again • Unsuccessful: choose a different drug • 4-6 week trial period for drug effectiveness • Consider poor response: increase dose, check compliance, change drug • Lowest possible effective dose

32. Examples of “Target” Symptoms • Agitation • Combativeness • Hostility • Hallucinations • Acute delusions • Insomnia • Anorexia • Poor self-care • Negativism • Withdrawal and seclusiveness

33. Phases of Treatment • Acute Phase • Goal: alleviate the most severe psychotic sx (e.g. severe agitation, frightening delusions, hallucinations, suspiciousness, stimulant abuse) • Initiate treatment as soon as possible since delay may worsen prognosis • Duration: 4-8 weeks • Agents used: antipsychotics, benzodiazepines • Single IM injection for rapid calming effect without sedation: Haloperidol (Haldol), Fluphenazine (Prolixin, Permitil), Olanzapine (Zyprexa), Ziprasidone (Geodon) • IM injection without substantial EPS: Ziprasidone, Olanzapine • EPS e.g. dystonias, akathisia – seen with haloperidol, fluphenazine

34. Role of BZDs • Effective or agitation • Lorazepam (Ativan) – reliably absorbed PO or IM • Reduce the amount of antipsychotic needed for control

35. Stabilization/Maintenance Phase • Goals: prevent relapse and help improve functioning • Relative state of remission with minimal psychotic symptoms • 53-72% without meds experience relapse; only 16-23% with meds have a relapse • Duration: at least 5 years but may be indefinite

36. Pharmacotherapy

37. Typical antipsychotics – act on the mesolimbic and the nigostriatal pathways Mesolimbic pathway: limbic system, with D2 receptor predominance; hyperactivity causes positive symptoms Mesocortical pathway: prefrontal complex, with D1 receptor predominance; hypoactivity causes negative symptoms Nigostriatal pathway: substantia nigra to the basal ganglia ; inhibition causes parkinsonian symptoms Tuberoinfundibular pathway: hypothalamus to posterior pituitary; responsible for side effects e.g. prolactin elevation, but not for positive or negative symptoms

38. Potency and Adverse Effects

39. Factors Influencing Pharmacokinetics

40. Effective: when 60% of D2 receptors are occupied • EPS manifest: when 80% of D2 receptors are occupied • Other effects: blockage of noradrenergic, cholinergic, and histaminergic receptors

41. Most Common Side Effects • Mostly neurologic • Acute extrapyramidal symptoms (days to weeks) • Akathisia – motor restlessness, not anxiety or agitation • Acute dystonia – spasm of muscles of tongue, face, neck, back, may mimic seizures • Drug-induced parkinsonism – bradykinesia, rigidity, variable tremor, mask facies, shuffling gate • Neuroleptic malignant syndrome – catatonia, stupor, fever, unstable BP, myoglobulinemia, may be fatal • Chronic extrapyramidal syndromes (months to years) • Tardive dyskinesia and dystonia – oral-facial dyskinesia, widespread choreoathetosis or dystonia • Perioral tremor – “rabbit syndrome” – may be a late variant of parkinsonism

42. Neuroleptic Malignant Syndrome • Potentially fatal side effect of DRAs • Symptoms • extreme hyperthermia, severe muscular rigidity and dystonia, akinesia • Mutism, confusion, agitation • Increased HR and BP -> cardiovascular collapse • Labs: increased WBC, creatinine, liver enzymes, plasma Mgb, myoglobinuria +/- renal failire • Mortality rate: 20-30% wuth depot medications; higher with high doses of high-potency agents

43. Neuroleptic Malignant Syndrome • If suspected: • Stop DRA immediately • Initiate medical support to cool the patient • Symptomatic tx of fever • Monitor VS, electrolytes, fluid balance, I/O • Dantrolene – skeletal muscle relaxant • Consider switching to low-potency drug or SDAs

44. Chlorpromazine • First DRA • Mechanism of action: D2 receptor antagonist • Metabolism: hepatic P450 enzyme CYP2D6 • Adverse effects • Extrapyramidal symptoms: akathisia (60%) most prominent • Anticholinergic effects, sedation( most sedating typical AP), weight gain, erectile dysfunction • Cardiovascular and cerebrovascular: orthostatic hypotension (most common) • Hematologic: mild leukocytosis, leukopenia and eosinophilia; agranulocytosis (rare but serious)

45. Dermatologic: urticaria, dermatitis (~5%); epithelial keratopathy • GI and hepatic: mild jaundice • Drug interactions • Potentiation of miotic and sedative effects of morphine; increased respiratory depression with opioids • Increased metabolism with CYP inducers e.g. carbamazepine, phenobarbital, but NOT valproate • Competition with SSRIs (e.g. fluxocamine, paroxetine, venlafaxine, sertraline) for CYP enzymes, leading to elevated levels

46. Contraindicated combination • Increase QT interval • Amiodarone, Astemizole, Cisapride, Pentamidine • Pimozide, Procainamide, Quinidine, Terfenadine • Amitryptyline, bupropion, domperidone, fluoxetine, haloperidol • Beta-blockers e.g. propanolol, metroprolol, sotalol • Antibiotics: Clarithromycin

47. Haloperidol • MOA: D2 receptor antagonist • Metabolism: hepatic P450 CYP2D6 • Enzymes inhibited: CYP2D6 • Adverse effects: EPS, anticholinergic effects, sedation, weight gain, ED, oligomenorrhea/amenorrhea (similar to Chlorpromazine) • Drug interactions: similar to Chlorpromazine

48. Usage in Modern Psychiatry • Not the first-line of treatment; largely replaced by SDAs • Major deterrent to use: development of tardive dyskinesia • Still valuable for short-term therapy • Advantages: • Cost advantage: a DRA anti-Parkinsonian regimen is less costly compared to monotherapy with an atypical antipsychotic • Less weight gain: less weight gain compared to SDAs – DRAs still have a role in patients who are at risk of or who already have diabetes

49. Second Generation Antipsychotics • Atypical Antipsychotics • Serotonin-dopamine antagonists • E.g. Risperidone, Olanzapine, Quetiapine, Clozapine, Ziprasidone • Higher ratio of Serotonin type 2 to D2 dopamine receptor blockades • Improved tolerability • Affects the mesolimbic pathway

50. Second Generation Antipsychotics • Characteristics: • Low D2 receptor blocking effects • Reduced risk of extrapyramidal side effects • Proved efficacy as treatments for schizophrenia • Proved efficacy as treatments for acute mania