Pharmacotherapy Aphorisms. Steven F. Dingle, MD Chief Medical Officer The Arizona Division of Behavioral Health Services

Transcription

1 Pharmacotherapy Aphorisms Steven F. Dingle, MD Chief Medical Officer The Arizona Division of Behavioral Health Services

2 The Right Tool For the Right Job! Difficult to do in practice! Psychotropics treat symptoms, not diseases Verify the symptoms accurately Try to align symptoms with known clinical archetypes for optimal treatment Track your target symptoms Remember symptoms are both psychological and biological

3 Scenario 1 John is a 32 year old who carries the diagnosis of Schizoaffective Disorder. He has been reasonably stable for the past year, and has had only minimal psychotic symptoms. He comes to the clinic after being evicted and has been living in his car. He reports an increase in voices and depression, but otherwise is stating he feels safe. He reports that he is compliant with his medications.

4 Sometimes the Turtle Wins! Symptoms take time to resolve: remember what you have learned! There are reasons clinical trials have fixed doses over weeks assessments If you can get there with one treatment, does two treatments get you there faster? Certainly possible with adjunctives (psychotherapy plus meds, etc.) Why use two similar treatments if one will work? Compounding noncompliance, side effect burden, cost

5 Scenario 2 Martha is a 28 year individual who is admitted to the local BHIF for significant depression. She has had no previous treatment, but has a family history of Bipolar Disorder. She denies substance use, and her UDS was negative. Her physical health is good, and denies psychotic symptoms. She is passively suicidal, but you believe that she will not harm herself while inpatient. She does not really believe in taking medication, but reluctantly agrees because her level of distress is significant. You start her on escitalopram, 20 mg daily, with support for sleep. By day three she has shown little improvement, and is getting more despondent.

6 Pharmacology Facts Can Actually Help! Pay attention to half life! Steady state is important! Disassociation constants actually can tell you something and guide your selections. Try putting a round peg in a hole already filled with a square one! Pay attention to absorption characteristics, they can matter Watch for potential additive side effects: try to know the receptor properties of the drugs you use. Remember: absorption and metabolism are individual and can help you find the right dose.

7 Scenario 3 Your team has helped John find a placement, and he seems to be settling in, but his voices continue to bother him. He claims that he has worse voices at night. He seems to be taking his meds, olanzapine 40 mg at night, and you wonder if splitting the dose might help. You are also considering adding a small dose of loxapine at night. He admits that he has started smoking again.

8 Not All Light bulbs Can Be Dimmed Dose escalation, evaluation of efficacy must occur within the context of known mechanisms of action Dose response curves are difficult to assess for those drugs which do not work through a direct mechanism For antipsychotics and antidepressants, where is the evidence for a linear dose response curve?

9 Scenario 4 Upon further consideration, John does not wish you to add loxapine to his regimen. You have obtained a olanzapine blood level and have ruled out rapid metabolism. John is pushing now for a change in medication, but you are unwilling to give up the response you have seen from the current agent. You are convinced that he has had at least a 70% reduction in symptoms. There remains some significant depressive symptoms.

10 Dose Escalation For depression, many studies do not maintain a control group at the lower dose Many studies maintain the escalation within approved parameters Very difficult to tease out poor absorption or rapid metabolism Studies that focus on partial responders and dose escalation are equivocal

11 Psychotropic E-Harmony With the exception of few (BZDs, e.g.) we do not fully understand the linkage between known receptor occupancy and symptom improvement What you do must be supported by why you do it! Watch for bad pairings: (p450 incompatibilities, anticholinergic load, sedative burden)

12 Psychotropic E-Harmony Look for opportunities for synergism between known receptor occupancies Most acceptable with the treatment of depression Is the foundation of our PA process Also acceptable with the treatment of mania Synergism between non-sga stabilizers with different mechanisms Synergism between SGAs and mood stabilizers: is haldol a mood stabilizer? More difficult with treatment of schizophrenia

13 Lessons Learned From QOCs Mis-match of diagnoses and treatment Lack of mood stabilizer for Bipolar Disorder Typical antipsychotics in depression Stimulants without ADD Stimulants in Bipolar Disorder Multiple concomitant agents at suboptimal dosing Tricyclic antidepressants In combination with enzyme blockers In combination with narcotics High doses

14 Lessons Learned Narcotics, narcotics, narcotics! Multiple sources In combination with BZDs (often multiple) Check the CSPMP! Off label usage combined with limited documentation Coordination of care with acute care providers Use of controlled substances with history of substance abuse

15 Combination Therapy and Schizophrenia Little literature to guide us Most glaring example of not knowing underlying mechanism of symptom improvement Interclass combination therapy is aimed at control of comorbid symptoms/conditions Intraclass combination therapy is almost always an attempt to ameliorate refractory symptoms Beware of incomplete cross tapers: do you even need to cross taper?

16 Evaluating Core Pharmacologic Literature Steven F. Dingle, MD Chief Medical Officer The Arizona Division of Behavioral Health Services

17 Number Needed To Treat NNT= 1/AAR (AAR: Absolute Risk Reduction) AAR=CER-EER (CER: Control Event Rate; EER: Experimental Event rate) or 1/( (number getting better on drug/total number getting the drug)-(number getting better on control/number on control)) Example: drug A has a 40% placebo response, and a 60% drug response NNT= 1/ (60-40)=5

18 PANSS

19 PANSS

20 PANSS

21 PANSS A total of 30 items (30-210) 7 constitute the positive scale (7-49) 7 constitute a negative scale (7-49) 16 the general psychopathology scale ( )

22 PANSS Scoring 1: absent 2 (minimal): questionable or subtle or suspected pathology, or the extreme end of the normal range. 3 (mild): a symptom clearly established, but not pronounced, and interferes little in functioning. 4 (moderate): a symptom which, though representing a serious problem, either occurs only occasionally or intrudes on daily life to a moderate extent

23 PANSS SCORING 5 (moderate severe): marked manifestations that distinctly impact on functioning but not allconsuming and usually can be contained at will 6 (severe): gross pathology that is present very frequently, highly disruptive to one s life, and often calls for direct supervision 7 (extreme): most serious level of psychopathology, the manifestations drastically interfere in most or all major life functions, typically necessitating close supervision and assistance in many areas

24 Example of scoring

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26 PANSS Examples

27 Index Study of Aripirazole Kane et al: J Clin Psych 63:9, 2002

28 Index Study of Aripirazole Kane et al: J Clin Psych 63:9, 2002

29 Index Study of Aripirazole Kane et al: J Clin Psych 63:9, 2002

30 Lurasidone Reference Trials

31 Lurasidone/Bipolar Depression

32 Lurasidone/Bipolar Depression Loebel et al, Am J Psychiatry, 2014, 171:

33 Lurasione/Bipolar Depression

34 Duloxetine Reference Study Detke et al, J Clin Psych 2002, apr, 63(4)

35 Duloxetine Reference Study Detke et al, J Clin Psych 2002, apr, 63(4)

36 Duloxetine Reference Study Detke et al, J Clin Psych 2002, apr, 63(4) NNT 3 NNT 4 Less than or equal to 7

37 Aripiprazole/Risperidone V Placebo Potkin et al, Arch Gen Psychiatry, vol 60, July 2003

38 Aripiprazole/Risperidone V Placebo Potkin et al, Arch Gen Psychiatry, vol 60, July 2003 NNT (arip 20)= 9; NNT (Arip 30)=6.6; NNT (Risp)=7.14

39 Aripiprazole/Risperidone V Placebo Potkin et al, Arch Gen Psychiatry, vol 60, July 2003

40 Rating Scales For Depression Hamilton Developed in 1960, originally had 17 items They added more items for the later 24 item version Designed to assess changes with acute treatment Scored 0-50; 0-7 normal, 20 or more usual to enter a trial MADRS (Montgomery-Asberg Depression) Developed in late 70s Rated 0-60, recovered:7, mild 15, moderate 25, severe 31, very severe 44

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44 Lurasidone/Quetipine in Schizophrenia Loebel et al, Schizophrenia Res, 145 (2013)

45 Lurasidone/Quetipine in Schizophrenia Loebel et al, Schizophrenia Res, 145 (2013)

46 Lurasidone/Quetipine in Schizophrenia Loebel et al, Schizophrenia Res, 145 (2013)

47 Aripiprazole Augmentation Depression Stewart et al, J of Affective Disorders, 162 (2014) > or greater

48 Aripiprazole Augmentation Depression Stewart et al, J of Affective Disorders, 162 (2014) 20-25

49 Aripiprazole Augmentation Depression Stewart et al, J of Affective Disorders, 162 (2014) Greater than 50% reduction NNT: 7 NNT: 8 NNT: 7

50 Aripiprazole Augmentation Depression Stewart et al, J of Affective Disorders, 162 (2014) MADRS Less than 10 NNT 5 NNT 9 NNT 16

51 The CGI