Evidence Based Psychopharmacology of Conditions Commonly seen in Military Practice

1. Evidence Based Psychopharmacology of Conditions Commonly seen in Military Practice Dr. B. Diane Dodd Faculty Naval Hospital Camp Pendleton Family Practice Residency

2. Objectives • Review pharmacologic treatment of commonly seen psychiatric disorders • Discuss evidence based criteria for length of treatment and discontinuation of treatment • Define when Family Practice Physicians should refer patients to Psychiatry

3. Major Depressive Disorder The fourth leading cause of loss of disability adjusted life years by the World Health Organization National Comorbidity Survey: MDD is the most common mental illness and is one of the most common and disabling of all illnesses

4. The First Useful Antidepressants • Imipramine and Isoniazid • Found serendipitously to have antidepressant qualities in the 1950’s • It was observed that Riserpine, which depletes monoamines, induced depression • This lead to the development of the monoamine hypothesis of depression

5. Monoamines and the Central Nervous system • The previous discoveries lead to the development of drugs that affect central nervous system monoamines • Norepinephrine • Serotonin (5-HT) • Dopamine

6. The Evolution of Antidepressants

7. What is the first line therapy for MDD? • Meta-analyses of multiple antidepressant trials can improve the ability to distinguish between antidepressants or different classes of antidepressants • A Cochrane Collaboration Meta-analysis identified 98 trials comparing SSRI’s to other antidepressants, with a total of 5044 SSRI treated patients, and failed to detect any clinically significant difference in efficacy between drugs (Geddes et al, 2003)

8. Newer vs Older • SSRI’s also demonstrate efficacy for depression without clear evidence of superiority over older drugs when studied in particular patient sub groups • A smaller meta-analysis including 365 SSRI treated geriatric depressed patients found SSRI’s and TCA’s to be equally efficacious ( Wilson et al., 2003)

9. New vs Old in Medically Ill • Similarly, a meta-analysis including 18 antidepressant studies, including 6 with SSRI’s in medically ill patients noted efficacy for multiple classes, but did not find one to be superior • (Gill and Hatcher, 1999,2003)

10. Tolerability • A Cochrane Collaboration review that identified 136 randomized trials in which SSRI’s and tricyclics were compared among depressed patients found a moderate but significant difference favoring SSRI’s in terms of dropouts (Barbui et al., 2003) • Accordingly, the SSRI’s have advantages in terms of safety and tolerability compared to many newer and older agents, and their place as a primary treatment choice for major depression is not disputed.

11. Dual and Triple Action agents and RIMAs in MDD • The most recent generation of antidepressants (including buproprion, mirtazapine and venlafaxine) has proved effective for major depression in both out and inpatient settings in placebo controlled trials. • Whether these newer generation dual action agents improve response compared to SSRI’s is unclear, although there is some interesting data suggesting this may be the case

12. Medical Comorbidity • A Cochrane Collaboration meta-analysis of the antidepressant treatment of medically ill patient reveals substantial benefit to antidepressant treatment, with 52% responding to antidepressant overall compared to 30% responding to placebo. (13 studies, Odds ratio 0.37 95% ,CI 0.27-0.51) • Although the data suggest that response to antidepressants may not be impeded by the presence of medical illness, drug safety and tolerability are still concerns in treating MDD in the medically ill

13. Depression and Cardiac Mortality • Decreased heart rate variability is a powerful predictor of sudden cardiac death in patients with cardiac disease • Impaired platelet function is also associated with depression • Both platelet function and heart rate variability are state-dependent. • Increased platelet function and decreased heart rate variability become more prominent with depression and normalize with resolution of depression

14. Depression and Cardiac Mortality • TCA’s diminish overall heart rate variability, resulting in increased risk of sudden death • SSRI’s have an “anti-platelet” effect, resulting in the normalization of platelet function in the depressed patient • It has been proposed that all post MI patients be empirically placed on SSRI’s to reduce the relative risk of sudden cardiac death. (Salzman et al., 2006)

15. Depression Increases Risk of Cardiac Mortality > Age 70 • The vertical axis enumerates Relative Risk of Cardiac Mortality at a 95% CI • The horizontal axis represents non-depressed, minor depression and major depression in those with: • No pre-existing cardiac disease and those with pre-existing disease (Salzman et al., 2006)

16. Medical Comorbidity in the Elderly • Overall, medical comorbidity decreases the rate of response to antidepressants in the elderly, although overall response is not affected by illness • Response rate is particularly slow in chronic pulmonary disease • Response rate is faster in Atrial Fibrillation • Prostate Cancer increases risk of suicide • Depression is associated with poor medication adherence in diabetics (Salzman et al., 2006)

17. Suicide in Elderly Patients • The left axis represents number of suicides per 100,000 white males in 1990 • Elderly white men have the highest rate of suicide, although adolescent males as a group are unfortunately catching up • **75% of Elderly patients who committed suicide visited their Primary Care Physician within 1 month of the suicide • (Salzman et al., 2006)

18. How long should I treat? • The ideal length of time to continue antidepressant treatment after the resolution of an acute episode has not been definitively determined. • The 40-year follow up by Angst et al.(2003) of patients initially hospitalized for unipolar or bipolar depression found steady recurrence rates over the study for this more severely ill population, and suggests that maintenance treatment may be warranted for more severely ill patients. • A 10-year follow up study of 318 subjects after an index episode of depression found that the risk of recurrence increases with each subsequent episode. • The risk of recurrence decreased with increasing time as well (Solomon et al., 2000)

19. Relapse • A substantial percentage of patients in the placebo-controlled arm of maintenance trials never relapse. • In examining survival curves in these studies, it appears that most relapses occur in the first few months of follow up, and beyond that the rate of relapse for both groups is generally similar. • This suggests that the vast majority of the benefit of continuation and maintenance of antidepressant treatment is early in treatment, and that beyond that time the relative benefit diminishes greatly.

20. Maintenance • Because the risk of recurrence increases with successive episodes, subjects with recurrent MDD should be offered maintenance treatment. • For first affective episodes that have completely resolved, it is unclear whether maintenance treatment is warranted. • Keller et al., 1983) describe the risk of relapse as greatest for those patients who have had three previous episodes

21. Suggestions for Clinicians: When to Refer • Refer the following patients for psychiatric treatment or consultation; • Failure of more than one antidepressant at adequate dose for at least 4-6 weeks • Patients with chronic depression who keep reappearing; hypochondriacal patients • Help rejecting, complaining patients; non-compliant patients • Psychotic depressions; bipolar depressions (Salzman et al., 2006)

22. Evidence Based Psychopharmacology of Combat Induced PTSD Dr. B. Diane Dodd Faculty Naval Hospital Camp Pendleton Family Practice Residency

23. A Recent Addition… • Although PTSD has long been recognized as an important condition by clinicians (“shell shock, or “soldier’s heart”) It has only recently been in the official nosology (DSM III, American Psychiatric Assn., 1994) • Epidemiological studies show that PTSD is one of the most prevalent and costly psychiatric disorders. • Approximately 1/3 of all people are exposed to a traumatic event in their life, and a significant number of these develop PTSD (10-20%) (Brunello et al., 2001)

24. Characteristics • PTSD is twice as common among women than men (Kessler et al.,1995) • Rates of comorbid psychiatric disorders are relatively high, with data suggesting approximately 80% of patients with PTSD meet criteria for at least one other DSM disorder (Kessler et al.,1995, Kessler 2000) • PTSD severely impacts on patient functioning, and is associated with significant medical costs and economic loss ( Kessler et al., 1995; Solomon and Davidson, 1997)

25. Pharmacotherapy • The Medline, PsychLit and Cochrane data bases were searched using the following terms: • Post Traumatic Stress Disorder, PTSD treatment and therapy. • Articles were included up to 2003 • UpToDate was searched with the same terms from 2003-2007 without signifigant additions.

26. Evidence Base • The Evidence Base was used to answer the following questions: 1. What is the first line Pharmacotherapy of choice for PTSD? 2. For how long should maintenance pharmacotherapy be continued 3. What is the optimal pharmacotherapy approach for the treatment refractory patient?

27. Randomly Controlled Trials • 22 randomized controlled trials, more than 50 open trials and several case reports were found concerning pharmacotherapy of PTSD • Placebo controlled trials have been undertaken with: • tricyclic antidepressants imipramine (1), • amitriptyline (1), • desipramine (1), • the MonoAmineOxidase Inhibitor phenelzine (2), • the reversible MAOI (RIMA) brofaramine (2), • the SSRI’s fluoxetine (5), paroxetine (3), and sertraline (3), • the anticonvulsant lamotrigine (1), • the antipsychotic olanzapine (1), • the benzodiazepine alprazolam (1), • and inositol (1). • Imipramine has also been compared with phenelzine.

28. Results • Pharmacologic treatment can be effective in reducing PTSD symptoms. All symptom clusters can be influenced, irrespective of comorbid anxiety and depressive episodes. • Nevertheless, nine out of 22 of the controlled studies found no superiority of the active drug over placebo: • 1 (out of 2) trial with phenelzine, • 1 (out of 2) trial with brofaromine, • 2 (out of 5) trials with fluoxetine, • The trials with desipramine, alprazolam, inositol, olanzapine and lamotrigine • A number of these pharmacological agents may not be effective for PTSD, but methodological weaknesses (including small number of subjects and short durations of treatment) may have also led to negative results.

29. First Line Therapy • The earliest controlled medication trials in PTSD investigated tricyclics and MAOI’s in war veterans • Although these studies had methodological problems (e.g. short duration and non standardized rating scales), they nevertheless suggested that some of these medications are effective in the treatment of PTSD

30. First line therapy – SSRI’s • Several studies of the treatment of PTSD with SSRI’s have been published. There are placebo controlled trials with fluoxetine, paroxetine, and sertraline. • Some of the studies report efficacy of SSRI’s on the core symptoms of PTSD, as well as comorbid symptoms (depression, anxiety). • A large multi site trial of fluoxetine that included many subjects with combat-related PTSD had sufficient power to show efficacy for this agent (Martenyi et al., 2002a).

31. SSRI’s as first line therapy • From the studies that have been published so far, it may be argued that SSRI’s are the first choice in medication treatment for PTSD. • First, there is good evidence of their efficacy in controlled trials; the largest study demonstrating efficacy of medication in PTSD are those of the SSRI’s. • Second, ,many PTSD patients have co morbid depression and anxiety, responding well to SSRI’s. • Third, the SSRI’s are safer and better tolerated than older antidepressants; dropout rates in the sertraline, fluoxetine, and paroxetine trials are in the range of the placebo group. • Problems with the SSRI’s include sexual dysfunction and weight changes.

32. Treatment Refractory Patients • Relatively few RCT’s addressing the optimal pharmacotherapy of patients who fail to respond to a first line medication. • Options include augmenting with a second agent, or switching to a new agent.

33. Treatment Augmentation • There have been few augmentation trials for PTSD, however, there is now some evidence that augmenting SSRI’s with antipsychotic agents may be useful in treatment refractory PTSD.

34. Antipsychotics • Antipsychotic agents have long been reported effective in the treatment of PTSD, but there have been few RCT’s (Ahearn et al., Dillard et al., Hamner, 1996) • Several case reports and open-label studies suggesting improvement of PTSD symptoms by adjunctive risperidone, olanzapine, or quetiapine. • There are three RCT’s comparing adjunctive use of antipsychotics and placebo in PTSD. • Risperdone reduced irritability and intrusive thoughts (Monelly et al., 2003) and reduced psychotic symptoms (Hamner et al., 2003a) in war related PTSD. • Olanzapine augmentation reduced PTSD, depressive and sleep disorder symptoms (Stein, et al., 2002).

35. In Conclusion • SSRI’s are currently first line pharmacotherapy for PTSD. • Use of other antidepressants may also be helpful in treatment refractory patients, or for those not tolerating SSRI’s. • Doses should be raised to maximal if necessary, and treatment should continue for 12 weeks. • In those responding to pharmacotherapy, medication should be continued for at least one year. • If response to SSRI is insufficient, there is evidence that augmentation with an atypical antipsychotic may be effective in some patients.

36. Case Study • 10 y.o. female being seen by N.P. in Family Practice clinic for “rash on arm”. • N.P. approaches me stating “I don’t know what to do, and I don’t know if anyone else will either”. CC: Child is anxious, tearful, school avoidant. Has been scratching her right forearm with her fingernails, causing a superficial abrasion. Mother states that this is the worst that the child has manifested with these symptoms, however she has manifested with anxiety symptoms in one form or another since first grade.

37. Case study • Reported History: • Mother states the child first manifested with anxiety symptoms following a surgery during which she reportedly was “given anesthesia six times”, apparently to no avail, and it is thought that the child woke up during the surgery. • At that time she was given six months of treatment for “PTSD”, and a medication “that started with an “L”. This incident occurred in first grade. The mother states she did not see significant improvement in the child’s symptoms with the medication given at that time.

38. Case study • Mother states that subsequently the child was given diagnosis of ADHD, and started on Adderall. Again, no significant improvement in symptoms. • Personal History: • Child resides in household with mother and two siblings, one older, one younger. The father is deployed and returning to the household the Tuesday following this appt.

39. Case Study • No systemic symptoms • Psychological symptoms: • Anxiety with the anticipation of misfortune to self and others. This as a result of the anticipation of separation, also, anticipatory anxiety related to a concert she must play the viola in this week. • She is manifesting with school avoidance, although the mother is making her go to school. • She fears that a bully at school will beat her up, or that the bully will force her to beat up others. She is crying and states “I just want to fit in with the other kids at school”. • Mother states that the child has difficulty falling asleep.

40. Case Study • P.E.: • General Appearance Normal. Awake and oriented x 3. WDWN. • Child is sobbing vigorously throughout the entire interview. Mother is close to tears as well. • Child does not manifest any thought disorder, delusion or hallucination, save for the already mentioned fears. • Her speech is clear and coherent. Affect is grossly sad, crying throughout the interview. • Behavior is restless, changing postures frequently on the exam table, squirming, lying, sitting alternately. She stays in constant movement throughout the interview.

41. Case study • Thought content: She voices many fears related to activities going on at school. She fears a (specific child) will beat her up, or cause her to beat up others. She is school avoidant and erupts into sobs at the notion that she must perform in a school concert this week. She tearfully sobs that she does not want to take medication. Mother is cooperative and assures the writer that she will make sure the child gets the medication.

42. What is your diagnosis? • Separation Anxiety Disorder? • ADHD? • PTSD? • MDD?

43. Major Depressive Disorder • Depressed mood • Diminished interest in previously enjoyed activities • Insomnia • Psychomotor Agitation • Diminished ability to think or concentrate

44. Treatment • Pt. placed on low dose SSRI q am with Diphenhydramine Elixir at hs for sleep • Mother insured that the child took her medication daily • Returned to the office 10 days later for medication follow up • Mood Euthymic • Attending School without difficulty • Pt states “Everything is going well”

45. bibliography • Evidence Based Psychopharmacology, Stein, et al., Cambridge University Press, 2005. • DSM-IV-TR, American Psychiatric Association, 2005. • Rating Scales in Mental Health, Sajatovic et al., Lexi-Comp, 2003. • Managing PTSD and other Combat-Related Stress Conditions, Channing Bete, 2005. • Operation Iraqi Freedom Mental Health Advisory Team Report, 16 December 2003. Chartered by U.S. Army Surgeon General & HQDA G-1.