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 1950s
• 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 SSRIs 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

• SSRIs 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 SSRIs
  and TCAs 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 SSRIs 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 SSRIs and
  tricyclics were compared among depressed patients
  found a moderate but significant difference
  favoring SSRIs in terms of dropouts (Barbui et
  al., 2003)
• Accordingly, the SSRIs 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 SSRIs 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

• TCAs diminish overall heart rate variability,
  resulting in increased risk of sudden death
• SSRIs 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 SSRIs to reduce the
  relative risk of sudden cardiac death.
• (Salzman et al., 2006)

15
Depression Increases Risk of Cardiac Mortality gt
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 soldiers 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 SSRIs 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 MAOIs 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 SSRIs

• Several studies of the treatment of PTSD with
  SSRIs have been published. There are placebo
  controlled trials with fluoxetine, paroxetine,
  and sertraline.
• Some of the studies report efficacy of SSRIs 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
SSRIs as first line therapy

• From the studies that have been published so far,
  it may be argued that SSRIs 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 SSRIs.
• Second, ,many PTSD patients have co morbid
  depression and anxiety, responding well to
  SSRIs.
• Third, the SSRIs 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 SSRIs include sexual
  dysfunction and weight changes.

32
Treatment Refractory Patients

• Relatively few RCTs 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 SSRIs 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 RCTs (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 RCTs 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

• SSRIs are currently first line pharmacotherapy
  for PTSD.
• Use of other antidepressants may also be helpful
  in treatment refractory patients, or for those
  not tolerating SSRIs.
• 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 dont know what to
  do, and I dont 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 childs 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.