Beta blockers and Depression: an unjust association

1
Beta blockers and Depression an unjust
association?

• Vanessa R. Cole, MD
• AIM presentation
• March 27, 2002

2
Case presentation

• Prior TTE 1/02 EF70, no valve regurgitation
• BP109/53, HR 104
• Tachycardic, no m/r/g
• Lungs CTA B
• Evaluation of indication for continued b-blocker
  therapy

• 38 yo WF with hx of major depression, PTSD
• Started on Lopressor 25 mg bid by PCP for
  tachycardia
• Felt fatigued/lethargic
• To ED ? admitted to y for tx of depression

3
Beta-blocker indications

• Hypertension, arrythmias, angina, secondary
  prevention in CAD
• Anxiety, migraine headaches
• Hyperthyroidism
• Glaucoma
• Tremors

4
CNS effects of b-blockers

• Bad dreams, sleep disturbances, fatigue,
  hallucinations, memory mood changes
• Postulated to cross the blood-brain barrier and
  act on b-receptors in the brain
• Lipophilic drugs implicated in greater degree of
  CNS effects, i.e. propanolol
• Hydrophilic drugs should theoretically pose less
  risk of depression, i.e. atenolol nadolol

5
Criteria for diagnosis of depression, DSM IV

• Depressed mood
• Loss of interest or pleasure in activities
• Significant weight loss or gain
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Feelings of worthlessness or guilt
• Diminished ability to concentrate
• Recurrent thoughts of death

6
Association established

• Case reports in early 1980s - possible
  association between propanolol or ophthalmic
  timolol and depression
• Complicated by use of b-blockers in patient
  population with chronic disease states
  predisposing to depression

7
Association established

• Avorn et. al., 1986
• Medicaid population, n 143,253
• Cross-sectional study
• TCA use compared among patients on 7
  antihypertensives, insulin, hypoglycemics

• TCA use was significantly higher in pts on
  b-blockers
• Prevalence rate ratio of 1.5 (95CI 1.4-1.7)

8
Association established

• Thiessen et. al., 1990
• Saskatchewan Prescription Drug Plan, n 3218
• Retrospective cohort
• Relative risk for use of antidepressant in
  b-blocker cohort was 2.6 (95 CI 2.3-3.0)

• Relative risk for antidepressant use with
  propanolol was 4.8 (95 CI 4.1-5.5)
• No significant increased risk with hydrophilic or
  other lipophilic b-blockers

9
Causal association?

• Antidepressant dispensings not a valid proxy for
  depression
• Antidepressant meds have multiple indications
• Possible increased tendency for physicians to
  treat b-blocker side effects (fatigue, sedation)
  with antidepressants
• Unclear time course

10
Controversy

• Bright et. al., 1992
• Case-control study of Medicaid population, n
  4302
• Identified cases by prescription of
  antidepressant, depression dx, or ECT procedure
  code

11
Controversy

• Odds ratio for use of b-blockers in
  antidepressant RX was 1.45 (1.23 - 1.70)
• OR with depression diagnosis or ECT, 1.16 (0.90 -
  1.51)
• Adjusting for benzodiazepine use, frequent RX or
  frequent outpt office visits ? null effect

12
Using clinical criteria

• Gerstman et. al., 1996
• Prospective cohort in Harvard Community Health
  Plan, n 3782
• Examined occurrence of depression in new users of
  b-blockers other antihypertensives

• Used DSM III criteria for major depression, with
  minor depression meeting lt 5 criteria
• Adjusted RR for depression with b-blockers was
  0.8 (0.3-1.9), with propanolol was 0.8 (0.1-2.7)

13
Epidemiologic analysis

• Hallas, 1996
• 11,244 incident antidepressant users in Odense
  University Database
• Prescription sequence symmetry analysis,
  application of logistic regression model
• No clear causal association between b-blockers or
  propanolol antidepressant use
• Number of persons starting antidepressants after
  b-blockers was similar to following opposite
  order

14
Conclusions

• Beta-blockers are associated with side effects of
  fatigue, sedation, which may have significant
  impact on quality of life
• Available evidence does not clearly causally link
  b-blockers with depression, as diagnosed by
  strict clinical criteria
• Cross-sectional, case-control, retrospective
  studies provide suboptimal data
• Several unresolved issues, which could be
  elucidated by future research

15
Does this patient need Lopressor?

• No clear indication for use of b-blocker
• No cardiac risk factors
• Cardiac enzymes, TSH, FLP normal
• Recommended non-invasive stress testing as an
  outpatient
• If RX were indicated, unclear in patient with
  history of major depression

16
Future directions

• Randomized controlled trials needed - could be
  incorporated into studies of b-blockers
  therapeutic endpoints
• Analysis of subgroups patients with hx of MDD,
  serious conditions requiring b-blockers, those
  on b-blockers for less serious conditions (i.e.
  HTN)
• Risk/benefit ratio