Safety Considerations in

Anti-depressant and Anti-

anxiety Medication Use
Michael P. Sionzon, MD, FPPA
Philippine College of Psychopharmacology Annual Congress
December 1, 2016
Marco Polo Hotel
  Long-term safety of benzodiazepines and
antidepressants
 Recent guidelines provide for long-term
treatment of depression and anxiety
 “Patients with risk factors (for recurrence of
Scope of the depression) require longer term treatment for a
Lecture minimum of 2 years and, for some, lifetime.” –
Canadian Network for Mood and Anxiety Treatments
(CANMAT)

Kennedy SH, et al. Journal of Affective Disorders 117 (2009) S1–S2

Efficacy in long-
term use of
antidepressants

Reid S, Barbui C, et al. BMJ 2010;340:c1468

What are the
side-effects?
What are the potential
harm of long term
treatment with SSRI?
Self-harm and  Increased risk of self-harm in people aged below
suicide 25 prescribed SSRI but no clear relation with
complete suicide

Reid S, Barbui C, et al. BMJ 2010;340:c1468

Barbui C, et al. CMAJ 2009;180(3):291-7
  Venlafaxine and paroxetine are better avoided

Self-harm and
suicide

Barbui C, et al. CMAJ 2009;180(3):291-7

  Adding CBT to medication enhances safety
 RCT conducted in 13 sites
 327 patients aged 12 to 17

Self-harm and
suicide

Treatment for Adolescents with Depression: Long-term Effectiveness and Safety Outcomes. Arch Gen Psychiatry 2007; 64 (10): 1132-1144.
  SSRIs increase the risk of upper GI hemorrhage and
other bleeding disorders
 Probably by altering platelet function
 High risk with concurrent use of NSAIDs or
antiplatelet drugs
Bleeding  This risk might be reduced significantly by
Disorders concomitant use of acid-suppressing drugs

Jiang HY. Clin Gastroenterol Hepatol. 2015 Jan;13(1):42-50

 1. Systematic Review and Meta-analysis1
 Increased risk of upper GI bleeding with SSRI
medications
 OR=1.66 (95% CI=1.44,1.92) for case-control studies
 OR=1.68 (95% CI=1.13,2.50) for cohort studies
 NNH for upper GI bleeding with SSRI treatment:
 3,177 in low-risk population
Bleeding  881 a high-risk population
Disorders 2. Case-control Study2
Number (%)

Cases Controls Adjusted OR

Category (n = 581) (n = 1358) (95% CI)
All antidepressants 33 (5.7) 74 (5.4) 0.91 (0.54–1.52)
SSRIs 23 (4.0) 45 (3.3) 1.06 (0.57–1.96)d

1. Anglin R. et al. Am J Gastroenterol. 2014 Jun;109(6):811-9

2. Carvajal A. et al.. PLoS ONE 6(5): e19819. doi:10.1371/journal.pone.0019819
  Manifests with muscle cramps, fatigue and
confusion, may also result in seizures
 May be mediated by effect of SSRI on anti-
Hyponatremia diuretic hormone (ADH)1 or inner medullary
collecting tubules (IMCD)2
 Incidence: 3-5 cases / 1000 patients a year
 Higher rate in older people, particularly women

1. Jacob S, Spinler SA. Ann Pharmacother 2006;40:1618-22

2. Moyses ZP, et al. Nephrol Dial Transplant (2008) 23: 1173–1178
  Monitoring of serum Na levels is advisable
patients:
 > 80 years old
 With history of hyponatremia
 Receiving other drugs associated with
Hyponatremia hyponatremia (e.g. loop and thiazide diuretics, ACE
inhibitors)
 If detected, antidepressants should be
withdrawn immediately

Reid S, Barbui C, et al. BMJ 2010;340:c1468

  In contrast to TCAs, SSRIs does not slow
cardiac conduction, prolong QT interval, cause
orthostatic hypotension 1
 No evidence of increased risk of myocardial
Cardiovascular infarction or cardiovascular mortality with
Risk long-term treatment 2
 Four case controls reported a significantly lower
risk of myocardial infarction using SSRIs
 OR 0.59 (95% CI 0.39 to 0.91)

1. Reid S, Barbui C, et al. BMJ 2010;340:c1468

2. Von Ruden AE, Adson DE, Kotlyar M. J Cardiovasc Pharmcol Ther 2008; 13(1): 32-40
  No additional risk with SSRI after myocardial
infarction

Cardiovascular
Risk

Glassman AH,, et al. JAMA 2002;288:701-9.

  Reduced interest and desire for sex, erectile
dysfunction in men, diminished arousal in
women, difficulty in attaining orgasm in both
sexes , ejaculation disturbances
 Incidence: 4% to 80% after four to 12 weeks of
treatment
Sexual  Citalopram (73%), paroxetine, (71%), and
Dysfunction venlafaxine (67%) had the highest incidence
 Mirtazapine (24%) and nefazodone (8%) had the
lowest
 Spontaneous remission may occur, but for
most patients sexual dysfunction persists
during treatment
Reid S, Barbui C, et al. BMJ 2010;340:c1468
What are the
potential harm of
long-term
treatment with
benzodiazepines?
 Tolerance Dependence
• Little evidence • 35% of patients taking BDZ
that they retain for more than 4 weeks
Disadvantages their efficacy after develop dependence
of 4 months • Contributing factors
• Develops more • Regular continuous use at
Benzodiazepines slowly than high doses
as Anxiolytics tolerance to • Dependent personality
hypnotic effect characteristics
• Previous drug dependence

Ashton H. Drugs 1994; 48(1): 25-40.

Rational
Pharmacotherapy
for Anxiety
Combination
Antidepressant and
BDZ

Nash J and Nutt D. Psychiatry 2007; 6(4): 143-148.

  Interferes with formation and consolidation of
memories may induce complete anterograde
amnesia
 “Acquisition-impairing” molecules
 Events are not transferred from short-term
Cognitive Decline memory to long-term memory
with
Benzodiazepines

Reid S, Barbui C, et al. BMJ 2010;340:c1468

  Drowsiness, poor concentration, ataxia,
dysarthria, motor incoordination, diplopia,
muscle weakness, vertigo and mental
confusion
 Increased risk of motor vehicle crashes
Psychomotor because of slowed reaction time
Side-effects

Longo LP, et al. Am Fam Physician. 2000 Apr 1;61(7):2121-2128.

  Long-term treatment with SSRI may have a
role in depression and anxiety in patients with
high-risk for relapse
 SSRIs side effects may include suicidal
ideations, GI bleeding and hyponatremia.
Summary However, the risk for these events are minimal
and affect mainly high-risk populations
 Benzodiazepines must be used sparingly
because of the potential for dependence that
may lead to cognitive and motor side effects
Thank you for
your attention