Strumenti

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Off-label use of psychotropic medications
focus on antidepressants
Donatella Marazziti Dipartimento di Psichiatria,
Neurobiologia, Farmacologia e Biotecnologie Unive
rsità di Pisa

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Current Antidepressants

• TCA
• IMAO
• SSRI
• NARI
• NASSA
• SNRI

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Approved Uses of Antidepressants

• Depression
• Panic Disorder
• Social Anxiety Disorder
• Obsessive-Compulsive Disorder
• Post-traumatic Stress Disorder
• Generalized Anxiety Disorder
• Eating Disorders

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Antidepressants side effects

• - Anticholinergic effects (dry mouth,
  constipation, glaucoma, cognitive impairment)
• - Sexual dysfunctions
• - Seizures
• Weight gain
• Nausea
• Cardiovascular toxicity (hypotension, conduction
  disturbances)
• Hematologic abnormalities

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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia

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Delayed or inhibited ejaculation one of SSRIs
side effects
Citalopram Fluoxetine Fluvoxamine Paroxetine S
ertraline

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Treatment of premature ejaculation with sertraline
Sertraline
McMahon, 1998
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Migraine headaches

• Prophylactic treatments for migraine headaches
  have included
• Beta adrendergic blockers
• Calcium channel blockers
• Tricyclic antidepressants

Unfavorable side effect profile
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Migraine headaches

• Migraine pathophysiology focus on altered
  serotonergic metabolism
• Good tolerability of SSRI

Several studies about prophylaxis use of SSRI
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Migraine headaches and prophylaxis of SSRI

• The majority of the studies involved fluoxetine
  (20-40 mg/day)
• Three of four studies demonstrated that the
  frequency and severity of headaches had a
  significant decrease (plt.05)

Adly et al., 1992 Saper et al., 1994 Steiner et
al., 1998 DAmato et al., 1999
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A comparative study of amitriptyline and
fluvoxamine in migraine prophylaxis
- Amitriptyline significantly reduced the number
of headache attacks, but caused severe drowsiness
in many patients. - Fluvoxamine influenced
positively the number of headache attacks and
caused only slight side effects.
Bank, 1994
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Tension-type headaches (TTH) comparison between
SSRIs and other antidepressants
paroxetine vs sulpiride fluvoxamine vs
mianserine citalopram vs amitriptyline
fluoxetine vs desimipramine fluoxetine vs
amitriptyline sertraline vs amitriptyline
Langemark 1993 Manna 1994 Bendtsen 1996 Walker
1997 Oguzhanoglu 1999 Boz 2003
No significant differences both effective to
reduce headache severity
Both medications reduced the number of days with
TTH
Amitriptyline reduced headache duration
No significant differences in change of pain
score from baseline to three months
In chronic TTH amitriptyline reduced headache
frequency both at 8 and 12 weeks while fluoxetine
only at 8 weeks the situation was reversed in
episodic TTH
gt 50 reduction in headache
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In patients with chronic TTH, SSRIs are less
effictive than tricyclics which, in turn, produce
more severe adverse events.
Moja et al., 2005
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Other medications, such as venlafaxine, are
effective in other pain conditions, but have not
been rigorously studied in headache.
Loder et al., 2004
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Stress urinary incontinence (SUI)
It is the involuntary loss of urine associated
with physical activities such as running,
jumping, or lifting, or with sneezing and
coughing. For many patients it can be a
bothersome symptom, causing social isolation,
loss of self-esteem, and increased expenses.
Although there is currently no single
medication approved worldwide for the treatment
of SUI, a variety of off-label agents are often
prescribed.
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Off-label agents prescribed in SUI

• Alfa- adrenoceptor agonists
• Beta-adrenoceptor agonists and antagonists
• Estrogen replacement therapy
• Low doses of TCAs
• SNRI

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Treatment with Imipramine (50 mg/day) was
associated with clinical improvement in 72 of 22
women with SUI.
Woodman et al 2001
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The only antidepressant that has indication in
SUI Duloxetine
Duloxetine is believed to increase the strength
of urethral sphincter contractions and, thereby,
prevent accidental urine leakage by increasing
urethral closure forces. In clinical trials in
women with SUI, duloxetine has demonstrated
efficacy in reducing incontinence episodes and
increasing the quality of life with no serious
adverse effects.
Zinner et al., 2004
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Diabetic Neuropathy
They are well established as effective treatment
of the symptoms of diabetic neuropathy
Tricyclics
Carbamazepine and gabapentin are other drugs
shown to be effective in treating neuropathic pain
Anticonvulsants
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Diabetic Neuropathy
SSRIs (in particular paroxetine) should not be
considered as first-line therapy for Diabetic
Neuropathy, because the evidence for their use
for this purpose is limited
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia

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Pharmacotherapy for Fibromyalgia
Disturbances in biogenic amines are documented
in patients with Fibromyalgia
Agents interacting with these systems have been
tested extensively
There are no treatments for fibromyalgia
currently approved by the FDA or the European
Agency
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Use of antidepressants in Fibromyalgia

• Tricyclics
• SSRIs
• SNRI

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Tricyclics
Amitriptyline Doxepine
The most used

• Pain
• Stiffness
• Tenderness
• Fatigue
• Sleep quality

Significant effects in
Turk at al, 2002
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SSRIs
Fluoxetine Citalopram
The most common aused

• SSRIs may play a role in improvement of mood and
  fatigue
• SSRIs appear to have less impact on pain

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TCA SSRI
The combination of Fluoxetine and Amitriptyline
was shown to be more efficactive in FM than
either agent alone or placebo, possibly
indicating a weak analgesic effect of SSRIs in
the presence of a TCA
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• TCAs show a relevant side effect profile
• SSRIs show a superior safety and tolerability
  profile
• Antidepressant analgesic activity appears
  related to noradrenergic and serotonergic
  activities

SSRIs associated or not with TCAs can be
considered as an alternative tool in patients
with partial response to non-pharmacological
therapies
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SNRI
Duloxetine

• Statistically significant improvements on the
  total score of FIQ

• Significantly reduced pain and disability
  caused by FM
• Significantly decreased depression and anxiety

Venlafaxine
Arnold LM et al, 2003Sayar K et al, 2003
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Neurocardiogenic (or vasovagal) Syncope
Neurocardiogenic syncope is a common disorder of
transient autonomic nervous system dysfunction
No definitive treatment is available
Calkins et al., 1999
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Pharmacotherapy with SSRIs
20 mg daily was found to significantly improve
symptoms in patients refractory or intolerant to
standard treatments (atenolol, midodrine,
fluorocortisol)
Paroxetine
Fluoxetine Sertraline (in children)
Showed promising results most patients remained
symptom-free for at least six months
Di Girolamo et al, 1999 1 Grubb et al, 1994 2
Lenk et al, 1997
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Generalized Anxiety Disorder

• SSRIs have been prescribed safely and
  effectively for GAD1
• SSRI may be particularly useful in the treatment
  of GAD in paediatric patients
• SSRIs seem particularly suited for use in older
  patients with GAD2

Only paroxetine has been recently approved by
the FDA for GAD treatment
Kent et al, 1998 1 Wylie et al, 2000 2
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence

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Since mid-1980s there has been a rapid increase
in the off-label use of antidepressants,
particularly trazodone, for treating insomnia.
Mendelson et al., 2004
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Off-label applications of antidepressants

• Premature ejaculation
• Migraine headaches
• Tension-type headaches
• Stress urinary incontinence
• Diabetic neuropathy
• Fibromyalgia
• Neurocardiogenic syncope
• Generalized Anxiety Disorder
• Insomnia
• Nicotine dependence (and other impulse control
  disorders)

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Non-nicotine pharmacotherapies for nicotine
dependence
The primary FDA approved non-nicotine
pharmacotherapy agent is bupropion... ...but
studies summarize the effectiveness of other
off-label medications, such as Tricyclic
antidepressants IMAOs SSRIs
(Fluvoxamine) Clonidine
Dudas and George, 2005
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Hit parade of off-label use medications in the
clinical practice
1st Cardiovascular agents 2nd Psychotropic
agents 3rd Antiallergic agents
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Doctors pour drugs of which they know little, to
cure diseases of which they know less, into human
beings of whom they know nothing.
Voltaire