Off-label use of  psychotropic medications:
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Off-label use of psychotropic medications: focus on antidepressants. Donatella Marazziti Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie Università di Pisa. Current Antidepressants. TCA IMAO SSRI NARI NASSA SNRI. Approved Uses of Antidepressants.

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Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Off-label use of psychotropic medications:

focus on antidepressants

Donatella Marazziti

Dipartimento di Psichiatria, Neurobiologia,

Farmacologia e Biotecnologie

Università di Pisa


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Current Antidepressants

  • TCA

  • IMAO

  • SSRI

  • NARI

  • NASSA

  • SNRI


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Approved Uses of Antidepressants

  • Depression

  • Panic Disorder

  • Social Anxiety Disorder

  • Obsessive-Compulsive Disorder

  • Post-traumatic Stress Disorder

  • Generalized Anxiety Disorder

  • Eating Disorders


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Antidepressants: side effects

  • - Anticholinergic effects (dry mouth, constipation, glaucoma, cognitive impairment)

  • - Sexual dysfunctions

  • - Seizures

  • Weight gain

  • Nausea

  • Cardiovascular toxicity (hypotension, conduction disturbances)

  • Hematologic abnormalities


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Off-label applications of antidepressants

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Delayed or inhibited ejaculation: one of SSRI’s side effects

Citalopram

Fluoxetine

Fluvoxamine

Paroxetine

Sertraline

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Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Treatment of premature ejaculation with sertraline

Sertraline

McMahon, 1998


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Migraine headaches

  • Prophylactic treatments for migraine headaches have included:

  • Beta adrendergic blockers

  • Calcium channel blockers

  • Tricyclic antidepressants

Unfavorable side effect profile


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Migraine headaches

  • Migraine pathophysiology focus on altered serotonergic metabolism

  • Good tolerability of SSRI

Several studies about prophylaxis use of SSRI


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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 (p<.05)

Adly et al., 1992; Saper et al., 1994; Steiner et al., 1998; D’Amato et al., 1999


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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

> 50% reduction in headache


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

In patients with chronic TTH, SSRIs are less effictive than tricyclics which, in turn, produce more severe adverse events.

Moja et al., 2005


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Other medications, such as venlafaxine, are effective in other pain conditions, but have not been rigorously studied in headache.

Loder et al., 2004


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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.


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Off-label agents prescribed in SUI

  • Alfa- adrenoceptor agonists

  • Beta-adrenoceptor agonists and antagonists

  • Estrogen replacement therapy

  • Low doses of TCAs

  • SNRI


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Treatment with Imipramine (50 mg/day) was associated with clinical improvement in 72% of 22 women with SUI.

Woodman et al 2001


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Off-label applications of antidepressants

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Use of antidepressants in Fibromyalgia

  • Tricyclics

  • SSRIs

  • SNRI


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Tricyclics

Amitriptyline

Doxepine

The most used

  • Pain

  • Stiffness

  • Tenderness

  • Fatigue

  • Sleep quality

Significant effects in

Turk at al, 2002


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

  • 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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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, 2003;Sayar K et al, 2003


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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)


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

Hit parade of off-label use medications in the clinical practice

1stCardiovascular agents

2ndPsychotropic agents

3rdAntiallergic agents


Donatella marazziti dipartimento di psichiatria neurobiologia farmacologia e biotecnologie

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


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