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

Current Antidepressants • TCA • IMAO • SSRI • NARI • NASSA • SNRI

Approved Uses of Antidepressants • Depression • Panic Disorder • Social Anxiety Disorder • Obsessive-Compulsive Disorder • Post-traumatic Stress Disorder • Generalized Anxiety Disorder • Eating Disorders

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

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

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

Delayed or inhibited ejaculation: one of SSRI’s side effects Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline ++ ++ ++ +++ +++

Treatment of premature ejaculation with sertraline Sertraline McMahon, 1998

Migraine headaches • Prophylactic treatments for migraine headaches have included: • Beta adrendergic blockers • Calcium channel blockers • Tricyclic antidepressants Unfavorable side effect profile

Migraine headaches • Migraine pathophysiology focus on altered serotonergic metabolism • Good tolerability of SSRI Several studies about prophylaxis use of SSRI

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

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

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

In patients with chronic TTH, SSRIs are less effictive than tricyclics which, in turn, produce more severe adverse events. Moja et al., 2005

Other medications, such as venlafaxine, are effective in other pain conditions, but have not been rigorously studied in headache. Loder et al., 2004

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.

Off-label agents prescribed in SUI • Alfa- adrenoceptor agonists • Beta-adrenoceptor agonists and antagonists • Estrogen replacement therapy • Low doses of TCAs • SNRI

Treatment with Imipramine (50 mg/day) was associated with clinical improvement in 72% of 22 women with SUI. Woodman et al 2001

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

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

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

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

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

Use of antidepressants in Fibromyalgia • Tricyclics • SSRIs • SNRI

Tricyclics Amitriptyline Doxepine The most used • Pain • Stiffness • Tenderness • Fatigue • Sleep quality Significant effects in Turk at al, 2002

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

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

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

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

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

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

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

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

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)

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

Hit parade of off-label use medications in the clinical practice 1st Cardiovascular agents 2nd Psychotropic agents 3rd Antiallergic agents

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

Donatella Marazziti Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie

Donatella Marazziti Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie

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