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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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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

++

++

++

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Treatment of premature ejaculation with sertraline effects

Sertraline

McMahon, 1998


Off-label applications of antidepressants effects

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


Migraine headaches effects

  • Prophylactic treatments for migraine headaches have included:

  • Beta adrendergic blockers

  • Calcium channel blockers

  • Tricyclic antidepressants

Unfavorable side effect profile


Migraine headaches effects

  • Migraine pathophysiology focus on altered serotonergic metabolism

  • Good tolerability of SSRI

Several studies about prophylaxis use of SSRI


Migraine headaches and prophylaxis of SSRI effects

  • 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


Off-label applications of antidepressants migraine prophylaxis

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


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 tricyclics which, in turn, produce more severe adverse events.venlafaxine, are effective in other pain conditions, but have not been rigorously studied in headache.

Loder et al., 2004


Off-label applications of antidepressants tricyclics which, in turn, produce more severe adverse events.

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


Stress urinary incontinence (SUI) tricyclics which, in turn, produce more severe adverse events.

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 tricyclics which, in turn, produce more severe adverse events.

  • 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


Off-label applications of antidepressants Duloxetine

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


Diabetic Neuropathy Duloxetine

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 Duloxetine

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 Duloxetine

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia


Pharmacotherapy for Fibromyalgia Duloxetine

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 Duloxetine

  • Tricyclics

  • SSRIs

  • SNRI


Tricyclics Duloxetine

Amitriptyline

Doxepine

The most used

  • Pain

  • Stiffness

  • Tenderness

  • Fatigue

  • Sleep quality

Significant effects in

Turk at al, 2002


SSRIs Duloxetine

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 Duloxetine

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


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


SNRI Duloxetine

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


Off-label applications of antidepressants Duloxetine

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


Neurocardiogenic (or vasovagal) Syncope Duloxetine

Neurocardiogenic syncope is a common disorder of transient autonomic nervous system dysfunction

No definitive treatment is available

Calkins et al., 1999


Pharmacotherapy with SSRIs Duloxetine

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


Off-label applications of antidepressants Duloxetine

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


Generalized Anxiety Disorder Duloxetine

  • 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


Off-label applications of antidepressants Duloxetine

  • Premature ejaculation

  • Migraine headaches

  • Tension-type headaches

  • Stress urinary incontinence

  • Diabetic neuropathy

  • Fibromyalgia

  • Neurocardiogenic syncope

  • Generalized Anxiety Disorder

  • Insomnia

  • Nicotine dependence


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 off-label use of antidepressants, particularly

  • 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 off-label use of antidepressants, particularly

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


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