The FDA indication for
the use of the antidepressants in the treat-ment of major depression is fairly
broad. Most antidepressants are approved for both acute and long-term treatment
of major depres-sion. Acute episodes of MDD tend to last about 6–14 months
untreated, but at least 20% of episodes last 2 years or longer.
The goal of acute
treatment of MDD is remission of all symp-toms. Since antidepressants may not
achieve their maximum benefit for 1–2 months or longer, it is not unusual for a
trial of therapy to last 8–12 weeks at therapeutic doses. The antidepres-sants
are successful in achieving remission in about 30–40% of patients within a
single trial of 8–12 weeks. If an inadequate response is obtained, therapy is
often switched to another agent or augmented by addition of another drug. For
example, bupropion, an atypical antipsychotic, or mirtazapine might be added to
an SSRI or SNRI to augment antidepressant benefit if monotherapy is
unsuccessful. Seventy to eighty percent of patients are able to achieve
remission with sequenced augmentation or switching strategies. Once an adequate
response is achieved, continuation therapy is recommended for a minimum of 6–12
months to reduce the substantial risk of relapse.
Approximately 85% of
patients who have a single episode of MDD will have at least one recurrence in
a lifetime. Many patients have multiple recurrences, and these recurrences may
progress to more serious, chronic, and treatment-resistant episodes. Thus, it
is not unusual for patients to require maintenance treatment to pre-vent
recurrences. Although maintenance treatment studies of more than 5 years are
uncommon, long-term studies with TCAs, SNRIs, and SSRIs suggest a significant
protective benefit when given chronically. Thus, it is commonly recommended
that patients be considered for long-term maintenance treatment if they have
had two or more serious MDD episodes in the previous 5 years or three or more
serious episodes in a lifetime.
It is not clear
whether antidepressants are useful for all sub-types of depression. For
example, patients with bipolar depression may not benefit much from
antidepressants even when added to mood stabilizers. In fact, the
antidepressants are sometimes asso-ciated with switches into mania or more
rapid cycling. There has also been some debate about the overall efficacy of
antidepres-sants in unipolar depression, with some meta-analyses showing large
effects and others showing more modest effects. Although this debate is not
likely to be settled immediately, there is little debate that antidepressants
have important benefits for most patients.
Psychotherapeutic
interventions such as cognitive behavior therapy appear to be as effective as
antidepressant treatment for mild to moderate forms of depression. However,
cognitive behav-ior therapy tends to take longer to be effective and is
generally more expensive than antidepressant treatment. Psychotherapy is often
combined with antidepressant treatment, and the combina-tion appears more
effective than either strategy alone.
After major
depression, anxiety disorders represent the most com-mon application of
antidepressants. A number of SSRIs and SNRIs have been approved for all the
major anxiety disorders, including PTSD, OCD, social anxiety disorder, GAD, and
panic disorder. Panic disorder is characterized by recurrent episodes of brief
overwhelming anxiety, which often occur without precipi-tant. Patients may
begin to fear having an attack, or they avoid situations in which they might
have an attack. In contrast, GAD is characterized by a chronic, free-floating
anxiety and undue worry that tends to be chronic in nature. Although older
antide-pressants and drugs of the sedative-hypnotic class are still
occa-sionally used for the treatment of anxiety disorders, SSRIs and SNRIs have
largely replaced them.
The
benzodiazepines provide much more rapid
relief of both generalized anxiety and panic than do any of the
antidepressants. However, the antidepressants appear to be at least as
effective and perhaps more effective than benzodiazepines in the long-term
treatment of these anxiety disorders. Furthermore, antidepressants do not carry
the risks of dependence and tolerance that may occur with the benzodiazepines.
OCD is known to
respond to serotonergic antidepressants. It is characterized by repetitive
anxiety-provoking thoughts (obses-sions) or repetitive behaviors aimed at
reducing anxiety (compul-sions). Clomipramine and several of the SSRIs are
approved for the treatment of OCD, and they are moderately effective. Behavior
therapy is usually combined with the antidepressant for additional benefits.
Social anxiety
disorder is an uncommonly diagnosed but a fairly comon condition in which the
patient experiences severe anxiety in social interactions. This anxiety may
limit their ability to function adequately in their jobs or interpersonal relationships.
Several SSRIs and venlafaxine are approved for the treatment of social anxiety.
The efficacy of the SSRIs in the treatment of social anxiety is greater in some
studies than their efficacy in the treat-ment of MDD.
PTSD is manifested
when a traumatic or life-threatening event results in intrusive
anxiety-provoking thoughts or imagery, hyper-vigilance, nightmares, and
avoidance of situations that remind the patient of the trauma. SSRIs are
considered first-line treatment for PTSD and can benefit a number of symptoms
including anxious thoughts and hypervigilance. Other treatments, including
psycho-therapeutic interventions, are usually required in addition to
antidepressants.
It has been known for
over 40 years that antidepressants possess analgesic properties independent of
their mood effects. TCAs have been used in the treatment of neuropathic and
other pain conditions since the 1960s. Medications that possess both
nor-epinephrine and 5-HT reuptake blocking properties are often useful in
treating pain disorders. Ascending corticospinal mono-amine pathways appear to
be important in the endogenous anal-gesic system. In addition, chronic pain
conditions are commonly associated with major depression. TCAs continue to be
com-monly used for some of these conditions, and SNRIs are increas-ingly used.
In 2010, duloxetine was approved for the treatment of chronic joint and muscle
pain. As mentioned earlier, milnaci-pran has been approved for the treatment of
fibromyalgia. Other SNRIs, eg, desvenlafaxine, are being investigated for a
variety of pain conditions from postherpetic neuralgia to chronic back pain.
Approximately 5% of
women in the child-bearing years will have prominent mood and physical symptoms
during the late luteal phase of almost every cycle; these may include anxiety,
depressed mood, irritability, insomnia, fatigue, and a variety of other
physi-cal symptoms. These symptoms are more severe than those typi-cally seen
in premenstrual syndrome (PMS) and can be quite disruptive to vocational and
interpersonal activities. The SSRIs are known to be beneficial to many women
with PMDD, and fluox-etine and sertraline have been approved for this
indication. Treating for 2 weeks out of the month in the luteal phase may be as
effective as continuous treatment. The rapid effects of SSRIs in PMDD may be
associated with rapid increases in pregnenolone levels.
Bupropion was approved
in 1997 as a treatment for smoking ces-sation. Approximately twice as many
people treated with bupro-pion as with placebo have a reduced urge to smoke. In
addition, patients taking bupropion appear to experience fewer mood symp-toms
and possibly less weight gain while withdrawing from nico-tine dependence.
Bupropion appears to be about as effective as nicotine patches in smoking
cessation. The mechanism by which bupropion is helpful in this application is
unknown, but the drug may mimic nicotine’s effects on dopamine and
norepinephrine and may antagonize nicotinic receptors. Nicotine is also known
to have antidepressant effects in some people, and bupropion may substitute for
this effect.
Other antidepressants
may also have a role in the treatment of smoking cessation. Nortriptyline has
been shown to be helpful in smoking cessation, but the effects have not been as
consistent as those seen with bupropion.
Bulimia nervosa and
anorexia nervosa are potentially devastating disorders. Bulimia is
characterized by episodic intake of large amounts of food (binges) followed by
ritualistic purging through emesis, the use of laxatives, or other methods.
Medical complica-tions of the purging, such as hypokalemia, are common and
dan-gerous. Anorexia is a disorder in which reduced food intake results in a
loss of weight of 15% or more of ideal body weight, and the person has a morbid
fear of gaining weight and a highly distorted body image. Anorexia is often
chronic and may be fatal in 10% or more of cases.
Antidepressants appear
to be helpful in the treatment of buli-mia but not anorexia. Fluoxetine was
approved for the treatment of bulimia in 1996, and other antidepressants have
shown benefit in reducing the binge-purge cycle. The primary treatment for
anorexia at this time is refeeding, family therapy, and cognitive behavioral
therapy.
Bupropion may have
some benefits in treating obesity. Nondepressed, obese patients treated with
bupropion were able to lose somewhat more weight and maintain the loss relative
to a similar population treated with placebo. However, the weight loss was not
robust, and there appear to be more effective options for weight loss.
Antidepressants are
used for many other on- and off-label appli-cations. Enuresis in children is an
older labeled use for some TCAs, but they are less commonly used now because of
their side effects. The SNRI duloxetine is approved in Europe for the treatment
of urinary stress incontinence. Many of the serotoner-gic antidepressants
appear to be helpful for treating vasomotor symptoms in perimenopause.
Desvenlafaxine is under consider-ation for FDA approval for the treatment of
these vasomotor symptoms, and studies have suggested that SSRIs, venlafaxine,
and nefazodone may also provide benefit. Although serotonergic antidepressants
are commonly associated with inducing sexual adverse effects, some of these
effects might prove useful for some sexual disorders. For example, SSRIs are
known to delay orgasm in some patients. For this reason, SSRIs are sometimes
used to treat premature ejaculation. In addition, bupropion has been used to
treat sexual adverse effects associated with SSRI use, although its efficacy
for this use has not been consistently dem-onstrated in controlled trials.
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