Antidepressant Part 3

Adverse effects:

Difficulty tolerating adverse effects is the most common reason for antidepressant discontinuation. Over 1500 side effects have been cataloged for the SSRI alone.

• General:

SSRI side effects include but are not limited to: Serotonin syndrome, nausea, diarrhea, increased blood pressure, agitation, headaches, anxiety, nervousness, emotional lability, increased suicidal ideation, suicide attempts, insomnia, drug interactions, neonate adverse reactions, anorexia, dry mouth, somnolence, tremors, sexual dysfunction, decreased libido, asthenia, dyspepsia, dizziness, sweating, personality disorder, epistaxis, urinary frequency, menorrhagia, mania/hypomania, chills, palpitations, taste perversion, and micturition disorder drowsiness, GI irregularities,muscle weakness, long term weight gain.

SSRIs inhibit serotonin-mediated platelet activation. This leads to increased risk of gastrointestinal bleeding; at times as high as 57% increase in risk. This is especially important in the elderly, those with a history of peptic ulcer disease or previous gastrointestinal bleeding, and those on blood thinners, such as aspirin and clopidogrel. A recent observational study shows that SSRIs may increase the risk of transient ischemic attacks and strokes compared with tricyclic antidepressants.
Side-effects of an Noradrenergic and specific serotonergic antidepressant may include drowsiness, increased appetite, and weight gain.

Tricyclic antidepressants common side effects include: dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss. Toxicity occurs at about ten times normal dosages; these drugs are often lethal in overdoses, as they may cause a fatal arrhythmia. However, tricyclic antidepressants are still used because of their effectiveness, especially in severe cases of major depression, their favorable price, and off label uses.

MAOIs (monoamine oxidase inhibitors) side effects include:  MAOI can produce a potentially lethal hypertensive reaction if taken with foods that contain excessively high levels of tyramine, such as mature cheese, cured meats or yeast extracts. Likewise, lethal reactions to both prescription and over the counter medications have occurred. Patients undergoing therapy with MAO inhibiting medications are monitored closely by their prescribing physicians, who are consulted before taking an over the counter or prescribed medication. Such patients must also inform emergency room personnel and keep information with their identification indicating that they are on MAOI. Some doctors suggest the use of medical identification tags. Although these reactions may be lethal, the total number of deaths due to interactions and dietary concerns is comparable to over-the-counter medications.

Other side effects of MAOI include: hepatitis, heart attack, stroke, and seizures. Serotonin syndrome is a side-effect of MAOIs when combined with certain medications. Moclobemide may be preferred in the elderly as its pharmacokinetics are not affected by age, is well tolerated by the elderly as well as younger adults, has few serious adverse events, and, in addition, it is as effective as other antidepressants that have more side-effects; moclobemide also has beneficial effects on cognition. A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), which is as effective as SSRIs and tricyclic antidepressants, in depressive disorders, acts in a more short-lived and selective manner and does not require a special diet.
Breast cancer survivors risk having their disease come back if they use certain antidepressants while also taking the cancer prevention drug tamoxifen, according to research released in May 2009.
For bipolar depression, anti-depressant, most frequently SSRIs, can exacerbate or trigger symptoms of hypomania and mania.

• Pregnancy:

Pregnancy can trigger a range of emotions that make it more difficult to cope with depression. The risk of medication discontinuation and relapse have to be weighed against the risk to the developing fetus and baby. Some antidepressants have lower risk for the baby during pregnancy, but the FDA advises for the risk of birth defects with the use of Paxil and the MAOI should be avoided. A neonate may experience a withdrawal syndrome from abrupt discontinuation of the antidepressant at birth. The use of antidepressants during pregnancy is associated with an increased risk of spontaneous abortion, birth defects, and developmental delays. Antidepressants is present in varying amounts in breast milk but the effect on the baby is unknown.

Moreover, SSRIs inhibit nitric oxide synthesis, which leads to vasoconstriction. This is significant in pregnancy as SSRIs have been associated with the development of hypertension and pre-eclampsia of pregnancy. This in turn can lead to fetal prematurity. A 2006 industry based publication in the Journal of the American Medical Association (JAMA) found that discontinuing anti-depressive medication during pregnancy led to more frequent relapse. The JAMA later published a correction noting the financial ties and possible conflict of interest, however, the authors maintained that the ties have no bearing on their research work. Obstetrician and perinatologist Adam Urato told the Wall Street Journal that patients and medical professionals need advice free of industry influence.

• Suicide:

Whenever changes in antidepressant dosage occur, whether up or down, a doubling of the risk of suicide is seen. A study of 159,810 users of either amytriptyline, fluoxetine, paroxetine or dothiepin found that the risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days.
The Food and Drug Administration requires Black Box warnings on all SSRIs, which state that they double suicidal rates (from 2 in 1,000 to 4 in 1,000) in children and adolescents. although it's controversial whether this is due to the medication or as part of the depression itself (i.e. efficacious antidepressant effect can cause those that are severely depressed, to the point of severe psychomotor inhibition, are rendered more alert and thus have increased capacity to carry out suicide even though they are relatively improved in state). The increased risk for suicidality and suicidal behaviour among adults under 25 approaches that seen in children and adolescents.

Young patients should be closely monitored for signs of suicidal ideation or behaviors, especially in the first eight weeks of therapy.
People under the age of 24 who suffer from depression are warned that the use of antidepressants could increase the risk of suicidal thoughts and behaviour. Federal health officials unveiled proposed changes to the labels on antidepressant drugs in December 2006 to warn people of this danger.
The FDA warns against the use of Paxil for children and teens depression in favor of Prozac.
SSRI prescriptions for children and adolescents decreased after U.S. and European regulatory agencies issued warnings about a possible suicide risk with antidepressant use in pediatric patients, and these decreases were associated with increases in suicide rates in children and adolescents in both the United States with a 14% increase, and 50% increase in the Netherlands.

On September 6, 2007, the Centers for Disease Control and Prevention reported that the suicide rate in American adolescents, (especially girls, 10 to 24 years old), increased 8% (2003 to 2004), the largest jump in 15 years, to 4,599 suicides in Americans ages 10 to 24 in 2004, from 4,232 in 2003, giving a suicide rate of 7.32 per 100,000 people that age. The rate previously dropped to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990.Jon Jureidini, a critic of this study, says that the US "2004 suicide figures were compared simplistically with the previous year, rather than examining the change in trends over several years".

The pitfalls of such attempts to infer a trend using just two data points (years 2003 and 2004) are further demonstrated by the fact that, according to the new epidemiological data, the suicide rate in 2005 in children and adolescents actually declined despite the continuing decrease of SSRI prescriptions. "It is risky to draw conclusions from limited ecologic analyses of isolated year-to-year fluctuations in antidepressant prescriptions and suicides.

One promising epidemiological approach involves examining the associations between trends in psychotropic medication use and suicide over time across a large number of small geographic regions. Until the results of more detailed analyses are known, prudence dictates deferring judgment concerning the public health effects of the FDA warnings." Subsequest follow-up studies have supported the hypothesis that antidepressant drugs reduce suicide risk.

Another study was taken the overall rate of suicidal acts was 27 per 1000 person-years, and most events occurred within 6 months of medication initiation. According to this study, no commonly used antidepressant medication has an advantage in regard to suicide-related safety. It remains a question as to whether other therapeutic maneuvers, such as ongoing counseling, provide a protective counter-effect to children's and adolescents' antidepressant-associated risk of suicidal thoughts or behaviour.

• Sexual:

Sexual side-effects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm, and erectile dysfunction. Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction.

In a study of 1022 outpatients, overall sexual dysfunction with all antidepressants averaged 59.1% with SSRIs values between 57 and 73%, mirtazapine 24%, nefazodone 8%, amineptine 7% and moclobemide 4%. Moclobemide, a selective reversible MAO-A inhibitor does not cause sexual dysfunction, and can actually lead to an improvement in all aspects of sexual function.
Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5-HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels. Mirtazapine is reported to have fewer sexual side-effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors and may, in some cases, reverse sexual dysfunction induced by SSRIs by the same mechanism.

Bupropion, a dual reuptake inhibitor (NE and DA), often causes a moderate increase in sexual drive, due to increased dopamine activity. This effect is also seen with dopamine reuptake inhibitors, CNS stimulants and dopamine agonists, and is due to increases in testosterone production (due to inhibition of prolactin) and nitric oxide synthesis.

• Thymoanesthesia:

Closely related to sexual side-effects is the phenomenon of emotional blunting, or mood anesthesia. Many users of SSRIs complain of apathy, lack of motivation, emotional numbness, feelings of detachment, and indifference to surroundings. They may describe this as a feeling of "not caring about anything anymore." All SSRIs, SNRIs, and serotonergic TCAs can cause this to varying degrees, especially at high doses.

• REM Sleep:

All major antidepressant drugs, except trimipramine, mirtazapine and nefazodone suppress REM sleep, and it has been proposed that the clinical efficacy of these drugs largely derives from their suppressant effects on REM sleep. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep.

 Mirtazapine either has no effect on REM sleep or increases it slightly. The MAOIs almost completely suppress REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. This effect often causes increased fatigue in patients who take large doses of antidepressants for extended periods of time. Such fatigue can occasionally interfere with a patient's everyday activities. Abrupt discontinuation of MAOIs can cause a temporary phenomenon known as "REM rebound" in which the patient experiences extremely vivid dreams and nightmares.

• Weight gain:

Many antidepressants (TCA, TecA, paroxetine from the group of SSRI's) are associated with weight gain usually in the range of 5–25 kg (11–55 lb) but rarely upwards of 50 kg (110 lb). The specific cause is unknown, but antidepressants are associated with increased cravings, an inability to feel full despite consuming enough calories, low energy levels and increased daytime sleepiness, which can lead to overeating and a lack of desire to exercise, and dry mouth, which can lead to ingestion of calorie-laden beverages.

The antihistaminic properties of certain TCA and TeCA class antidepressants have been shown to contribute to the common side-effects of increased appetite and weight gain associated with these classes of medication. Eating low fat, low protein carbohydrate snacks and carbohydrate-rich dinners allows the brain to make serotonin, which then controls appetite and balances mood. Carbohydrates thus eaten, as part of a balanced diet, by virtue of their effect on brain serotonin levels, can support weight loss in the setting of antidepressant weight gain.

• Withdrawal symptoms:

If a SSRI is suddenly discontinued, it frequently produces a SSRI discontinuation syndrome that has a both a somatic and psychological withdrawal component.
Withdrawal syndromes have been reported with tricyclic antidepressants, monoamine oxidase inhibitors and with SSRI's. Researchers from the Nordic Cochrane Center in Denmark compared the signs and symptoms of SSRI discontinuation to those of the benzodiazepine withdrawal syndrome and concluded that the withdrawal reactions were so similar that both withdrawal reactions indicated a dependence syndrome. Elsewhere, concerns have been raised that SSRIs cause dependence.

Antidepressans may interact with transcription factors known as "clock genes", which may play a role in the addictive properties of drugs (drug abuse), and possibly in obesity. When treatment is prolonged over 6–9 months, processes oppose the initial acute effects of antidepressant drugs (loss of clinical effects). When drug treatment ends, these processes may be unopposed and yield withdrawal symptoms and increased vulnerability to relapse. Such processes are not necessarily reversible. The more antidepressants are switched or potentiated, the more likely oppositional tolerance can take place.

Some of the withdrawal symptoms of SSRI discontinuation include: Anger, anxiety, panic, depression, depersonalization, detachment, confusion, decreased concentration, memory problems, bouts of crying, hallucinations, mania, delirium, headache, sweating, convulsion, myalgias, lethargy, fatigue, sleep disturbances, nightmares, gastrointestinal, balance problems, visual disturbances, electric shock sensations, numbness, parasthesia, restless legs, tingling, tinnitus, tremors, shaking, parkinsonism, aggression, and catatonia.
Moreover, when changes in antidepressant dosage occur, whether up or down, a doubling of the risk of suicide is seen.

To minimize the intensity of withdrawal and rebound effects antidepressants should be discontinued over a period of several weeks or months depending on a person's response to reductions. The Ashton protocol for discontinuation suggest reducing 10% of the remaining dose every week or two Most cases of discontinuation syndrome last between one and four weeks but a substantial minority, perhaps up to 15% of users, have persistent withdrawal symptoms evident one year post-withdrawal. Paroxetine and venlafaxine seem to be particular difficult to discontinue and prolonged withdrawal syndrome lasting over 18 months have been reported with paroxetine. Several peer-support groups help patients to taper off of their antidepressants.

Society and culture:

• Prescription trends:

In the United Kingdom, the use of antidepressants increased by 234% in the 10 years up to 2002. In the USA a 2005 independent report stated that 11% of women and 5% of men in the non-institutionalized population (2002) take antidepressants A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant. A 2007 study suggested that 25% of Americans were overdiagnosed with depression, regardless of any medical intervention. The findings were based on a national survey of 8,098 people.

A 2002 survey found that about 3.5% of all people in France were being prescribed antidepressants, compared to 1.7% in 1992, often for conditions other than depression and often not in line with authorizations or guidelines Between 1996 and 2004 in British Columbia, antidepressant use increased from 3.4% to 7.2% of the population. Data from 1992 to 2001 from the Netherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of treatment. Surveys indicate that antidepressant use, particularly of SSRIs, has increased rapidly in most developed countries, driven by an increased awareness of depression together with the availability and commercial promotion of new antidepressants. Antidepressants are also increasingly used worldwide for non-depressive patients as studies continue to show the potential of immunomodulatory, analgesic and anti-inflammatory properties in antidepressants.

The choice of particular antidepressant is reported to be based, in the absence of research evidence of differences in efficacy, on seeking to avoid certain side-effects, and taking into account comorbid (co-occurring) psychiatric disorders, specific clinical symptoms and prior treatment history.
It is also reported that, despite equivocal evidence of a significant difference in efficacy between older and newer antidepressants, clinicians perceive the newer drugs, including SSRIs and SNRIs, to be more effective than the older drugs (tricyclics and MAOIs). Currently, the most commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), even though a Cochrane systematic review found no major difference in efficacy between SSRIs and tricyclic antidepressants. A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.

The number of antidepressants prescribed by the NHS in the United Kingdom almost doubled during one decade, authorities reported in 2010. Furthermore the number highly increased in 2009 when 39.1 million prescriptions were issued compared with 20.1 million issued in 1999. Also, physicians issued 3.18 million more prescriptions in 2009 than in 2008. Health authorities believed the increase was partly linked to the recession. However, other reasons include a diagnosis improvement, a reduction of the stigma on mental ill-health, and more distress caused by the economic crisis. Furthermore, physicians concern is that some people who exhibit milder symptoms of depression are being prescribed drugs unnecessarily due to the lack of other options including talking therapies, counseling and cognitive behavior therapy. One more factor that may be increasing the consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post traumatic stress.

The use of antidepressants in the USA doubled over one decade, from 1996 to 2005. Antidepressant drugs were prescribed to 13 million in 1996 and to 27 million people by 2005. In 2008, more than 164 million prescriptions were written. During this period, patients were less likely to undergo psychotherapy.

• Most commonly prescribed:

Structural formula of the SSRI escitalopram, in its free base form

• United States of America: 

The most commonly prescribed antidepressants in the US retail market in 2010 were:

Sertraline	Zoloft	SSRI	33,409,838
Citalopram	Celexa	SSRI	27,993,635
Fluoxetine	Prozac	SSRI	24,473,994
Escitalopram	Lexapro	SSRI	23,000,456
Trazodone	Desyrel	SARI	18,786,495
Duloxetine	Cymbalta	SNRI	14,591,949
Paroxetine	Paxil	SSRI	12,979,366
Amitriptyline	Elavil	TCA	12,611,254
Venlafaxine XR	Effexor XR	SNRI	7,603,949
Bupropion XL	Wellbutrin	NDRI	7,317,814
Mirtazapine	Remeron	TeCA	6,308,288
Venlafaxine ER	Effexor	SNRI	5,526,132
Bupropion SR		NDRI	4,588,996
Desvenlafaxine	Pristiq	SNRI	3,412,354
Nortriptyline	Sensoval	TCA	3,210,476
Bupropion ER		NDRI	3,132,327
Venlafaxine	Effexor	SNRI	2,980,525
Bupropion	Wellbutrin XL	NDRI	753,516

• Germany:

The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) Hypericum perforatum (St John's wort).

• Netherlands:

In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine.
MAOIs can be as effective as tricyclic antidepressants, although they are generally used less frequently because they have a higher incidence of dangerous side effects and interactions.

• Litigation:

1. 2012 GlaxoSmithKline 3 billion dollars (US) - Paxil, The company touted Paxil for off-label use in children and adolescents, despite data that failed to show it was effective for these age groups, –Wellbutrin for marketing its antidepressant for off-label uses, including weight loss, substance abuse and sexual dysfunction and the seizure drug Lamictal.
2. 2012 Johnson & Johnson $1.6 and $2.2 billion Risperdal off label marketing
3. 2012 Abbott Laboratories $698 million for off label marketing Depakote for use in dementia patients who became agitated or aggressive despite lack of evidence that the drug was effective for that use.
4. 2009 Eli Lilly $1.4 billion for marketing Zyprexa for children and the elderly dementia patients, both off-label uses. It is only approved to treat two disorders, schizophrenia and bipolar disorder.
5. 2010 AstraZeneca $520 million for off-label marketing of Seroquel.
6. 2009 Pfizer $301 million for off label marketing of Geodon.
7. 2007 Bristol-Myers Squibb $515 million for off-label marketing of Abilify for children and adolescent, and geriatric patients suffering from dememtia.
8. 2004 Pfizer $430 million for off-label marketing of Neurontin.
9. Ely Lilly In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly and Company was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead, recorded the case as settled. The value of the secret settlement deal has never been disclosed, but was reportedly "tremendous".

REFERENCE:
http://en.wikipedia.org/wiki/Antidepressant