Antidepressant drugs

An antidepressant is a medication designed to treat or alleviate the symptoms of clinical depression. Some antidepressants, notably the tricyclics, are commonly used off-label in the treatment of neuropathic pain, whether or not the patient is depressed. Smaller doses are generally used for this purpose, and they often take effect more quickly. Many antidepressants also are used for the treatment of anxiety disorders, and tricyclic antidepressants are used in the treatment of chronic pain disorders such as chronic functional abdominal pain (CFAP), myofascial pain syndrome, and post-herpetic neuralgia.

The main classes of antidepressants have similar efficacy, but the newer types are generally regarded to have a more benign side-effect profile and less risk of lethality if taken in overdose.

History
Like many psychiatric drugs, antidepressants were discovered by accident. The first usefull antidepressants, belonged to a group called Monoamine Oxidase Inhibitors and were discovered in the early 1950's. The original member of this group was Iproniazid. It was originally developed as a drug to treat tuberculosis. The next group were the Tricyclic antidepressants. The first was Imipramine. They were effective and safer than the MAOI but still quite dangerous in overdose. They are still used to-day but have been largely replaced by another group. This most recent group are called SSRI's, Selective Serotonin Reuptake Inhibitors. The first SSRI was fluoxetine (Prozac). Drugs from all three groups have been found to improve the depressed patients' mood. The SSRI antidepressants were early examples of rational drug design.

Classes

 * Monoamine oxidase inhibitors (MAOIs)
 * Tricyclic antidepressants
 * Selective serotonin reuptake inhibitors (SSRIs)
 * Serotonin-norepinephrine reuptake inhibitors (SNRIs)
 * Norepinephrine/noradrenaline reuptake inhibitors (NRIs aka NERIs/NARIs)
 * Dopamine reuptake inhibitors (DRIs)
 * Opioids
 * Selective serotonin reuptake enhancers (SSREs)
 * Novel antidepressants
 * Tetracyclic antidepressants
 * Norepinephrine reuptake inhibitors

Prominent members
Well-known antidepressants are:
 * Fluoxetine - of the SSRI class (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan)
 * Sertraline - of the SSRI class (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton)
 * Venlafaxine - of the SNRI class (Effexor)
 * Citalopram - of the SSRI class (Celexa, Cipramil, Talohexane)
 * Paroxetine - of the SSRI class (Paxil, Seroxat, Aropax)
 * Escitalopram - of the SSRI class (Lexapro, Cipralex)
 * Fluvoxamine - of the SSRI class (Luvox, Faverin)
 * Duloxetine - of the SNRI class (Cymbalta)
 * Bupropion - of the DRI class (Wellbutrin, Zyban)

Mechanism of action
The therapeutic effects of antidepressants are believed to be related to an effect on neurotransmitters, particularly by inhibiting the monoamine transporter proteins of serotonin and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) specifically prevent the reuptake of serotonin (thereby increasing the level of serotonin in synapses of the brain), whereas earlier monoamine oxidase inhibitors (MAOIs) blocked the destruction of neurotransmitters by enzymes which normally break them down. Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Although these drugs are clearly effective in treating depression, the current theory still leaves unanswered questions. For example, concentrations in the blood build to therapeutic levels in only a few days and begin affecting neurotransmitter activity immediately. Changes in mood, however, often take four weeks or more to appear. One explanation holds that the "down-regulation" of neurotransmitter receptors&mdash;an apparent consequence of excess signaling and a process that takes several weeks&mdash;is actually the mechanism responsible for the alleviation of depressive symptoms. Another theory, based on recent research published by the National Institutes of Health in the United States, suggests that antidepressants may derive their effects by promoting neurogenesis in the hippocampus.. Recent research suggests that antidepressants act on transcription factors termed "clock genes", which also are involved in actions of drugs of abuse and possibly in obesity.

Treatment strategies
On efficacy measures, a successful antidepressant trial involves just 50 % or more of the test subjects on the drug responding to the medication. “Response” signifies a mere 50 % or greater reduction in depression symptoms as opposed to “remission,” which indicates a virtual elimination of depression symptoms. A number of different treatment strategies, however, may produce better results:

Switching
The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder advises that where no response is achieved following six to eight weeks of treatment with an antidepressant to switch to an antidepressant in the same class, then to a different class of antidepressant.

A series of open-label studies by Michael Thase MD of the University of Pittsburgh found that more than half the patients who failed on their initial antidepressant achieved a response on their second antidepressant from the same class. (Thase ME et al. "Fluoxetine treatment of patients with major depressive disorder who failed initial treatment with sertraline." J Clin Psychiatry. 1997 Jan;58(1):16-21.)

A 2002 double-blind study by the same author found a positive benefit among treatment-resistant patients switching either from an SSRI to a tricyclic or from a tricyclic to an SSRI. (Thase ME et al. "Double-blind switch study of imipramine or sertraline treatment of antidepressant-resistant chronic depression." Arch Gen Psychiatry. 2002 Mar;59(3):233-9.)

Augmentation and combination
For a partial response, the American Psychiatric Association advises augmenting an antidepressant with a different pharmaceutical agent. These agents may include lithium, thyroid supplementation, atypical antipsychotics, and dopamine agonists, among others. Symbyax a combination olanzapine-fluoxetine (Zyprexa-Prozac) pill is approved in the US for treating bipolar depression, and is being investigated for other depression indications. In general, however, there are no major augmentation studies to guide psychiatrists.

Combination strategy involves using two or more antidepressants from different classes to target more than one neurotransmitter in order to hopefully achieve a more beneficial result. Again, this is a little-studied area of antidepressant treatment. (See article.)

Combining with psychotherapy
A 2000 study found that those on nefazadone (Serzone) plus a form of short-term psychotherapy called Cognitive Behavioral Analysis System of Psychotherapy (CBASP) fared significantly better (85 % response, 42 % remission) than those on Serzone alone (55 % response, 22 % remission) or CBASP alone (52 % response, 24 % remission). (Keller MB et al. "A comparison of nefazadone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression." N Engl J Med. 2000 May 18;342(20):1462-70.)

Preventing relapse
A 2003 meta-analysis of 31 placebo-controlled antidepressant trials found that continuing with antidepressants reduced the risk of relapse by 70 %. (Geddes JR et al. "Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review." Lancet. 2003 Feb 22;361(9358):653-61.)

The American Psychiatric Association advises four to five months of continuation treatment on an antidepressant following the resolution of symptoms. For patients with a history of depressive episodes, the British Association for Psychopharmacology's 2000 Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants advises remaining on an antidepressant for at least six months and as long as five years or indefinitely.

Tolerance and dependence
Antidepressants are not thought to produce tolerance, although sudden withdrawal may produce adverse effects. Antidepressants create little if any immediate change in mood and require between several days and several weeks to take effect.

Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants. (There is, however, controversy on the definition of addiction.) Some argue that antidepressants do not meet the general requirements for the commonly-established view. While some antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure. For example, if an SSRI medication is suddenly discontinued, it may produce both somatic and psychological withdrawal symptoms, a phenomenon known as "SSRI discontinuation syndrome" (Tamam & Ozpoyraz, 2002). When the decision is made to stop taking antidepressants it is common practice to &#8220;wean&#8221; off of them by slowly decreasing the dose over a period of several weeks.

It is generally not a good idea to take antidepressants without a prescription. The selection of an antidepressant and dosage suitable for a certain case and a certain person is a lengthy and complicated process, requiring the knowledge of a professional. Certain antidepressants can initially make depression worse, can induce anxiety, or can make a patient aggressive, dysphoric or acutely suicidal. In certain cases, an antidepressant can induce a switch from depression to mania or hypomania, can accelerate and shorten a manic cycle (i.e. promote a rapid-cycling pattern), or can induce the development of psychosis (or just the re-activation of latent psychosis) in a patient with depression who wasn't psychotic before the antidepressant.

Side effects
Antidepressants can often cause side effects, and an inability to tolerate these is the most common cause of discontinuing the medication.

General
Although recent drugs may have fewer side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine. Additionally, a certain percentage of patients do not respond to antidepressant drugs. Another advantage of some newer antidepressants is they can show effects within as few as five days, whereas most take four to six weeks to show a change in mood. However, some studies show that these medications might be even more likely to result in moderate to severe sexual dysfunction. However, there are medications in trials that appear to show an improved profile in regard to sexual dysfunction and other key side effects.

MAO inhibitors can produce a lethal hypertensive reaction if taken with foods that contain high levels of tyramine, such as cheese and wine. Likewise, lethal reactions to both prescription and over the counter medications have occurred. Any patient currently undergoing therapy with an MAO inhibiting medication should be monitored closely by the prescribing physician and always consulted before taking an over the counter or prescribed medication. Such patients should also inform emergency room personnel and information should be kept with one's identification indicating the fact that the holder is on MAO inhibiting medications. Some doctors even suggest the use of a medical alert ID bracelet.

Antidepressants often make the manic component of bipolar disorder worse, and should be used with great care in the treatment of that disorder, usually in conjunction with mood stabilisers. Their use should be monitored by a psychiatrist, but in countries such as Britain, New Zealand, and the United States, primary care physicians are able to prescribe antidepressants without consulting a psychiatrist.

In particular, it has been noted that the most dangerous period for suicide in a patient with depression is immediately after treatment has commenced, as antidepressants may reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve. Although this appears to be a paradox, studies indicate the suicidal ideation is a relatively common component of the initial phases of antidepressant therapy, and it may be even more prevalent in younger patients such as pre-adolescents and teenagers. It is strongly recommended that other family members and loved ones monitor the young patient's behavior, especially in the first eight weeks of therapy, for any signs of suicidal ideation or behaviors.

Sexual
Sexual dysfunction is a very common side effect, especially with SSRIs. Bupropion, a DRI, in many cases results in a moderately increased libido. Some clinicians have found that adding bupropion to a regimen of SSRI medications can sometimes alleviate some degree of sexual dysfunction. However, the mechanism of action for bupropion appears to be unique and quite different from other mood elevators, among these being a stimulant-like effect and concurrent insomnia, especially in the first few weeks of use. Moreover, some patients, as seen with most psycho-active drugs, cannot tolerate it at all.

Opioids
Opium has been known as an antidepressant since Biblical times. Various Opiates were commonly used as antidepressants until the mid-1950s, when they fell out of favor with medical orthodoxy due to their addictive nature. A clinical trial conducted at Harvard Medical School in 1995, demonstrated that a majority of treatment-refractory, unipolar, nonpsychotic, major depression patients could be successfully treated with an opioid medication called Buprenorphine. While opioids have been proven to substantially relieve symptoms of depression, re-acceptance of this fact has been severely hampered by governmental narcotic prohibition efforts.

Controversy
Several studies have stimulated doubt about the effectiveness of antidepressants. The studies cite that the difference between antidepressants and placebo is negligible. Antidepressants work only slightly better than placebo, and the Food and Drug Administration has not informed physicians of how little benefit most of these depression drugs offer (Kirsch I, Moore TJ, Scoboria A, Nicholls SS (2002a), The emperor's new drugs: an analysis of antidepressant medication data submitted to the U.S. Food and Drug Administration. Prevention & Treatment 5:Article 23).

Through a Freedom of Information Act request, two psychologists obtained 47 studies used by the FDA for approval of the six antidepressants prescribed most widely between 1987-99. Overall, antidepressant pills worked 18 % better than placebos, a statistically significant difference, "but not meaningful for people in clinical settings," says University of Connecticut  psychologist Irving Kirsch. He and co-author Thomas Moore released their findings in "Prevention and Treatment," an e-journal of the American Psychological Association.

More than half of the 47 studies found that patients on antidepressants improved no more than those on placebos, Kirsch says. "They should have told the American public about this. The drugs have been touted as much more effective than they are." He says studies finding no benefit have been mentioned only on labeling for Celexa, the most recently approved drug. The others included in his evaluation: Prozac, Paxil, Zoloft, Efexor and Serzone.

Additional papers have been published regarding the benefits of atypical vs. typical antidepresants. These are timely papers given the need for evidence based medicine, as well as the cost of health care. Discussion of a key paper reviewing this topic titled "Quantitative analysis of sponsorship bias in economic studies of antidepressants" can be found at an an on line journal club

Alternative medicine
Despite controversy, alternative treatments for depression such as the herbal remedy St John's wort and the amino acid derivative SAM-e have also gained popularity in recent years, although their effectiveness varies. Clinical trials have shown SAM-e to be as effective as standard antidepressant medication, with many fewer side effects (Delle Chiaie et al., 2002; Mischoulon and Fava, 2002). Most studies conclude that St. John's wort is usually as effective against depressions as other modern medication, again with fewer side effects, and it is widely prescribed for depression in Europe. However, a recent study showed St. John's wort to be no more effective than a placebo in cases of severe depression (Hypericum Depression Trial Study Group, 2002). Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants. Dietary supplements of 5-HTP, a chemical the body forms from tryptophan and uses to make serotonin, have shown some promising research results but need further study.