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For detail of individual antidepressants see: List of antidepressants
An antidepressant, in the most common usage, is a medication taken to alleviate clinical depression or dysthymia ('milder' depression). Several groups of drugs are particularly associated with the term, notably MAOIs and tricyclics (whose serendipitous discovery and psychiatric use dates from the 1950s) as well as SSRIs and more recent variations developed by pharmaceutical companies. These medications are now amongst the most commonly prescribed by psychiatrists and general practitioners, and their effectiveness and adverse effects are the subject of many studies and competing claims. A number of other antidepressant drugs, notably St John's Wort, are also widely studied and used.
Antidepressants are generally, if not in pharmacology, considered separately from stimulants. They are usually taken as a course over several weeks, months or years, and have a delayed onset of therapeutic action. Drugs used for an immediate euphoric effect only are not generally considered antidepressants. Despite the name, antidepressants are often used in the treatment of other conditions, including anxiety disorders, bipolar disorder, eating disorders and chronic pain. Some have also become known as lifestyle drugs, sometimes referred to as "mood brighteners". Conversely other medications not known as antidepressants, including antipsychotics in low doses and benzodiazepines are also widely used to manage depression. In fact the antidepressant term is sometimes applied to any therapy (e.g. psychotherapy, electro-convulsive therapy, acupuncture) or process (e.g. sleep disruption, increased light levels, regular exercise) found to improve clinically depressed mood. It is also the case that placebos tend to have a significant antidepressant effect, so that establishing something as an antidepressant in a clinical trial involves demonstrating a significant additional effect.
- 1 History
- 2 Classes and members
- 3 Prescription trends
- 4 Mechanisms of action
- 5 Therapeutic efficacy
- 6 Tolerance and dependence
- 7 Side effects
- 8 Controversy
- 9 Non-mainstream treatments
- 10 See also
- 11 References
- 12 Additional reading
- 13 External links
Opium and St John's Wort (as a "nerve tonic") had long been used to alleviate depression (amongst many other things), but iproniazid was the first synthetic chemical compound generally accepted as an antidepressant. The chemical from which it was derived, isoniazid was independently recognized as having clinically significant effects on depression, in 1952 by Jean-Francois Buisson in France and Max Lurie in the United States, after it had come into widespread use as a treatment for tuberculosis. Iproniazid was then observed to have a greater "psychostimulant" effect and to inhibit the enzyme Monoamine Oxidase. Nathan Kline and colleagues conducted the first clinical trial to demonstrate a significant effect of iproniazid on depression in psychiatric patients. Kline approached Roche with what he called a "psychic energizer" and the first MonoAmine Oxidase Inhibitor (MAOI) was introduced as Marsilid. Sales grew massively in the following years, and others of the class were introduced by several drug companies, but adverse effects such as hypertension crisis related to food amines, and acute hepatic necrosis, curtailed their use.
The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was also first made in the early 1950s, by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistamine derivatives were coming in to use to treat surgical shock and then as psychiatric neuroleptics. Although, in 1955, reserpine was indicated to be more effective than placebo in alleviating anxious depression, neuroleptics (literally "to seize the neuron") were developing for use as sedatives and antipsychotics. In attempting to improve the effectiveness of one of them, chlorpromazine, in conjunction with the Geigy pharmaceutical company, Kuhn discovered that compound "G 22355" (manufactured and patented in the US in 1951 by Häfliger and Schinder) had a beneficial effect in patients with depression with mental and motor retardation He first reported his findings on what he called a "thymoleptic" (literally "taking hold of the emotions", by contrast with neuroleptics, "taking hold of the nerves") in 1955/56 and they gradually became established, resulting in the marketing of the first tricyclic antidepressant, imipramine, soon followed by variants.
These new drug therapies became prescription-only medications (POM) in the 1950s. It was estimated that no more than 50 to 100 people per million suffered from the kind of depression that these new drugs would treat and pharmaceutical companies were not enthusiastic. Sales through the 1960s remained poor compared to the major tranquilizers (neuroleptics/antipsychotics) and minor tranquilizers (benzodiazepines), which were being marketed for different uses. The term antidepressant is reported to have been coined by Lurie and to not have been widely adopted until at least the 1960s. Imipramine remained in common use and numerous successors were introduced. The field of MAO inhibitors remained quiet for many years until "reversible" forms affecting only the MAO-A subtype were introduced, avoiding some of the adverse effects.
Most pharmacologists by the 1960s thought the main therapeutic action of tricyclics was to inhibit norepinephrine reuptake, but it was gradually observed that this action was associated with energizing and motor stimulating effects whilst some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably proposed by Carlsson and Lindqvist (1969) and Lapin and Oxenkrug (1969)). Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would 'selectively' (specifically) target these systems. The first such compound to be patented, in 1971, was zimelidine, whilst the first released clinically was indalpine. Fluoxetine, which from 1988 became the first blockbuster SSRI (Selective Serotonin Reuptake Inhibitor) was developed at Eli Lilly in the early 1970s by Bryan Molloy, Ray Fuller, David Wong and others.
While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John's Wort had become increasingly popular in Germany where Hypericum extracts eventually became licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out from the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these. It remained an over-the-counter drug or supplement in most countries, however, and research continued to investigate its neurotransmitter effects and active components, particularly hyperforin
Classes and members
The following clickable info-box is from the Anatomical Therapeutic Chemical Classification System published by the World Health Organization. See also list of antidepressants.
A 1998 survey found that 67% of patients in the United States diagnosed with depression had been prescribed an antidepressant.. A 2002 survey found that 3.5% of 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 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 promotion of new 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-occuring) psychiatric disorders, specific clinical symptoms and prior treatment history It is also reported that, despite lack of evidence of a significant difference in efficacy between older and newer antidepressants, clinicians perceive the newer drugs, including SSRIs, to be more effective than the older drugs (tricyclics and MAOIs).
Most commonly prescribed antidepressants
The most commonly prescribed antidepressants in the US in 2005) were:
- Sertraline - of the SSRI class (e.g. Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton)
- Escitalopram - of the SSRI class (e.g. Lexapro, Cipralex)
- Fluoxetine - of the SSRI class (e.g. Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan)
- Venlafaxine - of the SNRI class (e.g. Effexor XR, Efexor)
- Citalopram - of the SSRI class (e.g. Celexa, Cipramil, Talohexane)
- Paroxetine - of the SSRI class (e.g. Paxil, Seroxat, Aropax)
- Trazodone - of the Tetracyclic class (e.g. Desyrel)
- Amitriptyline - of the TCA class (e.g. Elavil)
- Bupropion - of the DRI and NRI classes (e.g. Wellbutrin, Zyban)
The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) hypericum perforatum (St John's Wort).
Mechanisms of action
The therapeutic effects of antidepressants are believed to be related to their effects on neurotransmitters. Monoamine oxidase inhibitors (MAOIs) block the break-down of monoamine neurotransmitters (serotonin and norepinephrine) by inhibiting the enzymes which oxidize them, thus leaving higher levels still active in the brain. Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Selective serotonin reuptake inhibitors (SSRIs) more specifically prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants specifically affect serotonin and other neurotransmitters.
A theory centered on neurotransmitter effects appears to be incomplete, however. Neurotransmitter levels are altered as soon as the antidepressant chemicals build up in the bloodstream, but effects on mood appear to occur several days or weeks later. One explanation of this holds that the "down-regulation" of neurotransmitter receptors— an apparent consequence of excess signaling and a process that takes several weeks — is actually the mechanism responsible for the alleviation of depressive symptoms. Another hypothesis is that antidepressants may have some longer-term effects due to the promotion of neurogenesis in the hippocampus, an effect found in mice . Other animal research suggests that antidepressants can also effect the expression of genes in brain cells, by influencing "clock genes" .
There is a large amount of research evaluating the potential therapeutic effects of antidepressants, whether through efficacy studies under experimental conditions (including randomized clinical trials) or through studies of "real world" effectiveness. A sufficient response to a drug is often defined as at least a 50% reduction in self-reported or observed symptoms, with a partial response often defined as at least a 25% reduction. The term remission indicates a virtual elimination of depression symptoms, albeit with the risk of a recurrence of symptoms or complete relapse. Full remission or recovery signifies a full sustained return to a "normal" psychological state with full functioning.
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Recent clinical reviews include:
- A comparison of the relative efficacy of different classes of antidepressants in different settings and in regard to different kinds of depression
- An assessment of antidepressants compared with an "active placebo"
- An assessment of the newer types of the MAOI class
- A meta-analysis of randomized trials of St John's Wort
- A review of the use of antidepressants for childhood depression
Acute major depression is common and serious. Controversy rages about what and whether drugs help. Trials favorable to a product are more likely to be published. Three investigators in Italy, publishing in the CMAJ in 2008, report a large comprehensive study of 29 published and 11 unpublished randomized trials from 5 major databases, including 3704 patients with acute moderate-to-severe major depression who received paroxetine (trade name Paxil) and 2687 who received placebo, up to 2006. Paroxetine was better than placebo at improving symptoms but worse than placebo at causing dropout from the trial because of side effects and much worse than placebo on suicidal tendencies. Conclusion: Paroxetine is not better than placebo in therapeutic effectiveness and acceptability in treating acute major depression.
The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder indicates that, if preferred by the patient, antidepressant medications may be provided as an initial primary treatment for mild major depressive disorder; antidepressant medications should be provided for moderate to severe major depressive disorder unless electroconvulsive therapy is planned; and a combination of antipsychotic and antidepressant medications or electroconvulsive therapy should be used for psychotic depression. It states that efficacy is generally comparable between classes and within classes and that the initial selection will largely be based on the anticipated side effects for an individual patient, patient preference, quantity and quality of clinical trial data regarding the medication, and its cost.
The UK National Institute for Clinical Excellence (NICE) 2004 guidelines indicate that antidepressants should not be used for the initial treatment of mild depression, because the risk-benefit ratio is poor; that for moderate or severe depression an SSRI is more likely to be tolerated than a tricyclic; and that antidepressants for severe depression should be combined with a psychological treatment such as Cognitive Behavioural Therapy.
Efficacy limitations and strategies
Between 30% and 50% of individuals treated with a given antidepressant do not show a response. Even where there has been a robust response, significant continuing depression and dysfunction is common, with relapse rates 3 to 6 times higher in such cases. In addition, antidepressant drugs tend to lose efficacy over the course of treatment A number of strategies are used in clinical practice to try to overcome these limits and variations.
"Trial and error" switching
The American Psychiatric Association 2000 Practice Guideline 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 recent meta-analysis review found wide variation in the findings of prior studies; for patients who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug, with between 5% and 39% ending treatment due to adverse effects. The more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.
Augmentation and Combination
For a partial response, the American Psychiatric Association guidelines advise adding a different kind of pharmaceutical agent to the antidepressant. Studies suggest that most patients fail to achieve remission on a given antidepressant, and augmentation strategies used in clinical practice include the use of lithium and thyroid augmentation, but there is not a good evidence base for these practices or for more novel strategies such as the use of selective dopamine agonists, sex steroids, norepinephrine reuptake inhibitors, glucocorticoid-specific agents, or the newer anticonvulsants
A combination strategy involves adding one or more additional antidepressants, usually from different classes so as to have a diverse neurochemical effect. Although this may be used in clinical practice, there is little evidence for the relative efficacy or adverse effects of this strategy.
The therapeutic effects of antidepressants typically do not continue once the course of medication ends, resulting in a high rate of relapse. A recent meta-analysis of 31 placebo-controlled antidepressant trials, mostly limited to studies covering a period of one year, found that 18% of patients who had responded to an antidepressant relapsed while still taking it, compared to 41% whose antidepressant was switched for a placebo. The American Psychiatric Association guidelines advise 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 Guidelines for Treating Depressive Disorders with Antidepressants advise remaining on an antidepressant for at least six months and as long as five years or indefinitely.
Whether or not someone relapses after stopping an antidepressant does not appear to be related to the duration of prior treatment, however, and gradual loss of therapeutic benefit during the course also occurs. A strategy involving the use of pharmacotherapy in the treatment of the acute episode, followed by psychotherapy in its residual phase, has been suggested by some studies.
Tolerance and dependence
Most antidepressants, including the SSRIs and tricyclics, are known to produce tolerance (i.e. a patient receiving antidepressant therapy for some years will often have to increase the dose over time, or add other drugs, to receive the same therapeutic effect), and withdrawal (particularly if abrupt) may produce adverse effects, which can range from mild to extremely severe.
Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants - in other words, while antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure, and thus do not meet the strict definition of an addictive substance. However, antidepressants do meet the World Health Organisation definition of "dependency-inducing", and indeed the SSRIs are listed by the organisation as among the most strongly dependency-inducing substances in existence.
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 "wean" off of them by slowly decreasing the dose over a period of several weeks or months, although often this will reduce the severity of the discontinuation reaction, rather than prevent it. Most cases of discontinuation syndrome last between one and four weeks, though there are examples of patients (especially those who have used the drugs for longer periods of time, or at a higher dose) experiencing adverse effects such as impaired concentration, poor short-term memory, elevated anxiety and sexual dysfunction, for months or even years after discontinuation.
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.
Antidepressants can often cause side effects, and an inability to tolerate these is the most common cause of discontinuing an otherwise working medication.
Side effects of SSRIs: Nausea, diarrhea, headaches. Sexual side effects are also common with SSRIs, such as loss of libido, failure to reach orgasm and erectile problems. Seratonergic syndrome is also a worrying condition associated with the use of SSRIs. The Food and Drug Administration has included Black Box warnings on all SSRIs stating how they double suicidality (from 2 in 1,000 to 4 in 1,000) in children and adolescents who are prescribed these drugs.
Side effects of TCAs (tricyclic antidepressants): Fairly common side effects include dry mouth, blurred vision, drowsiness, dizziness, tremors, sexual problems, skin rash, and weight gain or loss.
Side effects of MAOIs (monoamine oxidase inhibitors): Rare side effects of MAOIs like phenelzine (brand name: Nardil) and tranylcypromine (brand name: Parnate) include liver inflammation, heart attack, stroke, and seizures
Although recent drugs may have fewer side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine and venlafaxine[How to reference and link to summary or text]. 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 potentially lethal hypertensive reaction if taken with foods that contain 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. 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. Although the reactions in question are dramatic when they happen, the total number of deaths due to interactions and dietary concerns are comparable to over-the-counter medications.
Antidepressants should be used with great care, usually in conjunction with mood stabilisers, in the treatment of bipolar disorder, as they can exacerbate symptoms of mania. They have also been known to trigger mania or hypomania in some patients with bipolar disorder and in a small percentage of patients with depression. SSRIs are the antidepressants most frequently associated with this side effect.
Use of antidepressants should be monitored by a psychiatrist, but in countries such as France, New Zealand, the United Kingdom, 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. Until the black box warnings on these drugs were issued by FDA as well as by agencies in other nations, side effects and alerting families to risk were largely ignored and downplayed by manufacturers and practitioners. This may have resulted in some deaths by suicide although direct proof for such a link is largely anecdotal. The higher incidence of suicide ideation reported in a number of studies has drawn attention and caution in how these drugs are used.
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 the inherent danger.
Sexual dysfunction is a very common side effect, especially with SSRIs. Although usually reversible, these sexual side effects can, in rare cases, last for months or years after the drug has been completely withdrawn. This disorder is known as Post SSRI Sexual Dysfunction. Bupropion, a dual reuptake inhibitor (NE and DA), in many cases results in a moderately increased libido, 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 increased nitric oxide synthesis. Apomorphine, nefazodone and nitroglycerin have been shown to reverse some sexual dysfunction via increased nitric oxide activity. MAOIs are reported to have fewer negative effects on sexual function and libido, particularly moclobemide at a 1.9% rate of occurrence. Betanechol has been reported to reverse MAOI-induced sexual dysfunction via its cholinergic agonist properties (Gross 1982).
In order for the physician to select the appropriate response, the patient should provide the physician with information to distinguish between reduced libido (little or no desire for sex), reduced sexual function (impotence, vaginal dryness) and anorgasmia, as these have separate causes and prompt different treatment.
It is well recognized that virtually all major antidepressant drugs suppress REM sleep and it has, in fact, 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. The MAOIs virtually completely abolish REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. Ironically, a common side effect of most antidepressants is an increase in vivid dreams, and nightmares are a common result of rapid withdrawal from MAOIs.
Several studies have stimulated doubt about the effectiveness of antidepressants. The studies cite that the difference between antidepressants and placebo is negligible (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).
The paper in question has been severely criticized by independent researchers, however. One reason for this is that it deals almost exclusively with the SSRI class of medication. In leveling criticism against the efficacy of SSRIs, critics state, it is not the best paper, merely the most widely known one. Also, other classes of antidepressants have demonstrated superior efficacy, and it has been argued that this paper is "throwing the baby out with the bathwater", while its thrust should in fact be levelled at the serotonin hypothesis of depression.
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.[How to reference and link to summary or text]
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, Effexor and Serzone.
Additional papers have been published regarding the benefits of atypical vs. typical antidepressants. 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 on-line journal club.
Dr Joseph Glenmullen, a Harvard psychiatrist, has written a book on the subject for the layperson; see link below.
Antidepressant medications, such as Zoloft and Prozac generally fall short of providing significantly more relief for depressed patients than placebo pills do, according to an analysis of multiple clinical trials from the U.S. Food and Drug Administration
The study found that antidepressants substantially outperformed placebos only among extremely depressed patients. Dr. Irving Kirsch of the University of Hull, UK, stated, "There is little evidence to support the prescription of antidepressant medication to any but the most severely depressed patients, unless alternative treatments with fewer side effects have failed to provide benefit" (Emphasis added) Dr. Kirsch and colleagues obtained the data from 47 clinical trials submitted to the FDA. They edited out 12 and the 35 left used clinical trials lasting approximately six weeks, had substantial completion rates, and consistent monitoring of depressive symptoms. The trails compared randomly assigned placebo treatment to treatment with one of four antidepressant medications: Prozac fluoxetine, Effexor, venlafaxine, Serzone nefazodone, and Paxil paroxetine. A total of 5,133 depressed patients participated in the 35 studies.
There are numerous alternative treatments for depression, whether medications or other kinds of intervention.
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, the tolerance buildup issues and their side-effect profile. Today the use of opioids in treating depression is a large taboo in the medical field due to associations with drug abuse; hence, research has proceeded at a very slow rate. A small clinical trial conducted at Harvard Medical School in 1995, demonstrated that a majority of treatment-refractory, unipolar, non-psychotic, major depression patients could be successfully treated with an opioid medication called Buprenorphine, which is a partial mu agonist and potent kappa antagonist. The exact mechanism of its action in depression is not known, as kappa antagonists are antidepressants in their own right. While opioids have been proven to substantially relieve symptoms of depression for a large class of patients, re-acceptance of this fact has been severely hampered by governmental narcotic prohibition efforts, and the (until buprenorphine) lack of alternatives with low risk of tolerance and addiction. Buprenorphine is generally preferred as the first-line opiate in depression treatment, as managing the tolerance buildup of other opiates can be complicated.
Gamma-Hydroxybutyric acid (GHB) has been used by some as an antidepressant. Claude Rifat, a French biologist, conducted some early research into GHB's antidepressant potential. Rifat noted that GHB did not cause the emotional blunting effects caused by conventional antidepressants, but instead intensified pleasurable and rewarding feelings in the user while powerfully suppressing depression. However, GHB has now been outlawed, except for use as a prescription treatment for narcolepsy.
Clinical trials have shown the effect of acupuncture to be comparable with amitriptyline; in addition, acupuncture has been found to be more effective in depressive patients with decreased excretion of 3-methyl-4-hydroxy-phenylglycol (the principal metabolite of the central neurotransmitter norepinephrine), while amitriptyline is more effective for those with inhibition in the dexamethasone suppression test. Acupuncture has also been proven to prompt the body to produce greater levels of endorphins.
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. A recent study showed St. John's wort to be no more effective than a placebo in cases of severe depression, although an SSRI was also no more effective on the primary outcome measure.
Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants.[How to reference and link to summary or text] 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.
NMDA antagonists such as ketamine and dextromethorphan have recently gained some interest in this field as their apparent ability to reverse opioid tolerance, and can give fast-acting dramatic effects. However, their acute psychoactive effects have been a problem.
Memantine, a moderate affinity NMDA antagonist, has been used to avoid tolerance buildup, and has seen use in opioid tolerance reversal. Proglumide is used to induce acute reversal of tolerance prior to this maintenance strategy; it does not work by itself in the long term, due to tolerance to its effects.
Opiorphin is a very recently discovered substance that increases the effectiveness of endorphins, meaning that it has effects similar to opioid agonists without the addiction and withdrawal effects. While it has been shown to be extremely effective for analgesia, any ability to treat depression or the presence of an abuse potential are largely informed guesswork at this stage.
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- Pharmacological treatment of Mood Disorder
- A brief history of depression - 1950s
- Treating depression - Antidepressant drugs
- Creation of New Neurons Critical to Antidepressant Action in Mice
- Do Antidepressants Cure or Create Abnormal Brain States? - Article by Joanna Moncrieff and David Cohen in PLoS Medicine.
- NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
- NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
- American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder
- Children and Medication - a multimodal presentation
- British Association for Psychopharmacology 2000 Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants
- The Good Drug Guide: new mood-brighteners and antidepressants
- Review of "The Anti-depressant Solution" by Joseph Glenmullen
- Video of Loren Mosher, M.D. (first Chief of Schizophrenia Studies at NIMH and founding editor of the Schizophrenia Bulletin) discussing the difficulties in giving true informed consent regarding the SSRI's and his belief that there is a link between school shooters, suicide, and the SSRI's
- The Antidepressant Web von Charles Medawar
- Joanna Moncrieff: Evidence base for older antidepressants is shaky too. BMJ 2005;330:420 (19 February)
- Introduction to Let Them Eat Prozac by David Healy
- An information leaflet from the Royal College of Psychiatrists
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