Antidepressant

Review studies

Recent clinical reviews include:

• A comparison of the relative efficacy of different classes of antidepressants^[60] in different settings^[61] and in regard to different kinds of depression^[62]
• An assessment of antidepressants compared with an "active placebo"^[63]
• An assessment of the newer types of the MAOI class^[64]
• A meta-analysis of randomized trials of St John's Wort^[65]
• A review of the use of antidepressants for childhood depression^[66][67]

Clinical guidelines

The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder [15] 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. [16]

Efficacy limitations and strategies

Between 30% and 50% of individuals treated with a given antidepressant do not show a response.^[68][69] 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.^[70] In addition, antidepressant drugs tend to lose efficacy over the course of treatment^[71] A number of strategies are used in clinical practice to try to overcome these limits and variations.^[72]

"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.^[69]

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, NRI's, glucocorticoid-specific agents, or the newer anticonvulsants^[73]

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.^[74]

Long-term use

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.^[75] 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.^[76][77]

Medication failure

Approximately 30% of patients have remission of depression with medications.^[78] For patients with inadequate response, either adding sustained-release bupropion (initially 200 mg per day then increase by 100 mg up to total of 400 mg per day) or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients,^[79] while switching medications can achieve remission in about 25% of patients.^[80]

By pregnancy

There is uncertainty whether pregnancy contributes to medication failure, because the only report so far has drawn much controversy on itself:

In 2006, a widely reported study published in the Journal of the American Medical Association (JAMA) challenged the common assumption that hormonal changes during pregnancy protected expectant mothers against depression, finding that discontinuing anti-depressive medication during pregnancy led to more frequent relapse.^[81] The JAMA article did not disclose that several authors had financial ties to pharmaceutical companies making antidepressants. The JAMA later published a correction noting the ties^[82] and the authors maintain 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.^[83]

Tolerance and dependence

Most antidepressants, including the SSRIs and tricyclics, are known to produce tolerance (i.e. a decrease in the effects of a drug over time), 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.^{[citation needed]}

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.^{[citation needed]}

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 was not 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 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. Serotonin 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.Serotonin syndrome is a side effect of MAOIs and SSRIs when they are combined.

General

Although recent drugs may have fewer side effects, patients sometimes report severe side effects associated with their discontinuation, particularly with paroxetine and venlafaxine^{[citation needed]}. 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.[17] SSRIs are the antidepressants most frequently associated with this side effect.

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.

On September 6, 2007, the Centers for Disease Control and Prevention reported suicide rate in American adolescents (especially girls, 10 to 24 years old) increased 8% (2003 to 2004), the largest jump in 15 years.^[84] Specifically, in 2004 - 4,599 suicides in Americans ages 10 to 24, up from 4,232 in 2003, for a rate of 7.32 per 100,000 people that age. Before, the rate dropped to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990. The findings also reinforced the fact that antidepressant drugs reduce suicide risk. Psychiatrists found that the increase is due to the decline in prescriptions of antidepressant drugs like Prozac to young people since 2003, leaving more cases of serious depression untreated. In a December 2006 study, The American Journal of Psychiatry said that a decrease in antidepressant prescriptions to minors of just a few percentage points coincided with a 14 percent increase in suicides in the United States; in the Netherlands, the suicide rate was 50% up, upon prescription drop.^[85] The critics of this study contend that the US "2004 suicide figures were compared simplistically with the previous year, rather than examining the change in trends over several years".^[86] 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."^[87][88] Subsequest follow-up studies have supported the hypothesis that antidepressant drugs reduce suicide risk.^{[89] [90]} However, the conclusion that societal suicide rate decreases are due to antidepressant prescription is extraordinarily dubious given the plethora of confounding variables.

Sexual

Sexual dysfunction is a very common side effect, especially with SSRIs. Common sexual side effects include problems with libido (sexual desire), lack of interest in sex, and anorgasmia (trouble achieving orgasm). [18] 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.

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 are liable to cause this effect to varying degrees, especially at higher dosages.

REM Sleep

It is well recognized that virtually all major antidepressant drugs but trimipramine 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.[19] 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. 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 in all categories are associated with weight gain usually in the range of 10-50 pounds but not uncommonly upwards of 100 pounds. The specific cause is unknown, but it is known that antidepressants are associated with increased cravings (usually for high fat carbohydrates), an inability to feel full despite ingestion of adequate 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. 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, thus support weight loss in the setting of antidepressant weight gain.^[91][92]

Controversy

Several studies have stimulated doubt about the effectiveness of antidepressants. A 2002 study cited that the difference between antidepressants and placebo is close to negligible.^[93]

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 leveled at the serotonin hypothesis of depression.

Furthermore, not all patients necessarily respond to a given medication, studies do not always address dosage versus drug-placebo differences for those who do. Data submitted to the FDA can also underestimate how a drug will perform in clinic practice, as studies sometimes are designed as much for marketing purposes as they are to estimate the magnitude of a medication's effects.^[94]

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.[20]

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.^{[citation needed]}

Dr Joseph Glenmullen, a Harvard psychiatrist, has written a book on the subject for the layperson; see link below.

In 2007, anti-depressants became the most prescribed drug in the United States, causing more debate over the issue. Some doctors believe this is a positive sign that people are finally seeking help for their issues. Others disagree, saying that this shows that people are becoming too dependent on anti-depressants. [21]

Lawsuits

In many cases SSRI drug manufacturers have withheld information from the FDA and the public to play down the risks and adverse effects associated with SSRIs. This had led to litigation against many of the pharmaceutical manufacturers of SSRI anti-depressants in cases covering suicidality, SSRI withdrawal and birth defects in neonates from nursing mothers on SSRIs.

In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly 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".^[95]

On December 22, 2006, a US court decided in Hoorman, et al. v. SmithKline Beecham Corp. that individuals who purchased Paxil(R) or Paxil CR(TM) (paroxetine) for a minor child may be eligible for benefits under a $63.8 million Proposed Settlement. The lawsuit won the claim that pharmaceutical maker GlaxoSmithKline (GSK) promoted Paxil(R) or Paxil CR(TM) for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors.^[96]

The lawsuit stemmed from a consumer advocate protest against Paroxetine manufacturer GSK. Since the FDA approved paroxetine in 1992, approximately 5,000 U.S. citizens – and thousands more worldwide – have sued GSK. Most of these people feel they were not sufficiently warned in advance of the drug's side effects and addictive properties.

According to the Paxil Protest website, hundreds more lawsuits have been filed against GSK.^[97] The Paxil Protest website was launched August 8, 2005 to offer both information about the protest and information on Paxil previously unavailable to the public. Just three weeks after its launch, the site received more than a quarter of a million hits.

The original Paxil Protest website is no longer available. It is understood that the action to remove the site from the internet was undertaken as part of a confidentiality agreement or 'gagging order' which the owner of the site entered into as part of a settlement of his action against GlaxoSmithKline. (However, in March 2007, the website Seroxat Secrets [22]discovered that an archive of Paxil Protest site [23]was still available on the internet via Archive.org) Gagging orders are common in such cases and can extend to documents that defendants wish to remain hidden from the public. However, in some cases, such documents can become public at a later date, such as those made public by Peter Breggin in February 2006. A press release from Dr. Breggin can be seen here: [24]

In January 2007, according to the Seroxat Secrets website, [25], the national group litigation in the United Kingdom, on behalf of several hundred people who allege withdrawal reactions through their use of the drug Seroxat, against GlaxoSmithKline plc, moved a step closer to the High Court in London, with the confirmation that Public Funding had been reinstated following a decision by the Public Interest Appeal Panel. The issue at the heart of this particular action claims Seroxat is a defective drug in that it has a propensity to cause a withdrawal reaction. Hugh James Solicitors confirm this news on their website [26]

On January 29, 2007, the BBC in the UK aired a fourth documentary in its 'Panorama' [27] series about the controversial drug Seroxat. This programme, entitled Secrets of the Drug Trials, focuses on three GSK paediatric clinical trials on depressed children and adolescents. The documentary claims Seroxat could not be proven to work for teenagers, and that one clinical trial indicated they were six times more likely to become suicidal after taking it.^{[citation needed]}

Non-mainstream treatments

There are numerous alternative treatments for depression, whether medications or other kinds of intervention.

Opiates

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, 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[28], 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 (κ) antagonists are antidepressants in their own right.

In 2006, The Journal of European Neuropsychopharmacology published a follow-up study to the 1995 Harvard experiment, with results very consistent with the original Harvard findings. Eleven severely depressed patients, refractory to all the conventional depression treatments, were given small doses of buprenorphine. Most of these patients found the buprenorphine to be of significant benefit in relieving their inner torment. The researchers theorized that "Possibly, the response to opiates describes a special subtype of depressive disorders e.g corresponding to a dysregulation of the endogenous opioid system and not of the monaminergic system." [29]

Yet another relevant scientific paper was published in the American Journal of Psychiatry in 1999, detailing how researchers found Oxycodone/Oxymorphone to help 5 out of 6 'incurable' refractory severe depression patients. [30]

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.

Other treatments

• 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.[31] 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, specifically Electroacupuncture 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.^[98] Acupuncture has also been proven to prompt the body to produce greater levels of endorphins.^[99]
• 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.^[100]
• The amino acid derivative SAM-e has been studied in recent years^[101][102]
• Tryptophan dietary supplements, although banned in many countries due to impurities that caused a blood disease, have also been used as natural antidepressants.^{[citation needed]} 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.^[103]
• 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.

Classes and members

The following clickable info-box is from the Anatomical Therapeutic Chemical Classification System published by the World Health Organization. See also Wikipedia's list of antidepressants.

See also

• Antidepressants in Japan
• Depression and natural therapies

References

Additional reading

• David Healy, The Antidepressant Era, Paperback Reprint Edition, Harvard University Press (1999) ISBN 0674039580
• Peter D. Kramer, Listening to Prozac: The Landmark Book about Anti-Depressants and the Remaking of the Self, Paperback Revised Edition, Penguin (1997) ISBN 0140266712
• Syd Baumel, Natural Antidepressants, Paperback 1st edition, McGraw-Hill (1999) ISBN 0879839007
• Stephen M. Stahl, Psychopharmacology of Antidepressants, Paperback 1st Edition, Taylor & Francis (1997) ISBN 1853175137
• Pacher P, Kecskemeti V. Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem. 2004 Apr;11(7):925-43. PMID 15078174
• Pacher P, Kohegyi E, Kecskemeti V, Furst S. Current trends in the development of new antidepressants.Curr Med Chem. 2001 Feb;8(2):89-100. PMID 11172668