Antidepressants act on the flow of the neurotransmitters epinephrine, serotonin, and norepinephrine across neural synapses. Common antidepressants include monamine oxidase inhibitors (MAOIs) such as isocarboxazid (Marplan), tricyclics such as imipramine (Tofranil) and amitriptyline (Elavil), and the newer selective serotonin reuptake inhibitors (SSRIs) as fluoxetine (Prozac) and sertraline HCL (Zoloft). Venlafaxine (Effexor) inhibits both serotonin and norepinephrine reuptake.
The choice of antidepressant often has more to do with its side effects (variously sedation, constipation, hypotension, tachycardia, weight gain, sexual dysfunction) than efficacy, as they are generally regarded to be equally effective. The newer drugs, especially SSRIs, are tolerated better and are currently by far the most widely prescribed, but SSRIs also appear to be less effective in children and teenagers and may cause some of them to become suicidal.
An antidepressant is a psychiatric medication used for alleviating major depression or dysthymia ('milder' depression). Drug groups known as MAOIs, tricyclics, and second-generation antidepressants such as SSRIs are particularly associated with the term. These medications are now amongst the drugs most commonly prescribed by psychiatrists and other physicians, and their effectiveness and adverse effects are the subject of many studies and competing claims.
Most antidepressants have a delayed onset of action and are usually taken over the course of weeks, months, or sometimes years. They are generally considered distinct from stimulants, and 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, obsessive compulsive disorder, eating disorders, and chronic pain. Some have also become known as lifestyle drugs or "mood brighteners".
Other medications that are not usually called antidepressants, including antipsychotics in low doses and benzodiazepines, may also be used to manage depression, though in the case of "Benzos", there is a serious risk of physical dependence. An extract of the herb St John's Wort is commonly used as an antidepressant, labeled as a dietary supplement in some countries. The term antidepressant 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.
Various opiates were commonly used as antidepressants until the mid-1950s, when they fell out of favor due to their addictive nature, tolerance buildup issues and their side-effect profile. Extracts from the herb St John's Wort have long been used (as a "nerve tonic") to alleviate depression.
Another anti-tuberculosis drug tried at the same time by Selikoff and Robitzek, iproniazid, was observed to have a greater "psychostimulant" effect, albeit at the cost of a greater toxicity. Subsequently to the publications on isoniazid, papers by Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd describing the psychiatric applications of iproniazid also appeared, and Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor. Nevertheless, iproniazid had remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began its popularization both in medical and popular press as a "psychic energizer". While isoniazid was not patentable, Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression. Its sales grew massively in the following years, until it was recalled from the market in 1961 due to the cases of lethal hepatotoxicity.
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.
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 (Prozac), FDA approved for commercial use in 1988, became the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly in the early 1970s by Bryan Molloy, 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 (OTC) or supplement in most countries and research continued to investigate its neurotransmitter effects and active components, particularly hyperforin
This family of drugs includes fluoxetine (Prozac), paroxetine (Paxil, Seroxat), escitalopram (Lexapro, Esipram), citalopram (Celexa), and sertraline (Zoloft). These antidepressants typically have fewer adverse events and side effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, and decreased ability to function sexually may occur. Some side effects may decrease as a person adjusts to the drug, but other side effects may be persistent. Though safer than first generation antidepressants, SSRIs may not work on as many patients as previous classes of antidepressants, suggesting the role of norepinephrine in depression is still important.
Recently, work by two researchers has called into question the link between serotonin deficiency and symptoms of depression, noting that the efficacy of SSRIs as treatment does not in itself prove the link. Recent research indicates that these drugs 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.
Recent randomized controlled trials published in the Archives of General Psychiatry showed that up to one-third of the effect of SSRI Treatment can be seen in the first week. These early effects have also been shown to have a secondary effect of increasing the absolute reduction in HRSD scores by 50%. Even more recent studies, published in the Archives of General Psychiatry, found that 25% of so-called clinical depression does not meet the disease criteria for the disease and could be considered to be ordinary sadness and adjustment to the difficulties in life.
Tranquillizers and sedatives, typically the benzodiazepines, may be prescribed to ease anxiety and promote sleep. Because of their high potential for fostering dependence, these medications are intended only for short-term or occasional use. Medications often are used not for their primary function but to exploit what are normally side effects. Quetiapine fumarate (Seroquel) is designed primarily to treat schizophrenia and bipolar disorder, but a frequently reported side-effect is somnolence. Therefore, this drug can be used in place of an antianxiety agent such as clonazepam (Klonopin, Rivotril).
Antipsychotics such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) are prescribed as mood stabilizers and are also effective in treating anxiety. Their use as mood stabilizers is a recent phenomenon and is controversial with some patients. Antipsychotics (typical or atypical) may also be prescribed in an attempt to augment an antidepressant, to make antidepressant blood concentration higher, or to relieve psychotic or paranoid symptoms often accompanying clinical depression. However, they may have serious side effects, particularly at high dosages, which may include blurred vision, muscle spasms, restlessness, tardive dyskinesia, and weight gain.
Psycho-stimulants are sometimes added to an antidepressant regimen if the patient suffers from anhedonia, hypersomnia and/or excessive eating as well as low motivation. These symptoms which are common in atypical depression can be quickly resolved with the addition of low to moderate dosages of amphetamine or methylphenidate (brand names Adderall and Ritalin, respectively) as these chemicals enhance motivation and social behavior, as well as suppress appetite and sleep. These chemicals are also known to restore sex drive. Extreme caution must be used however with certain populations. Stimulants are known to trigger manic episodes in people suffering from bipolar disorder. Close supervision of those with substance abuse disorders is urged. Emotionally labile patients should avoid stimulants, as they exacerbate mood shifting.
Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications, depending on whether mania or depression is being treated. Lithium's potential side effects include thirst, tremors, light-headedness, and nausea or diarrhea. Some of the anticonvulsants, such as carbamazepine (Tegretol), sodium valproate (Epilim), and lamotrigine (Lamictal), are also used as mood stabilizers, particularly in bipolar disorder.
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). A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.
The most commonly prescribed antidepressants in the US retail market in 2006 were:
The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) hypericum perforatum (St John's Wort). In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine.
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 affect the expression of genes in brain cells, by influencing "clock genes".
Other research suggests that delayed onset of clinical effects from antidepressants indicates involvement of adaptive changes in antidepressant effects. Rodent studies have consistently shown upregulation of the 3, 5-cyclic adenosine monophosphate (cAMP) system induced by different types of chronic but not acute antidepressant treatment including serotonin and norepinephrine uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and electroconvulsions. cAMP is synthesized from adenosine 5-triphosphate (ATP) by adenylyl cyclase and metabolized by cyclic nucleotide phosphodiesterases (PDEs). Data also suggest antidepressants to have the ability of modulating neural plasticity in longterm administration.
One theory regarding the cause of depression is that it is characterized by an overactive hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.
Studies also show that the chronic secretion of stress hormones as a result of disease, including somatic infections or autoimmune syndromes may reduce the effect of neurotransmitters or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones. SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.
Antidepressants, specifically TCAs and dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.
These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy. Future antidepressants may be made to specifically target the immune system by either blocking the actions of pro-inflammatory cytokines or increasing the production of anti-inflammatory cytokines.
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.
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.
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.
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.
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. 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 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.
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 rare cases, an antidepressant can induce a switch from depression to mania or hypomania.
Side effects of SSRIs: Nausea, diarrhea, agitation, 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 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 when combined with certain medications.
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.
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. 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. 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". 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. However, the conclusion that societal suicide rate decreases are due to antidepressant prescription is extraordinarily dubious given the plethora of confounding variables.
SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression. Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5HT2 and 5HT3 receptors; decreased dopamine; blockade of cholingeric and alpha-1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.
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). Mirtazapine (Remeron) is also reported to have less sexual side effects, most likely due to is antagonisation of 5-HT2 and 5-HT3 receptors.
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.
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.
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, Effexor and Serzone.
Dr Joseph Glenmullen, a Harvard psychiatrist, has written a book on the subject for the layperson; see link below.
In 2005, 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.
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".
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.
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. 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 Secretsdiscovered that an archive of Paxil Protest sitewas 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:
In January 2007, according to the Seroxat Secrets website,, 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
On January 29, 2007, the BBC in the UK aired a fourth documentary in its 'Panorama' 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.
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.
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.
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.