Antidepressant

Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes (2005) people with a depressive illness will experience a therapeutic effect to their mood; however, this will not be experienced in healthy individuals. Drugs including the monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants(TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) are most commonly associated with the term. These medications are among those most commonly prescribed by psychiatrists and other physicians, and their effectiveness and adverse effects are the subject of many studies and competing claims. Most typical antidepressants have a delayed onset of action (2–6 weeks) and are usually administered for anywhere from months to years. Despite the name, antidepressants are often used to treat other conditions, such as anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, and some hormone-mediated disorders such as dysmenorrhea. Some of these uses are FDA-approved and some are off-label. Alone or together with anticonvulsants (e.g., carbamazepine or valproate), these medications can be used to treat attention-deficit hyperactivity disorder (ADHD) andsubstance abuse by addressing underlying depression. Also, antidepressants have been used sometimes to treat snoring and migraines. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription is a risk, despite claims of superior efficacy. Opioids were used to treat major depression until the late 1950s. Amphetamines were used until the mid 1960s. Prescribing opioids or amphetamines for depression falls into a legal grey area. Research has only rarely been conducted into the therapeutic potential of opioid derivatives for depression in the past sixty years, whereas amphetamines have found a thriving market for conditions as widely arrayed as attention deficit disorder, narcolepsy, and obesity, and continue to be studied for myriad applications. Both opioids and amphetamines induce a therapeutic response very quickly, showing results within twenty-four to forty-eight hours; the therapeutic ratios for both opioids and amphetamines are greater than those of the tricyclic anti-depressants. In a small study published in 1995, the opioid buprenorphine was shown to have potential for treating severe, treatment-resistant depression.[1] Other medications that are not usually called antidepressants, including antipsychotics in low doses[2] and benzodiazepines,[3] may be used to manage depression, although the use of benzodiazepines can cause a physical dependence. Stopping benzodiazepine treatment abruptly can cause unpleasant withdrawal symptoms. An extract of the herb St John's Wort is commonly used as an antidepressant especially in Europe, although it is labeled as a dietary supplement in some countries. The term antidepressant is sometimes applied to any therapy (e.g., psychotherapy, electroconvulsive therapy, acupuncture) or process (e.g., sleep disruption, increased light levels, regular exercise) found to improve a clinically depressed mood. Inert placebos can have significant antidepressant effects, and so to establish a substance as an "antidepressant" in a clinical trial it is necessary to show superior efficacy to placebo.[4][5] A review of both published and unpublished trials submitted to the U.S. Food and Drug Administration (FDA) found that the published trials had

a 94% success in treating depression while the unpublished literature had below 50% success.[5][6] Combined, 51% of all studies showed efficacy.[6] The difference in effect between active placebosand several anti-depressants appeared small and strongly affected by publication bias.[5][6] There is some evidence to suggest that mirtazapine and venlafaxine may have greater efficacy than other antidepressants in the treatment of severe depression.[7] ]Types Main article: List of antidepressants

]Selective serotonin reuptake inhibitors
The Selective serotonin reuptake inhibitors (SSRIs) are the class of antidepressants commonly used as the first line treatment for depression because they have a favorable side-effect profile and low toxicity. Depression can be treated by increasing the amount of available serotonin, a chemical used in the brain to transmit signals between neurons. SSRIs are said to work by preventing the reuptake of serotonin (also known as 5-hydroxytryptamine, or 5HT) by the presynaptic neuron, thus maintaining higher levels of 5-HT in the synapse. Chemists Klaus Schmiegel and Bryan Molloy of Eli Lilly discovered the first SSRI, fluoxetine. This class of drugs includes: Citalopram (Celexa, Cipramil) Escitalopram (Lexapro, Cipralex, Seroplex, Lexamil) Fluoxetine (Prozac, Sarafem, Symbyax) Fluvoxamine (Luvox) Paroxetine (Paxil, Aropax) Sertraline (Zoloft) Vilazodone (Viibryd) These antidepressants typically have fewer adverse effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, long-term weight gain 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. 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.[8] Research indicates that these drugs may interact with transcription factors known as "clock genes",[9] which may play a role in the addictive properties of drugs (drug abuse), and possibly in obesity.[10][11] A systematic review of randomized controlled trials published in the Archives of General Psychiatry showed that up to one-third of the 6-week effect of SSRI Treatment can be seen in the first week. The same study also found that patients treated with SSRIs were 64% more likely to achieve a 50% absolute reduction in HRSD than patients given a placebo.[12] [edit]Serotonin-norepinephrine reuptake inhibitors Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a newer form of antidepressant that work on both norepinephrine and 5HT. They typically have similar side-effects to the SSRIs, though there may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering. These include: Desvenlafaxine (Pristiq) Duloxetine (Cymbalta) Milnacipran (Ixel) Venlafaxine (Effexor) The mechanism of these types of antidepressants involves affecting the neurotransmitters that are used to communicate between brain cells; they interfere with re-uptake process of the specific chemical messengers.[13] Re-uptake is the process by which a terminal button retrieves the molecules of transmitter substance that it has just released; terminates the effect of the

transmitter substance on the receptors of the postsynaptic neuron.[14] Inhibition of the re-uptake process would prolong the effects of the neurotransmitter on the postsynaptic neuron. Changing the balance of serotonin and norepinephrine would help the brain cells send and receive messages; therefore boosting the mood. That also is the main reason why these types of medications are called dual re-uptake inhibitors. Antidepressants have the possibility of making one person less prone to harm other people around him/her. When a hypothetical dilemma was given to 24 people and according to the dilemma they had the capability of pushing a stranger in front of a train so that they could rescue five people, individuals who had taken selective serotonin reuptake inhibitors were not so likely to support the idea of pushing the person. (Proc. Natl. Acad. Sci. USA 107, 17433-17438, 2010).[15] There are some general side effects with the use of SNRIs which includes: Nausea Dry Mouth Dizziness Insomnia (numbness) Sleepiness Constipation Increased Blood Pressure Excessive Sweating Tremor Headache Agitation Muscle Weakness [edit]Noradrenergic and specific serotonergic antidepressants Noradrenergic and specific serotonergic antidepressants (NaSSAs) form a newer class of antidepressants which purportedly work to increase norepinephrine (noradrenaline) and serotonin neurotransmission by blocking presynaptic alpha-2 adrenergic receptors while at the same time blocking certain serotonin receptors.[16] Side-effects may include drowsiness, increased appetite, and weight gain.[17] Examples include: Mianserin (Tolvon) Mirtazapine (Remeron, Avanza, Zispin) [edit]Norepinephrine (noradrenaline) reuptake inhibitors Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) act via norepinephrine (also known as noradrenaline). NRIs are thought to have a positive effect on the concentration and motivation in particular. These include: Atomoxetine (Strattera) Mazindol (Mazanor, Sanorex) Reboxetine (Edronax) Viloxazine (Vivalan) [edit]Norepinephrine-dopamine reuptake inhibitors Norepinephrine-dopamine reuptake inhibitors inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline).[18] These include: Bupropion (Wellbutrin, Zyban) [edit]Selective serotonin reuptake enhancers Tianeptine (Stablon, Coaxil, Tatinol) Amineptine [edit]Norepinephrine-dopamine disinhibitors Norepinephrine-dopamine disinhibitors (NDDIs) act by antagonizing the serotonin 5-HT2C receptor, which normally acts to inhibit norepinephrine and dopamine release, thereby promoting outflow of these neurotransmitters. Agomelatine (Valdoxan, Melitor, Thymanax) [edit]Tricyclic antidepressants Tricyclic antidepressants are the second oldest class of antidepressant drugs. Tricyclics block the reuptake of certain

neurotransmitters such as norepinephrine (noradrenaline) and serotonin. They are used less commonly now due to the development of more selective and safer drugs. Side-effects include increased heart rate, drowsiness, dry mouth, constipation, urinary retention, blurred vision, dizziness, confusion, and sexual dysfunction. Toxicity occurs at approximately ten times normal dosages; these drugs are often lethal in overdoses, as they may cause a fatal arrhythmia. However, tricyclic antidepressants are still used because of their effectiveness, especially in severe cases of major depression. As well, people who cannot tolerate the side-effects of SSRIs, in particular agitation, may do better on tricyclics. The tricyclics include: Tertiary amine tricyclic antidepressants: Amitriptyline (Elavil, Endep) Clomipramine (Anafranil) Doxepin (Adapin, Sinequan) Imipramine (Tofranil) Trimipramine (Surmontil) Secondary amine tricyclic antidepressants Desipramine (Norpramin) Nortriptyline (Pamelor, Aventyl, Noritren) Protriptyline (Vivactil)

[Monoamine oxidase inhibitor
Irreversible monoamine oxidase inhibitors (MAOIs) may be used if other antidepressant medications are ineffective. MAOIs work by blocking the enzyme monoamine oxidase, which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). As there are potentially fatal interactions between this class of medication and certain foods (particularly those containing tyramine), as well as certain drugs, classic MAOIs are rarely prescribed anymore. However, this does not apply to Emsam, the transdermal patch form of selegiline, which due to its bypassing of the stomach has a lesser propensity to induce such events.[19] MAOIs can be as effective as tricyclic antidepressants, although they are generally used less frequently because they have a higher incidence of dangerous side-effects and interactions. A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), which is as effective as SSRIs and tricyclic antidepressants, in depressive disorders,[20] acts in a more short-lived and selective manner and does not require a special diet. The MAOI group of medicines include: Isocarboxazid (Marplan) Moclobemide (Aurorix, Manerix) Phenelzine (Nardil) Selegiline (Eldepryl, Emsam) Tranylcypromine (Parnate) [edit]Nicotine Nicotine is believed to act as an antidepressant,[21] via it stimulating the release of Dopamine and Norepinephrine; additionally nicotine is believed to exert an antidepressant effect due to the desensitisation of nicotinic receptors which occurs as a result of tolerance.[22] Clinical trials have demonstrated that nicotine (administered via a nicotine containing patch) exerts an antidepressant effect in both depressed non-smokers as well as smokers and can be considered for treatment resistant depression. The proposed mechanism of chronic nicotine causing desensitisation of nicotinic receptors thereby leading to an antidepressant effect is consistent with the theory first proposed over 30 years ago and subsequent research that confirmed that excessive acetylcholine activity in the brain lead to depressive symptoms. Varenicline, a nicotinic receptor acting drug used to wean people off of nicotine dependence has also demonstrated antidepressant properties.[23] [edit]Augmenter drugs

Psychostimulants, such as amphetamine (Adderall), methylphenidate (Ritalin) or modafinil (Provigil, Alertec), are sometimes added to an antidepressant regimen.[24] Modafinil is unique in its effect on sleep: it increases alertness and reduces drowsiness while the patient is active, but does not inhibit normal sleep. 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. A review article published in 2007 found that psychostimulants "may" be effective in treatment-resistant depression with concomitant antidepressant therapy. A more certain conclusion could not be drawn due to substantial deficiencies in the studies available for consideration, and the "somewhat" contradictory nature of their results. However, the authors claim that psychostimulants are likely to have a higher level of clinical effectiveness under circumstances in which the patient will probably die soon, so rapid relief is of great importance. In this situation, the patient is likely to die before dependence on, or tolerance of the medication interferes with their care.[25] There is also evidence that chronic nicotine intake via nicotine patches, results in an increased response to standard antidepressants. Similarly varenicline has been shown to augment subtherapeutic dose levels of SSRIs to produce an antidepressant effect.[23] 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, nausea, and 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. Both lithium and lamotrigine have also been studied and used to augment antidepressants in treatment-resistant unipolar depression.[citation needed] [Cannabinoids Phyto and synthetic cannabinoids have long been known to act as as antidepressants and anxiolytics by acting as an agonist at the CB1 receptor. In fact the CB1 antagonist, Rimonabant, was withdrawn from the market for treating obesity (by supressing appetite) because it was found to have potent depressant effects on patients. ]Alternative therapies ]Herbalism St. John's Wort is by far the most widely-used and well-studied herbal antidepressant. A number of other herbs have been used traditionally to treat depression and related ailments like anxiety, but the research on most of these treatments is sparse.[ In a small (30 patient) double-blind randomized clinical trial, saffron (Crocus sativus L.) was to be equally effective with imipramine for treating mild to moderate depression. However, no other researchers have confirmed these results, nor has a larger population study been published.[26] Another small (40 patient) 8-week double-blind randomized trial found saffron to have a similar effect to fluoxetine (Prozac) in the treatment of mild to moderate depression, including a similar remission rate and similar rate of side-effects.[27] Neither study has been confirmed in larger trials at other centers. Several plants in the Salvia genus have been studied for antidepressant properties, although most of the research conducted so far has only been from mice and rat studies. Salvia elegans, also known as pineapple sage, is widely used in Mexican traditional medicine, and has been found in single study in mice to have antidepressant and antianxiety properties.[28] Salvia sclarea,

also known as clary, is known to have an antidepressant-like effect in rats, which is thought to be explained by modulation of dopamine.[29] [Nutrition Nutrition has been proposed as one of the causes and risk factors for depression, and accordingly, one approach to depression involves the use of nutritional supplements or changes in diet. A study of older adults found that poor nutrition was a strong predictor of depressive symptoms a year later.[30] A few nutrients have been studied directly for their antidepressant properties, both to treat and prevent depression, as well as related conditions such as anxiety. Omega 3 fatty acids have been proposed as a treatment for depression, often suggested to be combined with other treatments. One small pilot study of childhood depression (ages 6–12) suggested that omega 3 may have therapeutic benefits for treating childhood depression.[31] A 2005 review of the scientific literature concluded that there were several different independent lines of evidence suggesting that omega-3 fatty acids play a role in depression, and that the theory of omega-3's role in depression was biologically plausible. The evidence includes a few double-blind randomized control trials, epidemiological studies linking low fish consumption (the primary source of omega-3) to increased rates of depression, and case-control and cohort studies of unipolar and postpartum depression indicating low blood levels of omega-3 in depressed patients.[32] A recent review of clinical studies of the effect of omega 3 fatty acids on depression has shown somewhat inconsistent results: "Of the evaluated studies, 13 showed a significant positive association between omega-3 and depression, while six studies did not show a relationship between the referred variables."[33] To be read with caution because of limited data, a 2008 Cochrane systematic review found in the one eligible study that omega-3s are an effective adjunctive therapy for depressed but not manic symptoms in bipolar disorder. The authors found an "acute need" for more randomised controlled trials.[34] Therapeutic efficacy 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.[citation needed] A sufficient response to a drug is often defined as at least a 50% reduction in self-reported or observed symptoms, with apartial response often defined as at least a 25% reduction.[citation needed] 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.[citation needed] There has also been a great deal of study about whether antidepressants address the underlying causes of depression. A 2002 review concluded that there was no evidence that antidepressants reduce the risk of recurrence of depression when their use is terminated. The authors of this review advocated that antidepressants be combined with therapy, and pointed to Interpersonal Psychotherapy (IPT) and Cognitive Behavioral Therapy (CBT).[35] [Review studies Recent clinical reviews include: A comparison of the relative efficacy of different classes of antidepressants[36] in different settings[37] and in regard to different kinds of depression[38] An assessment of antidepressants compared with an "active placebo"[39] An assessment of the newer types of the MAOI class[40] A meta-analysis of randomized trials of St John's Wort[41]

A review of the use of antidepressants for childhood depression[42][43] A review of all antidepressant trials submitted to the U.S. FDA of 12 anti-depressants, published and unpublished, from 1987 to 2004 was submitted to the FDA in 2004.[6] In the published literature, anti-depressants had 94% success in treating depression.[6] In the withheld literature, they had below 50% success.[6] Combined, all studies showed 51% efficacy[6] - only two points better than that of placebo. This increased the apparent efficacy of different anti-depressants from between 11% to 69% over placebo.[6] A meta-analysis by UK, US and Canadian researchers, published in 2008, surveyed all pharmaceutical-company-sponsored drug trials on the six most widely prescribed new-generation antidepressants submitted for approval to the FDA between 1987 and 1999. The results showed, consistent with a prior metaanalysis, that the difference in efficacy between antidepressants and placebo was minimal, but that it increased from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression. The difference reached conventional criteria for clinical significance for patients at the upper end of the very severely depressed category, due to a reduction in the efficacy of placebo.[44] The study received widespread media coverage in some countries, but was met with criticism from the professional community.[45] Eli Lilly and Company responded by highlighting that the study did not take into account more recent studies on its product, Prozac, and that it was proud of the difference Prozac has made to millions of people. GlaxoSmithKline warned that this one study should not be used to cause unnecessary alarm and concern for patients. Wyeth pointed out that the data were good enough for FDA approval of the drugs.[46] Two leading UK psychiatrists/pharmacologists, with financial and professional links to pharmaceutical companies, argued that short-term approval trials are not very suitable for evaluating effectiveness, that the unpublished ones are poorer quality, that the metaanalysis authors came from a "psychology background" rather than drug testing background, and that the media and "elements of the medico/scientific community" have "a down on antidepressants" and that the media does not appreciate the seriousness of depression and blames and stigmatizes sufferers in a manner rooted in medieval religious attitudes.[47] A May 7, 2002 article in The Washington Post titled "Against Depression, a Sugar Pill Is Hard to Beat" stated, "A new analysis has found that in the majority of trials conducted by drug companies in recent decades, sugar pills have done as well as—or better than—antidepressants. Companies have had to conduct numerous trials to get two that show a positive result, which is the Food and Drug Administration's minimum for approval. What's more, the sugar pills, or placebos, cause profound changes in the same areas of the brain affected by the medicines, according to research published last week... the makers of Prozac had to run five trials to obtain two that were positive, and the makers of Paxil and Zoloft had to run even more... When Leuchter compared the brain changes in patients on placebos, he was amazed to find that many of them had changes in the same parts of the brain that are thought to control important facets of mood... Once the trial was over and the patients who had been given placebos were told as much, they quickly deteriorated. People's belief in the power of antidepressants may explain why they do well on placebos..." [48] ]Clinical guidelines The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder [49] 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.[50] ]Efficacy limitations and strategies Between 30% and 50% of individuals treated with a given antidepressant do not show a response.[51][52] 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.[53] In addition, antidepressant drugs tend to lose efficacy over the course of treatment.[54] A number of strategies are used in clinical practice to try to overcome these limits and variations.[55] [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 2006 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.[52] However, a later meta-analysis found no difference between switching to a new drug and staying on the old medication; although 34% of treatment resistant patients responded when switched to the new drug, 40% responded without being switched.[56] Thus, the clinical response to the new drug might be a placebo effect associated with the belief that one is receiving a different medication. [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[57] 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.[58] []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.[59] 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.[60][61] [Medication failure Approximately 30% of patients have remission of depression with medications.[62] For patients with inadequate response, adding either 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,[63] while switching medications can achieve remission in about 25% of patients.[64] ]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.[65] 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[66] 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.[67] The use of antidepressants during pregnancy is associated with an increased risk of spontaneous abortion.[68] [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.[69] 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 psychologist Irving Kirsch, lead author of the study. He and co-author Thomas Moore released their findings in "Prevention and Treatment", an e-journal of the American Psychological Association.[70] Another study by psychologists at the University of Pennsylvania, Vanderbilt University, the University of Colorado, and the University of New Mexico also found that antidepressant drugs hardly have better effects than a placebo in those cases of mild or moderate depression. The study was published in the Journal of the American Medical Association. The study focused on paroxetine(Paxil) from GlaxoSmithKline and imipramine.[71]

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.[72] Other notable psychiatrists and authors remain skeptical not only about the efficacy of anti-depressants or their overuse but also about the very principle of prescribing a mind-altering medications to treat something that cannot be objectively proven to be a biological disorder resulting from a chemical imbalance, yet is often presumed to be so. Professor of Psychiatry Thomas Szasz argues mental illness is a social phenomenon rather than a biological disease entity.[73] Harvard-trained psychiatrist Peter Breggin [74] argues that "[anti-depressants] 'work' by causing mental disabilities such as apathy and euphoria that are misinterpreted as improvements" [75][76] Cambridge-educated Bob Johnson, GP, Psychiatrist and author, argues that all psychiatric medications are emotionally damaging both due to the physical effects of the drugs and because they detract from addressing the root cause of depression, which is to be found, he argues, in the form of unaddressed fears - a product of mind and consciousness, rather than a biological imbalance; and a problem that he argues is more effectively treated by psychological or social interventions than by drug treatment.[77] Meanwhile Joanna Moncrieff, an academic psychiatrist, argues more pragmatically against the effectiveness of anti-depressants in her book 'The Myth of the Chemical Cure.' [78] In his book, 'The Emperor's New Drugs,' psychologist Irving Kirsch argues that the small benefit of antidepressants over placebo might itself be an "enhanced" placebo effect, brought about because patients in clinical trials are able to figure out whether they have been given the drug or the placebo on the basis of side-effects.[79] Robert Whitaker, an award-winning journalist, argues in his books, including 'Mad in America,' and 'Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America,' which have been highly critical of the profession of psychiatry, that large quantities of evidence about the harm caused by psychotropic drugs including anti-depressants is overlooked and evidence regarding antidepressant efficacy is overstated.[80] These voices critical of the use of anti-depressants are in a minority among psychiatric professionals who generally advocate use of medications according to the evidence base evolved from numerous large drug trials. Some critics, however, argue these drugs trials are subject to bias.[81] More broadly anti-psychiatry and anti-medication perspectives are commonly found in the lay press and especially on the World Wide Web.[82] Adverse effects Antidepressants often cause adverse effects, and difficulty tolerating these is the most common reason for discontinuing an effective medication. Side-effects of SSRIs include: nausea, diarrhea, agitation, headaches. Sexual sideeffects are also common with SSRIs, such as loss of sexual drive, failure to reach orgasm and erectile dysfunction.[5] Serotonin syndrome is also a worrying condition associated with the use of SSRIs. The Food and Drug Administration requires Black Box warnings on all SSRIs, which state that they double suicidal rates (from 2 in 1,000 to 4 in 1,000) in children and adolescents,[5][83] although it's controversial whether this is due to the medication or as part of the depression itself (i.e. efficacious antidepressant effect can cause those that are severely depressed, to the point of severe psychomotor inhibition, are rendered more alert and thus have increased capacity to carry out suicide even though they are relatively improved in state[5][84]). The increased risk for suicidality and suicidal behaviour among

adults under 25 approaches that seen in children and adolescents.[85] Moclobemide may be preferred in the elderly as its pharmacokinetics are not affected by age, is well tolerated by the elderly as well as younger adults, has few serious adverse events, and, in addition, it is as effective as other antidepressants that have more side-effects; moclobemide also has beneficial effects on cognition.[86] 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 sideeffects of MAOIs like phenelzine (Nardil) and tranylcypromine (Parnate) include hepatitis, heart attack, stroke, and seizures. Serotonin syndrome is a side-effect of MAOIs when combined with certain medications. [edit]General MAO inhibitors can produce a potentially lethal hypertensive reaction if taken with foods that contain excessively high levels of tyramine, such as mature cheese, cured meats or yeast extracts. Likewise, lethal reactions to both prescription and over the counter medications have occurred. Patients undergoing therapy with MAO inhibiting medications are monitored closely by their prescribing physicians, who are consulted before taking an over the counter or prescribed medication. Such patients must also inform emergency room personnel and keep information with their identification indicating that they are on MAO inhibitors. Some doctors suggest the use of medical identification tags. Although these reactions may be lethal, the total number of deaths due to interactions and dietary concerns is comparable to over-the-counter medications. Antidepressants are used with care, usually in conjunction with mood stabilisers, in the treatment of bipolar disorder, as they can exacerbate symptoms of mania. They can also trigger mania orhypomania in some patients with bipolar disorder and in a small percentage of patients with depression.[87] SSRIs are the antidepressants most frequently associated with this side-effect. Breast cancer survivors risk having their disease come back if they use certain antidepressants while also taking the cancer prevention drug tamoxifen, according to research released in May 2009.[88] Anti-depressants are not psychologically addictive in most people, One should never attempt to discontinue psychiatric medication without the knowledge and supervision of a medical practitioner.[89] [edit]Suicide Patients with depression are at greatest risk for suicide immediately after treatment has begun, as antidepressants can reduce the symptoms of depression such as psychomotor retardation or lack of motivation before mood starts to improve.[citation needed] Although this appears paradoxical, studies[which?] indicate that suicidal ideation is a relatively common[weasel words] at the start of antidepressant therapy, and it may be especially common in younger patients such as preadolescents and teenagers. Manufacturers and physicians often recommend that other family members and loved ones monitor the young patient's behavior for any signs of suicidal ideation or behaviors, especially in the first eight weeks of therapy. Until the black box warnings on these drugs were issued by FDA and equivalent 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.[original research?] 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.[5] Federal health officials unveiledproposed changes to the labels on antidepressant drugs in December 2006 to warn people of this danger. The FDA states that Paxil should be avoided in children and teens and that in cases of pediatric cases of depressive disorder the antidepressant drug to be used is Prozac.[90] On September 6, 2007, the Centers for Disease Control and Prevention reported that the suicide rate in American adolescents, (especially girls, 10 to 24 years old), increased 8% (2003 to 2004), the largest jump in 15 years,[91] to 4,599 suicides in Americans ages 10 to 24 in 2004, from 4,232 in 2003, giving a suicide rate of 7.32 per 100,000 people that age. The rate previously dropped to 6.78 per 100,000 in 2003 from 9.48 per 100,000 in 1990. Psychiatrists[who?] 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. A December 2006 study found that a decrease in antidepressant prescriptions to minors of just a few percentage points coincided with a 14% increase in suicides in the United States; in the Netherlands, the suicide rate was 50% up after a fall in antidepressant prescriptions.[92] Jon Jureidini, a critic of this study, says that the US "2004 suicide figures were compared simplistically with the previous year, rather than examining the change in trends over several years".[93]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."[94][95] Subsequest follow-up studies have supported the hypothesis that antidepressant drugs reduce suicide risk.[96][97] However, the conclusion that societal suicide rate decreases are due to antidepressant prescription is unsupported given the plethora of confounding variables.[original
research?]

Another study was taken the overall rate of suicidal acts was 27 per 1000 person-years, and most events occurred within 6 months of medication initiation. According to this study, no commonly used antidepressant medication has an advantage in regard to suicide-related safety. It remains a question as to whether other therapeutic maneuvers, such as ongoing counseling, provide a protective counter-effect to children's and adolescents' antidepressant-associated risk of suicidal thoughts or behaviour.[98] [Sexual Sexual dysfunction is a very common side-effect, especially with SSRIs. Common sexual side-effects include problems with sexual desire, lack of interest in sex, and anorgasmia (trouble achieving orgasm).[5][99] Although usually reversible, these sexual side-effects can, in rare cases, last for months or years after the drug has been completely withdrawn. This is known as Post SSRI Sexual Dysfunction.

SSRI-induced sexual dysfunction affects 30% to 50% or more of individuals who take these drugs for depression.[citation needed] Biochemical mechanisms suggested as causative include increased serotonin, particularly affecting 5-HT2 and 5HT3 receptors; decreased dopamine; decreased norepinephrine; blockade of cholinergic and α1 adrenergic receptors; inhibition of nitric oxide synthetase; and elevation of prolactin levels.[100] Bupropion, a dual reuptake inhibitor (NE and DA), often causes a moderate increase in sexual drive, due to increased dopamine activity. This effect is also seen with dopamine reuptake inhibitors, CNS stimulants and dopamine agonists, and is due to increases in testosterone production (due to inhibition of prolactin) and nitric oxide synthesis. Mirtazapine (Remeron) is reported to have fewer sexual side-effects, most likely because it antagonizes 5-HT2 and 5-HT3 receptors. Mirtazapine can in some cases reverse sexual dysfunction induced by SSRIs, which is also likely due to its antagonisation of 5-HT2 and 5HT3 receptors [101] Moclobemide, a selective reversible MAO-A inhibitor does not cause sexual dysfunction,[102] and can actually lead to an improvement in all aspects of sexual function.[103] ]Love Dr. Helen Fisher, an anthropologist from Rutgers University, has hypothesized that SSRIs may alter the perception of some emotions related to love such as desire and arousal. A psychological study showed a small effect to back up this hypothesis but the study has not been reproduced and no clinical evidence exists to lend support to this hypothesis. [104] ]Thymoanesthesia Closely related to sexual side-effects is the phenomenon of emotional blunting, or mood anesthesia. Many users of SSRIs complain of apathy, lack of motivation, emotional numbness, feelings of detachment, and indifference to surroundings. They may describe this as a feeling of "not caring about anything anymore." All SSRIs, SNRIs, and serotonergic TCAs can cause this to varying degrees, especially at high doses.[105] []REM Sleep All major antidepressant drugs, except trimipramine, mirtazapine and nefazodone suppress REM sleep, and it has been proposed that the clinical efficacy of these drugs largely derives from their suppressant effects on REM sleep. The three major classes of antidepressant drugs, monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), profoundly suppress REM sleep.[106] Mirtazapine either has no effect on REM sleep or increases it slightly.[107] The MAOIs almost completely suppress REM sleep, while the TCAs and SSRIs have been shown to produce immediate (40-85%) and sustained (30-50%) reductions in REM sleep. This effect often causes increased fatigue in patients who take large doses of antidepressants for extended periods of time. Such fatigue can occasionally interfere with a patient's everyday activities. Abrupt discontinuation of MAOIs can cause a temporary phenomenon known as "REM rebound" in which the patient experiences extremely vivid dreams and nightmares. []Weight gain Many antidepressants (TCA, TecA, paroxetine from the group of SSRI's) are associated with weight gain usually in the range of 5– 25 kg (11–55 lb) but rarely upwards of 50 kg (110 lb). The specific cause is unknown, but antidepressants are associated with increased cravings, an inability to feel full despite consuming enough calories, low energy levels and increased daytime sleepiness, which can lead to overeating and a lack of desire to exercise, and dry mouth, which can lead to ingestion of calorieladen beverages. The antihistaminic properties of certain TCA and TeCA class antidepressants have been shown to contribute to the common side-effects of increased appetite and weight gain associated with these classes of medication. Eating low fat, low

protein carbohydrate snacks and carbohydrate-rich dinners allows the brain to make serotonin, which then controls appetite and balances mood. Carbohydrates thus eaten, as part of a balanced diet, by virtue of their effect on brain serotonin levels, can support weight loss in the setting of antidepressant weight gain.[108][109] [edit]Withdrawal symptoms 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 depending on a person's response to reductions. Most cases of discontinuation syndrome last between one and four weeks.[citation needed] 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.[citation needed] In rare cases, an antidepressant can induce a switch from depression to mania or hypomania.[citation
needed]

[Mechanisms of action The therapeutic effects of antidepressants are believed to be caused by their effects on neurotransmitters and neurotransmission. The Monoamine Hypothesis is a biological theory stating that depression is caused by the underactivity in the brain of monoamines, such as dopamine, serotonin, and norepinephrine. In the 1950s the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were accidentally discovered to be effective in the treatment of depression. These findings and other supporting evidence led Joseph Schildkraut to publish his paper called "The Catecholamine Hypothesis of Affective Disorders" in 1965. Schildkraut associated low levels of neurotransmitters with depression. Research into other mental impairments such as schizophrenia also found that too little activity of certain neurotransmitters were connected to these disorders. The hypothesis has been a major focus of research in the fields pathophysiology and pharmacotherapy for over 25 years. Monoamine oxidase inhibitors (MAOIs) block the degradation of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine by inhibiting the enzyme monoamine oxidase, leading to increased concentrations of these neurotransmitters in the brain and an increase in neurotransmission. Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and to a much less extent, dopamine. Nowadays the most common antidepressants are selective serotonin reuptake inhibitors (SSRIs), which prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants affect norepinephrine reuptake, or different receptors on the nerve cell. While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2A receptors, suggesting it is too simplistic to say serotonin is a happy hormone. In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-

HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance. The stimulation or blocking of different receptors on a cell affects its genetic expression. Recent findings have shown that neurogenesis, and thus, changes in brain morphogenesis, mediate the effects of antidepressant drugs.[110] 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.[111][112] Other animal research suggests that antidepressants can affect the expression of genes in brain cells, by influencing "clock genes". [113] 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).[114] Data also suggest that antidepressants can modulate neural plasticity in long-term administration.[115] 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 (cortisol) response tostress. These HPA axis abnormalities participate in the development of depressive symptoms, and antidepressants serve to regulate HPA axis function.[116] Aimee Hunter and her team discovered that the brain has been somewhat conditioned to produce effects resulting from antidepressants, proven by the use of a placebo.[117] Even when the placebo was distributed to those who have never ingested any antidepressants in their lives have shown a brain response like that of previous users.[117] This shows that by just "remembering" what the drugs look like will induce the antidepressant response.[117] []Comparison A number of antidepressants have been compared below:[118][119][120][121] The values above are expressed as equilibrium dissociation constants. It should be noted that smaller dissociation constant indicates more efficacy. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors. [edit]Anti-inflammatory and immunomodulation Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system.[122][123][124][125][126] 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.[125] SSRIs, SNRIs and tricyclic antidepressants acti ng on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation ofInterferon-gamma (IFN-gamma) and Interleukin10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.[127][128][129][130][131] Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties.[132][133] These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psychoneuroimmunological approach may be required for optimalpharmacotherapy.[134] 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.[135] [edit]History

St John's Wort Various opiates (via the µ-opioid receptor and κ-opioid receptor) and amphetamines were commonly used as antidepressants until the mid-1950s, when they fell out of favor due to their addictive nature and side-effects.[136] Extracts from the herb St John's Wort have long been used (as a "nerve tonic") to alleviate depression.[137] ]Isoniazid and iproniazid In 1951, two people from Sea View Hospital on Staten Island, Irving Selikoff and Edward Robitzek, began clinical trials on two new anti-tuberculosisagents from HoffmanLaRoche, isoniazid and iproniazid. Only patients with a poor prognosis were initially treated; nevertheless, their condition improved dramatically. Selikoff and Robitzek noted "a subtle general stimulation . . . the patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."[138] The promise of a cure for tuberculosis in the Sea View Hospital trials was excitedly discussed in the mainstream press. In 1952, learning of the stimulating side-effects of isoniazid, the Cincinnati psychiatrist Max Lurie tried it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved depression in two thirds of their patients and coined the term antidepressant to describe its action.[139] A similar incident took place in Paris, where Jean Delay, head of psychiatry at Sainte-Anne Hospital, found out from his pulmonology colleagues at Cochin Hospital about the sideeffects of isoniazid. In 1952, before Lurie and Salzer, Delay, with the resident Jean-Francois Buisson, reported the positive effect of isoniazid on depressed patients.[140] For reasons unrelated to its efficacy, isoniazid as an antidepressant was soon overshadowed by the more toxic iproniazid,[139] although it remains a mainstay of tuberculosis treatment. The mode of antidepressant action of isoniazid is still unclear. It is speculated that its effect is due to the inhibition of diamine oxidase, coupled with a weak inhibition of monoamine oxidase A.[141] Another anti-tuberculosis drug tried at the same time by Selikoff and Robitzek, iproniazid, showed a greater "psychostimulant" effect, but more pronounced toxicity.[142] After the publications on isoniazid, papers by Jackson Smith, Gordon Kamman, George Crane, and Frank Ayd appeared, describing the psychiatric applications of iproniazid. Ernst Zeller found iproniazid to be a potentmonoamine oxidase inhibitor.[143] Nevertheless, iproniazid remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began to popularize it in the medical and popular press as a "psychic energizer".[143][144] Roche put a significant marketing effort behind

iproniazid, including promoting its off-label use for depression.[143]Its sales grew massively in the following years, until it was recalled from the market in 1961 due to cases of lethal hepatotoxicity.[143] [t]Imipramine The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was first made in 1957 by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistaminederivatives were increasingly used to treat surgical shock and then as psychiatric neuroleptics. Although in 1955 reserpine was shown to be more effective than placebo in alleviating anxious depression, neuroleptics (literally, "to seize the nerves" or "to take hold of nerves") were being developed as sedatives and antipsychotics. Attempting to improve the effectiveness of chlorpromazine, Kuhn, in conjunction with the Geigy pharmaceutical company, 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 accompanied by mental and motor retardation.[145] Kuhn first reported his findings on what he called a "thymoleptic" (literally, "taking hold of the emotions," in contrast with neuroleptics, "taking hold of the nerves") in 1955-56. These gradually became established, resulting in marketing of the first tricyclic antidepressant, imipramine, soon followed by variants. [Later history These new drug therapies became prescription drugs 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 (such as benzodiazepines), which were being marketed for different uses.[146] 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.[146][147] 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, while some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably proposed in 1969 by Carlsson and Lindqvist as well as Lapin and Oxenkrug). Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would selectively target these systems. The first such compound to be patented waszimelidine in 1971, while the first released clinically was indalpine. Fluoxetine was approved for commercial use by the Food and Drug Administration (United States) in 1988, becoming the firstblockbuster SSRI. Fluoxetine was developed at Eli Lilly and Company in the early 1970s by Bryan Molloy, David Wong and others.[148][149] While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John's Wort became increasingly popular in Germany, where Hypericum extracts were eventually licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out in the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these.[150] 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[151][152] SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various selective effects, such as venlafaxine, duloxetine, nefazodone andmirtazapine.[153]

Society and culture []Prescription trends In the United Kingdom, the use of antidepressants increased by 234% in the 10 years up to 2002.[154] In the United States a 2005 independent report stated that 11% of women and 5% of men in the non-institutionalized population (2002) take antidepressants[155] A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant.[156] A 2007 study suggested that 25% of Americans were overdiagnosed with depression, regardless of any medical intervention.[157] The findings were based on a national survey of 8,098 people. A 2002 survey found that about 3.5% of all people in France were being prescribed antidepressants, compared to 1.7% in 1992, often for conditions other than depression and often not in line with authorizations or guidelines[158] Between 1996 and 2004 in British Columbia, antidepressant use increased from 3.4% to 7.2% of the population.[159] Data from 1992 to 2001 from theNetherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of treatment.[160] 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.[161] Antidepressants are also increasingly used worldwide for non-depressive patients as studies continue to show the potential of immunomodulatory, analgesic and antiinflammatory 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.[162] 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).[163] A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.[164] The number of antidepressants prescribed by the NHS in the United Kingdom almost doubled during one decade, authorities reported in 2010. Furthermore the number highly increased in 2009 when 39.1 million prescriptions were issued compared with 20.1 million issued in 1999. Also, physicians issued 3.18 million more prescriptions in 2009 than in 2008. Health authorities believed the increase was partly linked to the recession. However, other reasons include a diagnosis improvement, a reduction of the stigma on mental ill-health, and more distress caused by the economic crisis. Furthermore, physicians concern is that some people who exhibit milder symptoms of depression are being prescribed drugs unnecessarily due to the lack of other options including talking therapies, counseling and cognitive behavior therapy. One more factor that may be increasing the consumption of antidepressants is the fact that these medications now are used for other conditions including social anxiety and post traumatic stress.[165] The use of antidepressants in the United States doubled over one decade, from 1996 to 2005. Antidepressant drugs were prescribed to 13 million in 1996 and to 27 million people by 2005. In 2008, more than 164 million prescriptions were written. During this period, patients were less likely to undergo psychotherapy.[166] [edit]Most commonly prescribed

Structural formula of the SSRIescitalopram, in its free base form.

United States: The most commonly prescribed antidepressants in he US retail market in 2010[167] were: Germany: The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) Hypericum perforatum (St John's Wort).[168] Netherlands: In the Netherlands, paroxetine, marketed as Seroxat among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline,citalopram and venlafaxine.[169] [edit]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 antidepressants 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 and Company was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire with an assault rifle killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The jury returned a 9-to-3 verdict in favor of Lilly. The judge, in the end, took the matter to the Kentucky Supreme Court, which found that "there was a serious lack of candor with the trial court and there may have been deception, bad faith conduct, abuse of judicial process and, perhaps even fraud." The judge later revoked the verdict and instead, recorded the case as settled. The value of the secret settlement deal has never been disclosed, but was reportedly "tremendous".[170] On December 22, 2006, a US court decided in Hoorman, et al. v. SmithKline Beecham Corp. that individuals who purchased Paxil or Paxil CR (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 or Paxil CR for prescription to children and adolescents while withholding and concealing material information about the medication's safety and effectiveness for minors.[171] 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.[citation needed] 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[172] discovered that an archive of Paxil Protest site[173] 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:[174] In January 2007, according to the Seroxat Secrets website,[175] the national group litigation in the United Kingdom, on behalf of several hundred people who allege withdrawal reactions after 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[176] On January 29, 2007, the BBC in the UK aired a fourth documentary in its 'Panorama'[177] 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. [edit]See also Antidepressants in Japan Depression and natural therapies

An antipsychotic (or neuroleptic) is
a tranquilizing psychiatric medication primarily used to manage psychosis (including delusions or hallucinations, as well as disordered thought), particularly in schizophrenia and bipolar disorder, and is increasingly being used in the management of non-psychotic disorders (ATC code N05A). A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, known as atypical antipsychotics, have been developed more recently, although the first atypical antipsychotic, clozapine, was discovered in the 1950s and introduced clinically in the 1970s. Both generations of medication tend to block receptors in the brain's dopamine pathways, but antipsychotic drugs encompass a wide range of receptor targets. A number of harmful and undesired (adverse) effects have been observed, including lowered life expectancy, extrapyramidal effects on motor control – including akathisia (an inability to sit still), trembling, and muscle weakness – weight gain, decrease in brain volume (although this is being debated, since schizophrenia, which is often treated with antipsychotics, also causes a shrinkage of brain volume[citation needed] ), enlarged breasts (gynecomastia) in men and milk discharge in men and women (galactorrhea due to hyperprolactinaemia), lowered white blood cell count (agranulocytosis), involuntary repetitive body movements (tardive dyskinesia), diabetes, sexual dysfunction, a return of psychosis requiring increasing the dosage due to cells producing more neurochemicals to compensate for the drugs (tardive psychosis), and a potential for permanent chemical dependence leading to psychosis worse than before treatment began, if the drug dosage is ever lowered or stopped (tardive dysphrenia).[2] Most of these side-effects disappear rapidly once the medication is discontinued or reduced, but others, particularly tardive dyskinesia, may be irreversible. Temporary withdrawal symptoms including insomnia, agitation, psychosis, and motor disorders may occur during dosage reduction of antipsychotics, and can be mistaken for a return of the underlying condition.[3][4] The development of new antipsychotics with fewer of these adverse effects and with greater relative effectiveness as compared to existing antipsychotics (efficacy), is an ongoing field of research. Sometimes, however, patients are switched back to typical antipsychotics because the newer ones are less effective in those patients.[citation needed] ]History The original antipsychotic drugs were happened upon largely by chance and then tested for their effectiveness. The first, chlorpromazine, was developed as a surgical anesthetic. It was first used on psychiatric patients because of its powerful calming effect; at the time it was regarded as a non-permanent "pharmacological lobotomy".[5] Lobotomy at the time was used to

treat many behavioral disorders, including psychosis, although its effect was to markedly reduce behavior and mental functioning of all types. However, chlorpromazine proved to reduce the effects of psychosis in a more effective and specific manner than lobotomy, even though it was known to be capable of causing severe sedation. The underlying neurochemistry involved has since been studied in detail, and subsequent antipsychotic drugs have been discovered by an approach that incorporates this sort of information. The discovery of chlorpromazine's psychoactive effects in 1952 led to greatly reduced use of restraint, seclusion, and sedation in the management of agitated patients,[5] and also led to further research that resulted in the development of antidepressants, anxiolytics, and the majority of other drugs now used in the management of psychiatric conditions. In 1952, Henri Laborit described chlorpromazine only as inducing indifference towards what was happening around them in nonpsychotic, nonmanic patients, and Jean Delay and Pierre Deniker described it as controlling manic or psychotic agitation. The former claimed to have discovered a treatment for agitation in anyone, and the latter team claimed to have discovered a treatment for psychotic illness.[6] Until the 1970s there was considerable debate within psychiatry on the most appropriate term to use to describe the new drugs.[7] In the late 1950s the most widely used term was "neuroleptic", followed by "major tranquilizer" and then "ataraxic".[7] The first recorded use of the term tranquilizer dates from the early nineteenth century.[8] In 1953 Frederik F. Yonkman, a chemist at the Swiss based Ciba pharmaceutical company, first used the term tranquilizer to differentiate reserpine from the older sedatives.[9] The word neuroleptic was derived from the Greek: "νεῦρον"(neuron, originally meaning "sinew" but today referring to the nerves) and "λαμβάνω" (lambanō, meaning "take hold of"). Thus, the word means taking hold of one's nerves. This may refer to common side effects such as reduced activity in general, as well as lethargy and impaired motor control. Although these effects are unpleasant and in some cases harmful, they were at one time, along with akathisia, considered a reliable sign that the drug was working.[5] The term "ataraxy" was coined by the neurologist Howard Fabing and the classicist Alister Cameron to describe the observed effect of psychic indifference and detachment in patients treated with chlorpromazine.[10] This term derived from the Greek adjective Greek: "ἀτάρακτος" (ataraktos) which means "not disturbed, not excited, without confusion, steady, calm".[7] In the use of the terms "tranquilizer" and "ataractic", medical practitioners distinguished between the "major tranquilizers" or "major ataractics", which referred to drugs used to treat psychoses, and the "minor tranquilizers" or "minor ataractics", which referred to drugs used to treat neuroses.[7] While popular during the 1950s, these terms are infrequently used today. They are being abandoned in favor of "antipsychotic", which refers to the drug's desired effects.[7] Today, "minor tranquilizer" can refer toanxiolytic and/or hypnotic drugs such as the benzodiazepines and nonbenzodiazepines which have some antipsychotic properties and are recommended for concurrent use with antipsychotics, and are useful for insomnia or druginduced psychosis.[11] They are powerful (and potentially addictive) sedatives. Antipsychotics are broadly divided into two groups, the typical or first-generation antipsychotics and the atypical or secondgeneration antipsychotics. The typical antipsychotics are classified according to their chemical structure while the atypical antipsychotics are classified according to their pharmacological properties. These include serotonin-dopamine antagonists (see dopamine antagonist and serotonin antagonist), multi-acting

receptor-targeted antipsychotics (MARTA, those targeting several systems), and dopamine partial agonists, which are often categorized as atypicals.[12] Antipsychotic drugs are now the top-selling class of pharmaceuticals in America, generating annual revenue of about $14.6 billion.[13] [edit]Medical uses Common conditions with which antipsychotics might be used include schizophrenia, bipolar disorder and delusional disorder. Antipsychotics might also be used to counter psychosis associated with a wide range of other diagnoses, such as psychotic depression. However, not all symptoms require heavy medication and hallucinations and delusions should only be treated if they distress the patient or produce dangerous behaviors.[14] In addition, "antipsychotics" are increasingly used to treat nonpsychotic disorders. For example, they are sometimes used offlabel to manage aspects of Tourette syndrome or autism spectrum disorders. They have multiple off-label uses as an augmentation agent (i.e. in addition to another medication), for example in "treatment-resistant" depression[15] or OCD.[16] Despite the name, the off-label use of "antipsychotics" is said to involve deploying them as antidepressants, anti-anxiety drugs, mood stabilizers, cognitive enhancers, anti-aggressive, anti-impulsive, anti-suicidal and hypnotic (sleep) medications.[17] Antipsychotics have also been increasingly used off-label in cases of dementia in older people, and for various disorders and difficulties in children and teenagers. A survey of children withpervasive developmental disorder found that 16.5% were taking an antipsychotic drug, most commonly to alleviate mood and behavioral disturbances characterized by irritability, aggression, and agitation. Recently, risperidone was approved by the US FDA for the treatment of irritability in children and adolescents with autism.[18] Antipsychotics are sometimes used as part of compulsory treatment via inpatient (hospital) commitment or outpatient commitment. This may involve various methods to persuade a person to take the medication, or actual physical force. Administration may rely on an injectable form of the drug rather than tablets. The injection could be of a long-lasting type known as a depot injection, usually applied at the top of the buttocks every 2–4 weeks. Those that are available in pills only are clozapine, olanzapine, and ziprasidone, and other recently discovered atypicals, while those available as depot (as well as pills) are haloperidol, fluphenazine and other phenothiazines, thioxanthenes such as flupenthixol and clopenthixol, and the atypical risperidone.[verification needed] Antipsychotics are among the biggest selling and most profitable of all drugs, generating $22 billion in global sales in 2008.[19] By 2003 in the US, an estimated 3.21 million patients received antipsychotics, worth an estimated $2.82 billion. Over 2/3 of prescriptions were for the newer more expensive atypicals, each costing on average $164 compared to $40 for the older types.[20] By 2008, sales in the US reached $14.6 billion, the biggest selling drugs in the US by therapeutic class.[21] The number of prescriptions for children and adolescents doubled to 4.4 million between 2003 and 2006, in part because of increases in diagnoses of bipolar disorder.[citation needed] Due to the chronic nature of the treated disorders, antipsychotic medications, once started, are seldom discontinued, and the aim of the treatment is often to gradually reduce dosage to a minimum safe maintenance dose that is enough to control the symptoms. Only when the side-effects have become too severe and/or a patient has been symptom-free for a long period of time is discontinuation carefully attempted. Improper discontinuation or abrupt restarting of neuroleptics have been shown to cause

dysfunction in regions of the brainstem as well as dysfunction of theautonomic nervous system. [edit]Side effects Antipsychotics are associated with a range of side effects. It is well-recognized that many people stop taking them (around twothirds even in controlled drug trials) due in part to adverse effects.[22] Extrapyramidal reactions include acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, intense dreams or nightmares, and hyperprolactinaemia.[23] Side effects from antipsychotics can be managed by a number of different drugs. For example, anticholinergics are often used to alleviate the motor side effects of antipsychotics.[24] Some of the side-effects will appear after the drug has been used only for a long time. Some studies have found decreased life expectancy associated with the use of antipsychotics, and argued that more studies are needed.[25][26] In Feb. 2011, a minor loss of brain tissue was reported in schizophrenics treated with antipsychotics.[27][28] Brain volume was negatively correlated with both duration of illness and antipsychotic dosage. No association was found with severity of illness or abuse of other substances. An accompanying editorial said: "The findings should not be construed as an indication for discontinuing the use of antipsychotic medications as a treatment for schizophrenia. But they do highlight the need to closely monitor the benefits and adverse effects of these medications in individual patients, to prescribe the minimal amount needed to achieve the therapeutic goal [and] to consider the addition of nonpharmacological approaches that may improve outcomes."[27][29] Continuous use of neuroleptics has been shown to decrease the total brain volume by 10% in macaque monkeys.[30] In "healthy" individuals without psychosis, doses of antipsychotics can produce the so-called "negative symptoms" (e.g. emotional and motivational difficulties) associated with schizophrenia.[31] From a subjective perspective, antipsychotics heavily influence one's perceptions of pleasurable sensations, causing a severe reduction in feelings of desire, motivation, pensive thought, and awe. This does not coincide with the apathy and lack of motivation experienced by the negative symptoms of schizophrenia. Detrimental effects on short term memory, which affect the way one figures and calculates (although this also may be purely subjective), may also be observed on high enough dosages. These are all the reasons why they are thought to affect "creativity". Also, for some individuals with schizophrenia, too much stress may cause "relapse". Following are details concerning some of the side effects of antipsychotics: Antipsychotics, particularly atypicals, appear to cause diabetes mellitus and fatal diabetic ketoacidosis, especially (in US studies) in African Americans.[32][33] Antipsychotics may cause pancreatitis.[34] The atypical antipsychotics (especially olanzapine and clozapine) seem to (due to occupancy of the histamine receptor) cause weight gain more commonly than the typical antipsychotics. The well-documented metabolic side effects associated with weight gain include diabetes, which can be life-threatening.[35] Antipsychotics increase the likelihood of a fatal heart attack, with the risk of death increasing with dose and the length of time on the drug.[citation needed] Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is in no danger.[36]

One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements (that are permanent and have no cure) often of the lips, face, legs, or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder. A potentially serious side effect of many antipsychotics is that they tend to lower an individual's seizure threshold. Chlorpromazine and clozapine, in particular, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions such as epilepsy, or brain damage. Neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency, as the patient's temperature suddenly increases to dangerous levels. Dysphoria. Drug-induced parkinsonism due to dopamine D2 receptor blockade may mimic idiopathic parkinsonism. The typical antipsychotics are more prone to cause this, compared to the atypical antipsychotics. Sexual dysfunction, which may rarely continue after withdrawal, similar to Post-SSRI sexual dysfunction (PSSD). Dystonia, a neurological movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. Hyperprolactinaemia. The breasts may enlarge and discharge milk, in both men and women due to abnormally-high levels of prolactin in the blood. Prolactin secretion in the pituitary is normally suppressed by dopamine. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin. There is evidence that exposure may cause demyelinating disease in laboratory animals.[37] Following controversy over possible increased mortality (death) related to antipsychotics in individuals with dementia, warnings have been added to packaging.[38] Some people suffer few apparent side effects from taking antipsychotic medication, whereas others may have serious adverse effects.[vague] Some side effects, such as subtle cognitive problems, may go unnoticed. There is a possibility that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benzatropine, although this remains to be established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia. [edit]Withdrawal Withdrawal symptoms from antipsychotics may emerge during dosage reduction and discontinuation. Withdrawal symptoms can include nausea, emesis, anorexia, diarrhea, rhinorrhea,diaphoresi s, myalgia, paresthesia, anxiety, agitation, restlessness, and insomnia. The psychological withdrawal symptoms can include psychosis, and can be mistaken for a relapse of the underlying disorder. Conversely, the withdrawal syndrome may also be a trigger for relapse. Better management of the withdrawal syndrome may improve the ability of individuals to discontinue antipsychotics.[3][4] Tardive dyskinesia can emerge as a physical withdrawal symptom, and may either gradually abate during the withdrawal phase, or become persistent.[39] Withdrawal-related psychosis from antipsychotics is called "supersensitivity psychosis", and is attributed to increased number and sensitivity of brain dopamine receptors, due to blockade of dopaminergic receptors by the antipsychotics,[40] which often leads to exacerbated symptoms in

the absence of neuroleptic medication.[41] Efficacy of antipsychotics may likewise be reduced over time, due to this development of drug tolerance.[4] Withdrawal effects may also occur when switching a person from one antipsychotic to another, (presumably due to variations of potency and receptor activity). Such withdrawal effects can include cholinergic rebound, an activation syndrome, and motor syndromes including dyskinesias. These adverse effects are more likely during rapid changes between antipsychotic agents, so making a gradual change between antipsychotics minimises these withdrawal effects.[42] The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse.[43] [edit]Efficacy There have been a large number of studies of the efficacy of typical antipsychotics, and an increasing number on the more recent atypical antipsychotics. The American Psychiatric Association and the UK National Institute for Health and Clinical Excellence recommend antipsychotics for managing acute psychotic episodes in schizophrenia or bipolar disorder, and as a longer-term maintenance treatment for reducing the likelihood of further episodes.[44][45] They state that response to any given antipsychotic can be variable so that trials may be necessary, and that lower doses are to be preferred where possible. A number of studies have looked at levels of "compliance" or "adherence" with antipsychotic regimes and found that discontinuation (stopping taking them) by patients is associated with higher rates of relapse, including hospitalization. Nevertheless, a 2009 systematic review and meta-analysis of trials in people diagnosed with schizophrenia found that less than half (41%) showed any therapeutic response to an antipsychotic, compared to 24% on placebo, and that there was a decline in treatment response over time, and possibly a bias in which trial results were published.[46] In addition, a 2010 Cochrane Collaboration review of trials of Risperidone, one of the biggest selling antipsychotics and the first of the new generation to become available in generic form, found only marginal benefit compared with placebo and that, despite its widespread use, evidence remains limited, poorly reported and probably biased in favor of risperidone due to pharmaceutical company funding of trials.[47]Another Cochrane review in 2009, of bipolar disorder, found the efficacy and risk/benefit ratio better for the traditional mood stabilizer lithium than for the antipsychotic Olanzapine as a first line maintenance treatment.[48] Antipsychotic polypharmacy (prescribing two or more antipsychotics at the same time for an individual) is said to be a common practice but not necessarily evidence-based or recommended, and there have been initiatives to curtail it.[49] Similarly, the use of excessively high doses (often the result of polypharmacy) continues despite clinical guidelines and evidence indicating that it is usually no more effective but is usually more harmful.[50] A review by the US Agency for Healthcare Research and Quality found that much of the evidence for the off-label use of antipsychotics (for example, for depression, dementia, OCD, PTSD, Personality Disorders, Tourette's) was of insufficient scientific quality to support such use, especially as there was strong evidence of increased risks of stroke, tremors, significant weight gain, sedation, and gastrointestinal problems.[51] A UK review of unlicensed usage in children and adolescents reported a similar mixture of findings and concerns.[52] Aggressive challenging behavior in adults with intellectual disability is often treated with antipsychotic drugs despite lack of an evidence base. A recent randomized controlled trial, however,

found no benefit over placebo and recommended that the use of antipsychotics in this way should no longer be regarded as an acceptable routine treatment.[53] A 2006 Cochrane Collaboration review of controlled trials of antipsychotics in old age dementia reported that one or two of the drugs showed a modest benefit compared to placebo in managing aggression or psychosis, but that this was combined with a significant increase in serious adverse events. They concluded that this confirms that antipsychotics should not be used routinely to treat dementia patients with aggression or psychosis, but may be an option in the minority of cases where there is severe distress or risk of physical harm to others.[54] Some doubts have been raised about the long-term effectiveness of antipsychotics for schizophrenia, in part because two large international World Health Organization studies found individuals diagnosed with schizophrenia tend to have better long-term outcomes in developing countries (where there is lower availability and use of antipsychotics and mental health problems are treated with more informal, community-led methods only) than in developed countries.[55][56] Some argue that the evidence for antipsychotics from discontinuation-relapse studies may be flawed, because they do not take into account that antipsychotics may sensitize the brain and provoke psychosis if discontinued, which may then be wrongly interpreted as a relapse of the original condition.[57] Evidence from comparison studies indicates that at least some individuals with schizophrenia recover from psychosis without taking antipsychotics, and may do better in the long term than those that do take antipsychotics.[58] Some argue that, overall, the evidence suggests that antipsychotics only help if they are used selectively and are gradually withdrawn as soon as possible[59] and have referred to the "Myth of the antipsychotic".[60] A review of the methods used in trials of antipsychotics, despite stating that the overall quality is "rather good," reported issues with the selection of participants (including that in schizophrenia trials up to 90% of people who are generally suitable do not meet the elaborate inclusion and exclusion criteria, and that negative symptoms have not been properly assessed despite companies marketing the newer antipsychotics for these); issues with the design of trials (including pharmaceutical company funding of most of them, and inadequate experimental "blinding" so that trial participants could sometimes tell whether they were on placebo or not); and issues with the assessment of outcomes (including the use of a minimal reduction in scores to show "response," lack of assessment of quality of life or recovery, a high rate of discontinuation, selective highlighting of favorable results in the abstracts of publications, and poor reporting of sideeffects).[61]

[edit]Typicals versus atypicals
While the atypical (second-generation) antipsychotics were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and Extrapyramidal symptoms in particular) than typical medications, the results showing these effects often lacked robustness, and the assumption was increasingly challenged even as atypical prescriptions were soaring.[62]One review concluded there were no differences[12] while another[63] found that atypicals were "only moderately more efficacious".[12] These conclusions were, however, questioned by another review, which found that clozapine, amisulpride, and olanzapine and risperidone were more effective[12][64] Clozapine has appeared to be more effective than other atypical antipsychotics,[12][65]although it has previously been banned due to its potentially lethal side effects. While controlled clinical trials of atypicals reported that extrapyramidal

symptoms occurred in 5–15% of patients, a study of bipolar disorder in a real world clinical setting found a rate of 63%, questioning the generalizability of the trials.[66] In 2005 the US government body NIMH published the results of a major independent (not funded by the pharmaceutical companies) multi-site, double-blind study (the CATIE project).[67] This study compared several atypical antipsychotics to an older typical antipsychotic, perphenazine, among 1493 persons with schizophrenia. The study found that only olanzapine outperformed perphenazine in discontinuation rate (the rate at which people stopped taking it due to its effects). The authors noted an apparent superior efficacy of olanzapine to the other drugs in terms of reduction in psychopathology and rate of hospitalizations, but olanzapine was associated with relatively severe metabolic effects such as a major weight gain problem (averaging 44 pounds (20 kg) over 18 months) and increases in glucose, cholesterol, and triglycerides. The mean and maximal doses used for olanzapine were considerably higher than standard practice, and this has been postulated as a biasing factor that may explain olanzapine's superior efficacy over the other atypical antipsychotics studied, where doses were more in line with clinically relevant practices.[68] No other atypical studied (risperidone, quetiapine, and ziprasidone) did better than the typical perphenazine on the measures used, nor did they produce fewer adverse effects than the typical antipsychotic perphenazine (a result supported by a meta-analysis by Dr. Leucht published in Lancet), although more patients discontinued perphenazine owing to extrapyramidal effects compared to the atypical agents (8% vs. 2% to 4%, P=0.002). A phase 2 part of this CATIE study roughly replicated these findings.[69] This phase consisted of a second randomization of the patients that discontinued taking medication in the first phase. Olanzapine was again the only medication to stand out in the outcome measures, although the results did not always reach statistical significance (which means they were not reliable findings) due in part to the decrease of power. The atypicals again did not produce fewer extrapyramidal effects than perphenazine. A subsequent phase was conducted[70] that allowed clinicians to offerclozapine which was more effective at reducing medication drop-outs than other neuroleptic agents. However, the potential for clozapine to cause toxic side effects, including agranulocytosis, limits its usefulness. It had been hoped that patient adherence to antipsychotics would be higher with the atypicals, but a 2008 review found that the data have failed to substantiate the notion that novel antipsychotic drug use leads to improved medication compliance and favorable clinical outcomes.[71] Overall evaluations of the CATIE and other studies have led many researchers to question the first-line prescribing of atypicals over typicals, or even to question the distinction between the two classes.[72][73] In contrast, other researchers point to the significantly higher risk of tardive dyskinesia and EPS with the typicals and for this reason alone recommend first-line treatment with the atypicals, notwithstanding a greater propensity for metabolic adverse effects in the latter.[68][74] The UK government organization NICE recently revised its recommendation favoring atypicals, to advise that the choice should be an individual one based on the particular profiles of the individual drug and on the patient's preferences. The re-evaluation of the evidence has not necessarily slowed the bias towards prescribing the atypicals, however.[75] [edit]Common antipsychotics

Haloperidol.

Quetiapine. Commonly used antipsychotic medications are listed below by drug group. Trade names appear in parentheses.

First generation antipsychotics Main article: Typical antipsychotic
[edit] [edit]Butyrophenones Main article: Butyrophenones Haloperidol (Haldol, Serenace) Droperidol (Droleptan, Inapsine) [edit]Phenothiazines Main article: Phenothiazines Chlorpromazine (Thorazine, Largactil) Fluphenazine (Prolixin) - Available in decanoate (long-acting) form Perphenazine (Trilafon) Prochlorperazine (Compazine) Thioridazine (Mellaril) Trifluoperazine (Stelazine) Mesoridazine (Serentil) Periciazine Promazine Triflupromazine (Vesprin) Levomepromazine (Nozinan) Promethazine (Phenergan) Pimozide (Orap) Cyamemazine (Tercian) [edit]Thioxanthenes Main article: Thioxanthenes Chlorprothixene (Cloxan, Taractan, Truxal) Clopenthixol (Sordinol) Flupenthixol (Depixol, Fluanxol) Thiothixene (Navane) Zuclopenthixol (Cisordinol, Clopixol, Acuphase)

[edit]Second generation antipsychotics Main article: Atypical antipsychotic
Clozapine (Clozaril) - Requires weekly to biweekly complete blood count due to risk of agranulocytosis. Olanzapine (Zyprexa) - Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder Risperidone (Risperdal) -Divided dosing is recommended until initial titration is completed, at which time the drug can be administered once daily. Used off-label to treat Tourette syndromeand anxiety disorder. Quetiapine (Seroquel) - Used primarily to treat bipolar disorder and schizophrenia, and "off-label" to treat chronic insomnia and restless legs syndrome; it is a powerful sedative. Ziprasidone (Geodon) - Approved in 2004[76] to treat bipolar disorder. Side-effects include a prolonged QT interval in the heart, which can be dangerous for patients with heart disease or those taking other drugs that prolong the QT interval. Amisulpride (Solian) - Selective dopamine antagonist. Higher doses (greater than 400 mg) act upon post-synaptic dopamine receptors resulting in a reduction in the positive symptoms of schizophrenia, such as psychosis. Lower doses, however, act upon dopamine autoreceptors, resulting in increased dopamine transmission, improving the negative symptoms of schizophrenia. Lower doses of amisulpride have also been shown to have antidepressant and anxiolytic effects in non-schizophrenic

Chlorpromazine.

patients, leading to its use in dysthymia and social phobias. Amisulpride has not been approved for use by the Food and Drug Administration in the United States. Asenapine (Saphris) is a 5-HT2A- and D2-receptor antagonist under development for the treatment of schizophrenia and acute mania associated with bipolar disorder. Paliperidone (Invega) - Derivative of risperidone that was approved in 2006. Iloperidone (Fanapt) - Approved by the FDA on 6 May 2009. Zotepine (Nipolept, Losizopilon, Lodopin, Setous)- An atypical antipsychotic indicated for acute and chronic schizophrenia. It was approved in Japan circa 1982 and Germany in 1990. Sertindole (Serdolect, and Serlect in Mexico). Sertindole was developed by the Danish pharmaceutical company H. Lundbeck. Like the other atypical antipsychotics, it is believed to haveantagonist activity at dopamine and serotonin receptors in the brain. Lurasidone (Latuda), a recently FDA approved once daily antipsychotic with a favorable efficacy and safety profile. [edit]Third generation antipsychotics Aripiprazole (Abilify) - Mechanism of action is thought to reduce susceptibility to metabolic symptoms seen in some other atypical antipsychotics.[77] The extent to which these effects differ from other atypical antipsychotics is debated.[78] Partial agonists of dopamine. [edit]Other options Cannabidiol is one of the main components of Cannabis sativa. Cannabidiol differs from the active drug in cannabis, tetrahydrocannabinol, in that cannabidiol lacks the typical mind altering and recreational effects. One study has suggested that cannabidiol may be as effective as atypical antipsychotics in treating schizophrenia.[79] Some further research has supported these results, and found fewer side effects with cannabidiol than with amisulpride.[80][80] Tetrabenazine is similar in function to antipsychotic drugs, though is not, in general, considered an antipsychotic itself. Its main usefulness is the treatment of hyperkinetic movement disorders such as Huntington's disease and Tourette syndrome, rather than for conditions such as schizophrenia. Also, rather than having the potential to cause tardive dyskinesia, which most antipsychotics have, tetrabenazine can be an effective treatment for the condition. Metabotropic glutamate receptor 2 agonism has been seen as a promising strategy in the development of novel antipsychotics.[81][82][83] When tested in patients, the research substanceLY2140023 yielded promising results and had few side effects. The active metabolite of this prodrug targets the brain glutamate receptors mGluR2/3 rather than dopamine receptors.[84] Glycine transporter 1 inhibition. RG1678 has been shown in phase 2 clinical trials to be selectively effective for the negative symptoms of schizophrenia.[85] A placebo-controlled trial has suggested that adding L-theanine, an amino acid found in green tea and available as supplement, to ongoing antipsychotic medication may be helpful in reducing some symptoms of schizophrenia.[86] [edit]Mechanism of action All antipsychotic drugs tend to block D2 receptors in the dopamine pathways of the brain. This means that dopamine released in these pathways has less effect. Excess release of dopamine in the mesolimbic pathway has been linked to psychotic experiences. It is the blockade of dopamine receptors in this pathway that is thought to control psychotic experiences. Typical antipsychotics are not particularly selective and also block dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal

pathway. Blocking D2receptors in these other pathways is thought to produce some of the unwanted side effects that the typical antipsychotics can produce (see above). They were commonly classified on a spectrum of low potency to high potency, where potency referred to the ability of the drug to bind to dopamine receptors, and not to the effectiveness of the drug. High-potency antipsychotics such as haloperidol, in general, have doses of a few milligrams and cause less sleepiness and calming effects than lowpotency antipsychotics such as chlorpromazine and thioridazine, which have dosages of several hundred milligrams. The latter have a greater degree of anticholinergic and antihistaminergic activity, which can counteract dopamine-related side effects. Atypical antipsychotic drugs have a similar blocking effect on D2 receptors. Some also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors):ranging from risperidone, which acts overwhelmingly on serotonin receptors, to amisulpride, which has no serotonergic activity. The additional effects on serotonin receptors may be why some of them can benefit the "negative symptoms" of schizophrenia.[87] [edit]Structural effects Many studies now indicate that chronic treatment with antipsychotics affects the brain at a structural level, for example increasing the volume of the basal ganglia (especially the caudate nucleus), and reducing cortical grey matter volume in different brain areas. The effects may differ for typical versus atypical antipsychotics and may interact with different stages of disorders.[88][89] Death of neurons in the cerebral cortex, especially in women, has been linked to the use of both typical and atypical antipsychotics for individuals with Alzheimers.[90] Recent studies on macaque monkeys have found that administration of haloperidol or olanzapine for about two years led to a significant overall shrinkage in brain tissue,[91] in both gray and white matter across several brain areas, with lower glial cell counts,[92] due to a decrease in astrocytes and oligodendrocytes,[93] and increased neuronal density. It has been said that these studies require serious attention and that such effects were not clearly tested for by pharmaceutical companies prior to obtaining approval for placing the drugs on the market.[94] [edit]Controversy According to The Guardian newspaper: "At the heart of years of dissent against psychiatry through the ages has been its use of drugs, particularly antipsychotics, to treat distress. Do such drugs actually target any "psychiatric condition"? Or are they chemical control—a socially-useful reduction of the paranoid, deluded, distressed, bizarre and odd into semi-vegetative zombies?"[60] Use of this class of drugs has a history of criticism in residential care. As the drugs used can make patients calmer and more compliant, critics claim that the drugs can be overused. Outside doctors can feel under pressure from care home staff.[95] In an official review commissioned by UK government ministers it was reported that the needless use of anti-psychotic medication in dementia care was widespread and was linked to 1800 deaths per year.[96][97] In the US, the government has initiated legal action against the pharmaceutical company Johnson & Johnson for allegedly paying kickbacks to Omnicare to promote its antipsychotic Risperidone (Risperdal) in nursing homes.[98] There is some controversy over maintenance therapy for schizophrenia.[4][99] A review of studies about maintenance therapy concluded that long-term antipsychotic treatment was superior to placebo in reducing relapse in individuals with schizophrenia, although some of the studies were small.[100] A review of major longitudinal studies in North America found that a moderate number of patients with schizophrenia were seen to recover over time from their symptoms, raising the possibility that

some patients may not require maintenance medication.[99] It has also been argued that much of the research into long-term antipsychotic maintenance may be flawed due to failure to take into account the role of antipsychotic withdrawal effects on relapse rates.[4] There has also been controversy about the role of pharmaceutical companies in marketing and promoting antipsychotics, including allegations of downplaying or covering up adverse effects, expanding the number of conditions or illegally promoting off-label usage; influencing drug trials (or their publication) to try to show that the expensive and profitable newer atypicals were superior to the older cheaper typicals that were out of patent. Following charges of illegal marketing, settlements by two large pharmaceutical companies in the US set records for the largest criminal fines ever imposed on corporations.[13] One case involved Eli Lilly and Company's antipsychotic Zyprexa, and the other involved Bextra. In the Bextra case, the government also charged Pfizerwith illegally marketing another antipsychotic, Geodon.[13] In addition, Astrazeneca faces numerous personal-injury lawsuits from former users of Seroquel (quetiapine), amidst federal investigations of its marketing practices.[101] By expanding the conditions for which they were indicated, Astrazeneca's Seroquel and Eli Lilly's Zyprexa had become the biggest selling antipsychotics in 2008 with global sales of $5.5 billion and $5.4 billion respectively.[19] Harvard medical professor Joseph Biederman conducted research on bipolar disorder in children that led to an increase in such diagnoses. A 2008 Senate investigation found that Biederman also received $1.6 million in speaking and consulting fees between 2000 and 2007 — some of them undisclosed to Harvard — from companies including makers of antipsychotic drugs prescribed for children with bipolar disorder. Johnson & Johnson gave more than $700,000 to a research center that was headed by Biederman from 2002 to 2005, where research was conducted, in part, onRisperdal, the company's antipsychotic drug. Biederman has responded saying that the money did not influence him and that he did not promote a specific diagnosis or treatment.[13] Some critics have also analyzed the use of alleged front organizations and conflicted patient "advocacy" groups funded by pharmaceutical companies that seek to set the mental health agenda, including the use of the law to force people to take antipsychotics against their will, often justified by claims about risk of violence.[102]