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Prozac, a selective serotonin reuptake inhibitor (SSRI)
Serotonin-norepinephrine reuptake inhibitor, Venlafaxine
An antidepressant is a psychiatric medication or other substance (nutrient or herb) used for alleviating depression or dysthymia (\'milder\' depression). Drug groups known as MAOIs, tricyclics and SSRIs are particularly associated with the term. These medications are now amongst the drugs most commonly prescribed by medical psychologists, psychiatrists and general practitioners, and their effectiveness and adverse effects are the subject of many studies and competing claims. Nutrients for which there are claims of antidepressant activity include phenylalanine, tyrosine, tryptophan, 5-Hydroxytryptophan, and choline[citation needed].
Most antidepressants have a delayed onset of action and are usually taken over the course of weeks, months or years. They are generally considered distinct from stimulants, and drugs used for an immediate euphoric effect only are not generally considered antidepressants. Despite the name, antidepressants are often used in the treatment of other conditions, including anxiety disorders, bipolar disorder, obsessive compulsive disorder, eating disorders and chronic pain. Some have also become known as lifestyle drugs or "mood brighteners". Other medications not known as antidepressants, including antipsychotics in low dosesVega, JA., Mortimer, AM., Tyson, PJ. (2003) Conventional antipsychotic prescription in unipolar depression, I: An audit and recommendations for practice The Journal of clinical psychiatry 64(5), pp. 568-574. and benzodiazepines,Petty F, Trivedi MH, Fulton M, Rush AJ. (1995) Benzodiazepines as antidepressants: does GABA play a role in depression? Biological Psychiatry. 38(9):578-91 are also widely used to manage depression.
The term antidepressant is sometimes applied to any therapy (e.g. psychotherapy, electro-convulsive therapy, acupuncture) or process (e.g. sleep disruption, increased light levels, regular exercise) found to improve clinically depressed mood. An inert placebo tends to have a significant antidepressant effect, so establishing something as an antidepressant in a clinical trial involves demonstrating a significant additional effect.
Contents
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Saint John\'s Wort
OpiumWeber, M.M. & Emrich, H.M. (1988) Current and historical concepts of opiate treatment in psychiatric disorders. International Journal of Clinical Psychopharmacology. Jul;3(3):255-66. and St John\'s WortCzygan, F.C. (2003) From a 2500 year old apotropic comes a current antidepressive. The cultural history and mistique of St. John\'s wort Pharm Unserer Zeit. 32(3):184-90 (as a "nerve tonic") had long been used to alleviate depression, but the contemporary history of antidepressant medications begins with isoniazid.
In 1951, two physicians from the Sea View Hospital on Staten Island, Irving Selikoff and Edward Robitzek, began clinical trials to evaluate two new anti-tuberculosis agents from Hoffman-LaRoche, isoniazid and iproniazid. Only the patients with poor prognosis were initially treated; nevertheless, their condition improved dramatically. In addition, Selikoff and Robitzek noted "a subtle general stimulation... The patients exhibited renewed vigor and indeed this occasionally served to introduce disciplinary problems."SELIKOFF IJ, ROBITZEK EH (1952). "Tuberculosis chemotherapy with hydrazine derivatives of isonicotinic acid". Dis Chest 21 (4): 385–438. PMID 14906149. The promise of the cure for tuberculosis brought by the results of the Sea View Hospital trials was also excitedly discussed in the mainstream press. In 1952, learning of the stimulant-like side effects of the isoniazid, the Cincinnati psychiatrist Max Lurie decided to try it on his patients. In the following year, he and Harry Salzer reported that isoniazid improved the depression in two thirds of their patients and also coined the term antidepressant to describe its action.Weissman, Myrna M. (2001). Treatment of depression: bridging the 21st century. Washington, D.C: American Psychopathological Association, 10-11. ISBN 0-88048-397-0. A similar story happened in Paris, where Jean Delay, the head of psychiatry at Sainte-Anne Hospital, found out from his pulmonology colleagues from Cochin Hospital about the side effects of isoniazid. In 1952, that is even earlier than Lurie and Salzer, Delay with the resident Jean-Francois Buisson also reported the positive action of isoniazid on depressed patients.Healy, David (1996). The Psychopharmacologists: Interviews. London: Chapman & Hall, 8. ISBN 1-86036-008-4. For the reasons unrelated to the efficacy, isoniazid as antidepressant was soon overshadowed by more toxic iproniazid, although it remains one of the mainstays of the 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.Healy, David (1998). The Psychopharmacologists: Volume 2. A Hodder Arnold Publication, 132-134. ISBN 1-86036-010-6.
Another anti-tuberculosis drug tried at the same time by Selikoff and Robitzek, iproniazid, was observed to have a greater "psychostimulant" effect, albeit at the cost of a greater toxicity.ROBITZEK EH, SELIKOFF IJ, MAMLOK E, TENDLAU A (1953). "Isoniazid and its isopropyl derivative in the therapy of tuberculosis in humans: comparative therapeutic and toxicologic properties". Dis Chest 23 (1): 1–15. PMID 12998444. Subsequently to the publications on isoniazid, papers by Jackson Smith, Gordon Kamman, George Crane and Frank Ayd describing the psychiatric applications of iproniazid also appeared, and Ernst Zeller found iproniazid to be a potent monoamine oxidase inhibitor.López-Muñoz F, Alamo C, Juckel G, Assion HJ (2007). "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors". J Clin Psychopharmacol 27 (6): 555–9. doi:10.1097/jcp.0b013e3181bb617. PMID 18004120. Nevertheless, iproniazid had remained relatively obscure until Nathan Kline, the influential and flamboyant head of research at Rockland State Hospital, began its popularization both in medical and popular press as a "psychic energizer".Time Magazine (1957) "Psychic Energizer" While isoniazid was not patentable, Roche put a significant marketing effort behind iproniazid, including promoting its off-label use for depression.López-Muñoz F, Alamo C, Juckel G, Assion HJ (2007). "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors". J Clin Psychopharmacol 27 (6): 555–9. doi:10.1097/jcp.0b013e3181bb617. PMID 18004120. Its sales grew massively in the following years, until it was recalled from the market in 1961 due to the cases of lethal hepatotoxicity.
The discovery that a tricyclic ("three ringed") compound had a significant antidepressant effect was also first made in the early 1950s, by Roland Kuhn in a Swiss psychiatric hospital. By that time antihistamine derivatives were coming in to use to treat surgical shock and then as psychiatric neuroleptics. Although, in 1955, reserpine was indicated to be more effective than placebo in alleviating anxious depression, neuroleptics (literally "to seize the neuron") were developing for use as sedatives and antipsychotics.
In attempting to improve the effectiveness of one of them, chlorpromazine, in conjunction with the Geigy pharmaceutical company, Kuhn discovered that compound "G 22355" (manufactured and patented in the US in 1951 by Häfliger and Schinder) had a beneficial effect in patients with depression with mental and motor retardation.Kuhn, R. (1958) The Treatment of Depressive States with G 22355 (Imipramine Hydrochloride). American Journal of Psychiatry, 115:459-464, November He first reported his findings on what he called a "thymoleptic" (literally "taking hold of the emotions", by contrast with neuroleptics, "taking hold of the nerves") in 1955/56 and they gradually became established, resulting in the marketing of the first tricyclic antidepressant, imipramine, soon followed by variants.
These new drug therapies became prescription-only medications 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.[citation needed] 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.
The term antidepressant is reported to have been coined by Lurie and to not have been widely adopted until at least the 1960s.Biel JH. (1964). Some rationales for the development of antidepressant drugs. Molecular modification in drug design. Adv Chem; 45: 114–39 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.Pletscher, A. (1991) The discovery of antidepressants: A winding path. Journal of Cellular and Molecular Life Sciences, Volume 47(1)Healy, D.M.D. (1999)The Three Faces of the Antidepressants: A Critical Commentary on the Clinical-Economic Context of Diagnosis. Journal of Nervous & Mental Disease. 187(3):174-180
Most pharmacologists by the 1960s thought the main therapeutic action of tricyclics was to inhibit norepinephrine reuptake, but it was gradually observed that this action was associated with energizing and motor stimulating effects whilst some antidepressant compounds appeared to have differing effects through action on serotonin systems (notably proposed by Carlsson and Lindqvist (1969) and Lapin and Oxenkrug (1969)).
Researchers began a process of rational drug design to isolate antihistamine-derived compounds that would \'selectively\' (specifically) target these systems. The first such compound to be patented, in 1971, was zimelidine, whilst the first released clinically was indalpine. Fluoxetine (Prozac), FDA approved for commercial use in 1988, became the first blockbuster SSRI. Fluoxetine was developed at Eli Lilly in the early 1970s by Bryan Molloy, David Wong and others.Domino, E.F. (1999) [1] History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants Psychopharmacology and Psychosomatic Research, Special IssueWong DT, Bymaster FP, Horng JS, Molloy BB. (1975) [2] A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy) N-methyl-3-phenylpropylamine]. Journal of Pharmacology and Experimental Therapeutics. 193, p 804–811
While it had fallen out of favor in most countries through the 19th and 20th centuries, the herb St John\'s Wort had become increasingly popular in Germany where Hypericum extracts eventually became licensed, packaged and prescribed by doctors. Small-scale efficacy trials were carried out from the 1970s and 1980s, and attention grew in the 1990s following a meta-analysis of these.Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W & Melchart D (1996) St John’s wort for depression – an overview and meta-analysis of randomised clinical trials. British Medical Journal 313, p253–258. 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 hyperforinMuller, W.E. (2003) Current St John\'s wort research from mode of action to clinical efficacy. Pharmacol Res. Feb;47(2):101-9Nathan, P.J. (2001) J Hypericum perforatum (St John\'s Wort): a non-selective reuptake inhibitor? A review of the recent advances in its pharmacology. Psychopharmacol. 2001 Mar;15(1):47-54.
SSRIs became known as "novel antidepressants" along with other newer drugs such as SNRIs and NRIs with various different selective effects, such as venlafaxine, duloxetine, nefazodone and mirtazapineFreeman, H. (1996) Tolerability and safety of novel antidepressants. European Psychiatry, 11(supplement 4), p206.
Selective serotonin reuptake inhibitors (SSRIs) are a family of antidepressants considered to be the current standard of drug treatment. It is thought that one cause of depression is an inadequate amount of serotonin, a chemical used in the brain to transmit signals between neurons. SSRIs are said to work by preventing the reuptake of serotonin by the presynaptic neuron, thus maintaining higher levels of 5-HT in the synapse. Recently, however, 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.Lacasse J, Leo J (2005). "Serotonin and depression: a disconnect between the advertisements and the scientific literature". PLoS Med 2 (12): e392. PMID 16268734. Full text Recent research indicates that these drugs may interact with transcription factors known as "clock genes",Uz T, Ahmed R, Akhisaroglu M, Kurtuncu M, Imbesi M, Dirim Arslan A, Manev H (2005). "Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum". Neuroscience 134 (4): 1309-16. PMID 15994025. which may be important for the addictive properties of drugs of abuse, and possibly in obesity.Yuferov V, Butelman E, Kreek M (2005). "Biological clock: biological clocks may modulate drug addiction". Eur J Hum Genet 13 (10): 1101-3. PMID 16094306. Manev H, Uz T (2006). "Clock genes as a link between addiction and obesity". Eur J Hum Genet 14 (1): 5. PMID 16288309. Full text
Recent randomized controlled trials in Archives of General Psychiatry showed that up to one-third of effects of SSRI Treatment can be seen in first week. Early effects also shown to have secondary effect of reducing absolute reduction in HDRS score by 50%. Even more recent studies, published by the Archives of General Psychiatry note that 25% of so-called clinical depression does not meet a disease criteria and should be considered to be ordinary sadness and adjustment to the difficulties in life.
This family of drugs includes fluoxetine (Prozac), paroxetine (Paxil), escitalopram (Lexapro, Esipram), citalopram (Celexa), and sertraline (Zoloft). These antidepressants typically have fewer adverse side effects than the tricyclics or the MAOIs, although such effects as drowsiness, dry mouth, nervousness, anxiety, insomnia, decreased appetite, and decreased ability to function sexually may occur. Some side effects may decrease as a person adjusts to the drug, but other side effects may be persistent. Though safer than first generation antidepressants, SSRI\'s may not work as often, suggesting the role of norepinephrine.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta) are a newer form of antidepressant that works on both norepinephrine and 5-HT. They typically have similar side effects to the SSRIs, although there may be a withdrawal syndrome on discontinuation that may necessitate dosage tapering.
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 minimizing serotonin related side-effects by blocking certain serotonin receptors. The only example of this class in clinical use is mirtazapine (Avanza, Zispin, Remeron).
Norepinephrine (noradrenaline) reuptake inhibitors (NRIs) such as reboxetine (Edronax) act via norepinephrine (also known as noradrenaline). NRIs are thought to have a positive effect on concentration and motivation in particular, though they have been known to increase aggression.[citation needed]
Norepinephrine-dopamine reuptake inhibitors such as bupropion (Wellbutrin, Zyban) inhibit the neuronal reuptake of dopamine and norepinephrine (noradrenaline).www.psychiatrist.com/pcc/pccpdf/v06n04/v06n0403.pdf (PDF).
Tricyclic antidepressants are the oldest and include such medications as amitriptyline and desipramine. 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. Several 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. However, tricyclic antidepressants are still used because of their high potency, especially in severe cases of clinical depression.
Monoamine oxidase inhibitors (MAOIs) such as phenelzine (Nardil) may be used if other antidepressant medications are ineffective. Because 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. MAOIs work by blocking the enzyme monoamine oxidase which breaks down the neurotransmitters dopamine, serotonin, and norepinephrine (noradrenaline). MAOIs can be as effective as tricyclic antidepressants, although they can have a higher incidence of dangerous side effects (as a result of inhibition of cytochrome P450 in the liver). A new generation of MAOIs has been introduced; moclobemide (Manerix), known as a reversible inhibitor of monoamine oxidase A (RIMA), acts in a more short-lived and selective manner and does not require a special diet. Additionally, (selegiline) marketed as Emsam in a transdermal form is not a classic MAOI in that at moderate dosages it tends to effect MAO-B which does not require any dietary restrictions.
Some antidepressants have been found to work more effectively in some patients when used in combination with another drug. Such "augmenter" drugs include tryptophan (Tryptan) and buspirone (Buspar).
Tranquillizers and sedatives, typically the benzodiazepines, may be prescribed to ease anxiety and promote sleep. Because of their high potential for fostering dependence, these medications are intended only for short-term or occasional use. Medications often are used not for their primary function but to exploit what are normally side effects. Quetiapine fumarate (Seroquel) is designed primarily to treat schizophrenia and bipolar disorder, but a frequently reported side-effect is somnolence. Therefore, this drug can be used in place of an antianxiety agent such as clonazepam (Klonopin, Rivotril).
Antipsychotics such as risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel) are prescribed as mood stabilizers and are also effective in treating anxiety. Their use as mood stabilizers is a recent phenomenon and is controversial with some patients. Antipsychotics (typical or atypical) may also be prescribed in an attempt to augment an antidepressant, to make antidepressant blood concentration higher, or to relieve psychotic or paranoid symptoms often accompanying clinical depression. However, they may have serious side effects, particularly at high dosages, which may include blurred vision, muscle spasms, restlessness, tardive dyskinesia, and weight gain.
Antidepressants by their nature behave similarly to psychostimulants. Antianxiety medications by their nature are depressants. Close medical supervision is critical to proper treatment if a patient presents with both illnesses because the medications tend to work against each other.
Psycho-stimulants are sometimes added to an antidepressant regimen if the patient suffers from anhedonia, hypersomnia and/or excessive eating as well as low motivation. These symptoms which are common in atypical depression can be quickly resolved with the addition of low to moderate dosages of amphetamine or methylphenidate (brand names Adderall and Ritalin, respectively) as these chemicals enhance motivation and social behavior, as well as suppress appetite and sleep. These chemicals are also known to restore sex drive. Extreme caution must be used however with certain populations. Stimulants are known to trigger manic episodes in people suffering from bipolar disorder. They are also easily abused as they are effective substitutes for Methamphetamine when used recreationally. Close supervision of those with substance abuse disorders is urged. Emotionally labile patients should avoid stimulants, as they exacerbate mood shifting.
Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications, depending on whether mania or depression is being treated. Lithium\'s potential side effects include thirst, tremors, light-headedness, and nausea or diarrhea. Some of the anticonvulsants, such as carbamazepine (Tegretol), sodium valproate (Epilim), and lamotrigine (Lamictal), are also used as mood stabilizers, particularly in bipolar disorder.
In the United Kingdom the use of antidepressants increased by 234% in the 10 years up to 2002.(National Institute for Clinical Excellence, 2004) In the United States a 2005 independent report stated that 11% of women and 5% of men in the non-institutionalized population (2002) now take antidepressants[3]Stagnitti,M. (2005) Antidepressant Use in the US Civilian Non-Insitutionalised Population, 2002. Statistical Brief #77. Rockville,MD: Medical Expenditure Panel, Agency for Healthcare Research and Quality. A 1998 survey found that 67% of patients diagnosed with depression were prescribed an antidepressant.Sleath, B. & Shih, YC. (2003) [4] Sociological influences on antidepressant prescribing. Soc Sci Med. Mar;56(6):1335-44. A 2007 study purports that 25% of Americans were overdiagnosed with depression, regardless of any medical intervention.[5] Depression could be overdiagnosed: Up to 25% may be reacting normally to stresses, study says 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 guidelinesOlie JP, Elomari F, Spadone C, Lepine JP. (2002) Antidepressant consumption in the global population in France Encephale. Sep-Oct;28(5 Pt 1):411-7. Between 1996 and 2004 in British Columbia, antidepressant use increased from 3.4% to 7.2% of the populationRaymond CB, Morgan SG, Caetano PA. (2007) Antidepressant utilization in british columbia from 1996 to 2004: increasing prevalence but not incidence. Psychiatr Serv. 2007 Jan;58(1):79-84. Data from the Netherlands indicated an increasing rate of prescriptions of SSRIs, and an increasing duration of treatment.Meijer W, Heerdink E, Leufkens H, Herings R, Egberts A, Nolen W (2004). "Incidence and determinants of long-term use of antidepressants". Eur J Clin Pharmacol 60 (1): 57-61. PMID 14985889.
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.McManus P, Mant A, Mitchell PB, Montgomery WS, Marley J, Auland ME. (2000) Recent trends in the use of antidepressant drugs in Australia, 1990-1998.Med J Aust. November 6;173(9):458-61. Antidepressants are also increasingly used worldwide for non-depressive patients as studies continue show the potential of immunomodulatory, analgesic and anti-inflammatory properties in antidepressants.
The choice of particular antidepressant is reported to be based, in the absence of research evidence of differences in efficacy, on seeking to avoid certain side effects, and taking into account comorbid (co-occurring) psychiatric disorders, specific clinical symptoms and prior treatment historyMark Zimmerman, Michael Posternak, Michael Friedman, Naureen Attiullah, Scott Baymiller, Robert Boland, Stacie Berlowitz, Shahzad Rahman, Kirsten Uy, Steve Singer (2004) Which Factors Influence Psychiatrists’ Selection of Antidepressants? Am J Psychiatry 161:1285-1289
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).Petersen T, Dording C, Neault NB, Kornbluh R, Alpert JE, Nierenberg AA, Rosenbaum JF, Fava M. (2002) A survey of prescribing practices in the treatment of depression. Prog Neuropsychopharmacol Biol Psychiatry. Jan;26(1):177-87. A survey in the UK found that male general physicians were more likely to prescribe antidepressants than female doctors.BBC News (July 2002) Male GPs depression pills \'bias\'
Structural formula of the SSRI escitalopram, in its free base form.
The most commonly prescribed antidepressants in the US retail market in 2006 The number of prescriptions was calculated as the total of prescriptions for the corresponding generic and brand-name drugs using data from the charts for generic and brand-name drugs.Top 200 generic drugs by units in 2006. Top 200 brand-name drugs by units.. Drug Topics, Mar 5, 2007. Retrieved on 2007-12-24. were:
The most commonly prescribed antidepressant in Germany is reported to be (concentrated extracts of) hypericum perforatum (St John\'s Wort). [6] In the Netherlands, paroxetine, marketed as Seroxat® among generic preparations, is the most prescribed antidepressant, followed by the tricyclic antidepressant amitriptyline, citalopram and venlafaxine. [7]
The therapeutic effects of antidepressants are believed to be related to their effects on neurotransmitters. Monoamine oxidase inhibitors (MAOIs) block the break-down of monoamine neurotransmitters (serotonin and norepinephrine) by inhibiting the enzymes which oxidize them, thus leaving higher levels still active in the brain (synaptic cleft).
Tricyclic antidepressants (TCAs) prevent the reuptake of various neurotransmitters, including serotonin, norepinephrine, and dopamine. Selective serotonin reuptake inhibitors (SSRIs) more specifically prevent the reuptake of serotonin (thereby increasing the level of active serotonin in synapses of the brain). Other novel antidepressants specifically affect serotonin and other neurotransmitters.
A theory centered on neurotransmitter effects appears to be incomplete, however. Neurotransmitter levels are altered as soon as the antidepressant chemicals build up in the bloodstream, but effects on mood appear to occur several days or weeks later.
One explanation of this holds that the "down-regulation" of neurotransmitter receptors—an apparent consequence of excess signaling and a process that takes several weeks—is actually the mechanism responsible for the alleviation of depressive symptoms. Another hypothesis is that antidepressants may have some longer-term effects due to the promotion of neurogenesis in the hippocampus, an effect found in mice[8] Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000 December 15;20(24):9104-10.[9]Manev H, Uz T, Smalheiser NR, Manev R. Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro. Eur J Pharmacol. 2001 January 5;411(1-2):67-70. Other animal research suggests that antidepressants can also affect the expression of genes in brain cells, by influencing "clock genes".[10] Uz T, Ahmed R, Akhisaroglu M, Kurtuncu M, Imbesi M, Dirim Arslan A, Manev H. Effect of fluoxetine and cocaine on the expression of clock genes in the mouse hippocampus and striatum. Neuroscience. 2005;134(4):1309-16.
New 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).Zhang HT, Huang Y, Mishler K, Roerig SC, O\'Donnell JM. Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats. Psychopharmacology (Berl). 2005 Oct;182(1):104-15 Data also suggest antidepressants to have the ability of modulating neural plasticity in longterm administration.Carboni L, Vighini M, Piubelli C, Castelletti L, Milli A, Domenici E. Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists. Eur Neuropsychopharmacol. 2006 Oct;16(7):521-37.
Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disease, and is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological affect of antidepressants on the immune system.O\'Brien SM, Scully P, Scott LV, Dinan TG. "Cytokine profiles in bipolar affective disorder: focus on acutely ill patients." J Affect Disord. 2006 Feb;90(2-3):263-7.Obuchowicz E, Marcinowska A, Herman ZS. "Antidepressants and cytokines--clinical and experimental studies" Psychiatr Pol. 2005 Sep-Oct;39(5):921-36.Hong CJ, Yu YW, Chen TJ, Tsai SJ."Interleukin-6 genetic polymorphism and Chinese major depression". Neuropsychobiology. 2005;52(4):202-5.Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. "Abstract Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 2005;12(5):255-69Kubera M, Maes M, Kenis G, Kim YK, Lason W. "Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6" Psychiatry Res. 2005 April 30;134(3):251-8.
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.Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP. "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 2005;12(5):255-69 SSRIs, SNRIs and tricyclic antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of Interferon-gamma (IFN-gamma) and Interleukin-10 (IL-10), as well as TNF-alpha and Interleukin-6 (IL-6). Antidepressants have also been shown to suppress TH1 upregulation.Diamond M, Kelly JP, Connor TJ. "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". Eur Neuropsychopharmacol. 2006 Oct;16(7):481-90.Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M. "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio." J Clin Psychopharmacol. 2001 Apr;21(2):199-206Maes M."The immunoregulatory effects of antidepressants". Hum Psychopharmacol. 2001 Jan;16(1):95-103Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E."The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". Int Immunopharmacol. 2005 Mar;5(3):609-18.Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB. "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice." Int Immunopharmacol. 2006 Jun;6(6):903-7
Antidepressants, specifically TCAs and dual serotonergic-noradrenergic reuptake inhibition by dual SNRIs (or SSRI-NRI combinations), have also shown analgesic properties additionally.Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, Coderre T, Morley-Forster PK, Stinson J, Boulanger A, Peng P, Finley GA, Taenzer P, Squire P, Dion D, Cholkan A, Gilani A, Gordon A, Henry J, Jovey R, Lynch M, Mailis-Gagnon A, Panju A, Rollman GB, Velly A; Canadian Pain Society.Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag. 2007 Spring;12(1):13-21Jones CK, Eastwood BJ, Need AB, Shannon HE. Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: evidence for synergism between serotonergic and noradrenergic reuptake inhibition.Neuropharmacology. 2006 Dec;51(7-8):1172-80.
These studies warrant investigation for antidepressants for use in both psychiatric and non-psychiatric illness and that a psycho-neuroimmunological approach may be required for optimal pharmacotherapy.Kulmatycki KM, Jamali F. "Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response". J Pharm Pharm Sci. 2006;9(3):292-306. 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.O\'Brien SM, Scott LV, Dinan TG. "Cytokines: abnormalities in major depression and implications for pharmacological treatment". Hum Psychopharmacol. 2004 Aug;19(6):397-403.
There is a large amount of research evaluating the potential therapeutic effects of antidepressants, whether through efficacy studies under experimental conditions (including randomized clinical trials) or through studies of "real world" effectiveness. A sufficient response to a drug is often defined as at least a 50% reduction in self-reported or observed symptoms, with a partial response often defined as at least a 25% reduction. The term remission indicates a virtual elimination of depression symptoms, albeit with the risk of a recurrence of symptoms or complete relapse. Full remission or recovery signifies a full sustained return to a "normal" psychological state with full functioning.
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Recent clinical reviews include:
The American Psychiatric Association 2000 Practice Guideline for the Treatment of Patients with Major Depressive Disorder [11] 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. [12]
Between 30% and 50% of individuals treated with a given antidepressant do not show a response.Baghai, TC., Moller, HJ, Rupprecht, R. (2006) Recent progress in pharmacological and non-pharmacological treatment options of major depression. Curr Pharm Des. ;12(4):503-15.Ruhe HG, Huyser J, Swinkels JA, Schene AH. (2006)Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. Dec;67(12):1836-55. 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.Tranter, R., O\'Donovan, CO., Chandarana, P., Kennedy, S. (2002) Prevalence and outcome of partial remission in depression J Psychiatry Neurosci. July; 27(4): 241–247. In addition, antidepressant drugs tend to lose efficacy over the course of treatmentByrne, SE. & Rothschild, AJ. (1999) Loss of antidepressant efficacy during maintenance therapy: possible mechanisms and treatments. J Clin Psychiatry. Jun;59(6):279-88. A number of strategies are used in clinical practice to try to overcome these limits and variations.Mischoulon D, Nierenberg AA, Kizilbash L, Rosenbaum JF, Fava M. (2000) Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: a survey of clinicians. Can J Psychiatry. Jun;45(5):476-81.
The American Psychiatric Association 2000 Practice Guideline advises that where no response is achieved following six to eight weeks of treatment with an antidepressant, to switch to an antidepressant in the same class, then to a different class of antidepressant.
A recent meta-analysis review found wide variation in the findings of prior studies; for patients who had failed to respond to an SSRI antidepressant, between 12% and 86% showed a response to a new drug, with between 5% and 39% ending treatment due to adverse effects. The more antidepressants an individual had already tried, the less likely they were to benefit from a new antidepressant trial.
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 anticonvulsantsDeBattista C, Lembke A. (2005) Update on augmentation of antidepressant response in resistant depression. Curr Psychiatry Rep. Dec;7(6):435-40.
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.Lam RW, Wan DD, Cohen NL, Kennedy SH. (2002) Combining antidepressants for treatment-resistant depression: a review. J Clin Psychiatry. Aug;63(8):685-93.
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.Geddes JR et al. (2003) Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. February 22;361(9358):653-61. 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.Fava GA, Park SK, Sonino N. (2006) Treatment of recurrent depression. Expert Rev Neurother. Nov;6(11):1735-40.Peterson, TJ. (2006) Enhancing the efficacy of antidepressants with psychotherapy Journal of Psychopharmacology, Vol. 20, No. 3 suppl, 19-28, 2006
Approximately 30% of patients have remission of depression with medications.Trivedi MH, Rush AJ, Wisniewski SR, et al (2006). "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice". The American journal of psychiatry 163 (1): 28-40. doi:10.1176/appi.ajp.163.1.28. PMID 16390886. For patients with inadequate response, either adding sustained-release bupropion (initially 200 mg per day then increase by 100 mg up to total of 400 mg per day) or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients,Trivedi MH, Fava M, Wisniewski SR, et al (2006). "Medication augmentation after the failure of SSRIs for depression". N. Engl. J. Med. 354 (12): 1243-52. doi:10.1056/NEJMoa052964. PMID 16554526. while switching medications can achieve remission in about 25% of patients.Rush AJ, Trivedi MH, Wisniewski SR, et al (2006). "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression". N. Engl. J. Med. 354 (12): 1231-42. doi:10.1056/NEJMoa052963. PMID 16554525.
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.Cohen, MD, Lee S.; Lori L. Altshuler, MD; Bernard L. Harlow, PhD; Ruta Nonacs, MD, PhD; D. Jeffrey Newport, MD; Adele C. Viguera, MD; Rita Suri, MD; Vivien K. Burt, MD, PhD; Victoria Hendrick, MD; Alison M. Reminick, BA; Ada Loughead, BA; Allison F. Vitonis, BA; Zachary N. Stowe, MD (February 1, 2006). "Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment". Journal of the American Medical Association 295 (5): 499-507. American Medical Association. Retrieved on 2007-06-14. 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 (July 12, 2006) "Relapse of Major Depression During Pregnancy in Women Who Maintain or Discontinue Antidepressant Treatment—Correction". JAMA 296 (2): 170. Retrieved on 2007-06-14. 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.David Armstrong, "Drug Interactions: Financial Ties to Industry Cloud Major Depression Study At Issue: Whether It\'s Safe For Pregnant Women To Stay on Medication - JAMA Asks Authors to Explain". Wall Street Journal. July 11, 2006 (copy published on post-gazette.com)
Most antidepressants, including the SSRIs and tricyclics, are known to produce tolerance (i.e. a decrease in the effects of a drug over time), and withdrawal (particularly if abrupt) may produce adverse effects, which can range from mild to extremely severe.
Antidepressants do not seem to have all of the same addictive qualities as other substances such as nicotine, caffeine, cocaine, or other stimulants - in other words, while antidepressants may cause dependence and withdrawal they do not seem to cause uncontrollable urges to increase the dose due to euphoria or pleasure, and thus do not meet the strict definition of an addictive substance. However, antidepressants do meet the World Health Organisation definition of "dependency-inducing", and indeed the SSRIs are listed by the organisation as among the most strongly dependency-inducing substances in existence.[citation needed]
