Serotonin

Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants used in the treatment of depression, anxiety disorders, and some personality disorders. Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Anxiety disorder is a blanket term covering several different forms of abnormal pathological anxieties Fears and Phobias In clinical usage "fear" Personality disorder, formerly referred to as a Character Disorder is a class of mental disorders characterized by rigid and on-going patterns of feeling thinking and behavior They are also typically effective and used in treating premature ejaculation problems. Premature ejaculation (PE also known as rapid ejaculation, rapid climax, premature climax or early ejaculation, is the most common sexual

SSRIs increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin available to bind to the postsynaptic receptor. In Cell biology, Molecular biology and related fields the word extracellular (or sometimes extracellular space) means "outside the cell See Chemical synapse for an introduction to concepts and terminology used in this article Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Reuptake, or re-uptake, is the reabsorption of a Neurotransmitter by the Neurotransmitter transporter of a pre-synaptic Neuron after Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons They have varying degrees of selectivity for the other monoamine transporters, having little binding affinity for the noradrenaline and dopamine transporters. Monoamine transporters are structures in nerve-cell membranes that function as Neurotransmitter transporters transferring Monoamine neurotransmitters Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates

The first class of psychotropic drugs to be rationally designed, SSRIs are the most widely prescribed antidepressants in many countries. A psychoactive drug or psychotropic substance is a Chemical substance that acts primarily upon the Central nervous system where it alters Brain Drug design is the approach of finding drugs by design based on their Biological targets Typically a drug target is a key Molecule involved in a particular ^[1] Their effectiveness and safety have been questioned.

List of SSRIs

Drugs in this class include:
(Trade names in parentheses)

• citalopram (Celexa, Cipramil, Emocal, Sepram, Seropram)
• dapoxetine (no trade name yet; not yet approved by the FDA)
• escitalopram (Lexapro, Cipralex, Esertia)
• fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin (EUR), Fluox (NZ))
• fluvoxamine (Luvox, Faverin, Dumyrox, Movox)
• paroxetine (Paxil, Seroxat, Aropax, Deroxat, Rexetin, Xetanor, Paroxat)
• sertraline (Zoloft, Lustral, Serlain)
• zimelidine (Zelmid, Normud)

Related antidepressants

SSRIs form a subclass of serotonin uptake inhibitors, which includes other non-selective inhibitors as well. Citalopram is an Antidepressant drug used to treat major depression associated with Mood disorders It is also used on occasion in the treatment Dapoxetine is the International Nonproprietary Name of a short-acting SSRI drug currently being considered for approval by the Food and Drug Administration Escitalopram (trade names Lexapro, Cipralex) is the pure (S Enantiomer of Citalopram and is a Selective serotonin reuptake inhibitor Fluvoxamine ( Luvox) is an Antidepressant which functions as a Selective serotonin reuptake inhibitor. Paroxetine (trade names Seroxat, Paxil, Parotin, Aropax, Xetanor, ParoMerck, Rexetin) is a Selective serotonin Zimelidine ( Normud, Zelmid) was the first Selective serotonin reuptake inhibitor (SSRI Antidepressant to be marketed A serotonin uptake inhibitor is a drug which acts as a Neurotransmitter uptake inhibitor on Serotonin receptors Types The most well known members of In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule Serotonin-norepinephrine reuptake inhibitor, serotonin-noradrenaline-dopamine reuptake inhibitors and selective serotonin reuptake enhancers are also serotonergic antidepressants. Serotonin-norepinephrine reuptake inhibitors (SNRIs are a class of Antidepressant used in the treatment of major depression and other mood disorders Serotonin-norepinephrine-dopamine-reuptake-inhibitors ( SNDRI) are a class of Psychoactive Antidepressants They act upon Neurotransmitters in the Selective serotonin reuptake enhancers (SSREs are antidepressants that enhance the reuptake of Serotonin instead of inhibiting it as Tricyclic antidepressants and Serotonergic means "related to the Neurotransmitter Serotonin "

Medical indications

The main indication for SSRIs is clinical depression. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression SSRIs are frequently prescribed for anxiety disorders like social anxiety, panic disorders, obsessive-compulsive disorder (OCD), eating disorders, and chronic pain. Anxiety disorder is a blanket term covering several different forms of abnormal pathological anxieties Fears and Phobias In clinical usage "fear" Social Phobia Social anxiety is a term used to describe an experience of Anxiety ( Emotional discomfort Fear, apprehension or Worry Panic Disorder is a Psychological condition characterized by recurring Panic attacks in combination with significant behavioral change lasting at least a month Obsessive-compulsive disorder (OCD is a Chronic Anxiety disorder most commonly characterized by obsessive Distressing Intrusive thoughts An eating disorder is a compulsion to eat or avoid eating that negatively affects both one's physical and mental health Chronic pain is defined as Pain that persists longer than the temporal course of natural healing associated with a particular type of injury or disease process Though not specifically indicated by the manufacturers, they are also sometimes prescribed to treat irritable bowel syndrome (IBS), Lichen simplex chronicus, and premature ejaculation in up to 60% of men. In Gastroenterology, irritable bowel syndrome ( IBS) is a Functional bowel disorder characterized by mild to severe Abdominal pain, discomfort Lichen simplex chronicus (LSC is a Skin disorder characterized by chronic itching and scratching Premature ejaculation (PE also known as rapid ejaculation, rapid climax, premature climax or early ejaculation, is the most common sexual All SSRIs are approved in the US for use with psychiatric disorders as outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). Psychiatry is a medical specialty which exists to study, prevent, and treat Mental disorders in Humans Psychiatric The Diagnostic and Statistical Manual of Mental Disorders' ( DSM) is published by the American Psychiatric Association

Different SSRIs have different approval uses in different countries dependent on the overseeing medical branch of government in charge of regulating drugs. In the United States, the Food and Drug Administration (FDA) makes these approvals after trials have been submitted by pharmaceutical companies. In Europe, drugs can be approved either by the European Medicines Agency for human consumption throughout the EU or by the regulatory agencies of individual countries for use within those countries. The European Medicines Agency ( EMEA) is a European agency for the evaluation of medicinal products. The European Union ( EU) is a political and economic union of twenty-seven member states, located primarily in

Contraindications and drug interaction

One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). Monoamine oxidase inhibitors ( MAOIs) are a class of powerful antidepressant drugs prescribed for the treatment of depression. This is likely to cause severe serotonin syndrome. Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use inadvertent interactions between drugs or the recreational

People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). Pimozide (sold as Orap) is an Antipsychotic drug. It was discovered at Janssen Pharmaceutica in 1963. Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. The atypical opioid analgesic tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant. An opioid is a chemical Substance that has a Morphine -like action in the body Tramadol ( INN) (ˈtræmədɒl is an atypical Opioid which is a centrally acting Analgesic, used for treating moderate to severe Pain. Tricyclic antidepressants (abbreviation TCAs) are a class of Antidepressant drugs first used in the 1950s Hepatic impairment is another contraindication for medications of this type.

SSRIs may increase blood levels and risk of toxicities of certain medications:

1. highly protein-bound medications like warfarin (coumadin) and digoxin
2. antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor)
3. beta blockers like metoprolol (Toprol xl) or propranolol (Inderal)
4. tricyclic antidepressants like amitriptyline (Elavil) (may increase risk of serotonin syndrome)
5. benzodiazepines like alprazolam (Xanax) or diazepam (Valium)
6. carbamazepine (Tegretol)
7. cisapride (Propulsid)
8. clozapine (Clozaril)
9. ciclosporin (Neoral)
10. haloperidol (Haldol)
11. phenytoin (Dilantin)
12. pimozide (Orap)
13. theophylline (Theo-dur)

Certain drugs may increase toxicities of SSRIs:

1. alcohol and other CNS depressants
2. diuretics (water pills)
3. MAOIs
4. sympathomimetic drugs like pseudoephedrine (Sudafed)
5. lithium
6. sibutramine (Meridia)
7. MDMA (ecstasy)
8. zolpidem (ambien)^[2]
9. Dextromethorphan

Mode of action

SSRIs acts by inhibiting the reuptake of serotonin after being released in synapses. Warfarin (also known under the brand names Coumadin, Jantoven, Marevan, and Waran) is an Anticoagulant. Digoxin ( INN) (dɨˈdʒɒksɨn also known as Digitalis, is a purified Cardiac glycoside extracted from the Foxglove plant Digitalis Antiarrhythmic agents are a group of Pharmaceuticals that are used to suppress fast rhythms of the Heart ( Cardiac arrhythmias) such as Atrial fibrillation Propafenone (pro-PA-fen-own (brand name Rythmol Flecainide acetate ( fle KAY nide) is a class Ic Antiarrhythmic agent used to prevent and treat tachyarrhythmias (abnormal fast rhythms of the Heart Beta blockers (sometimes written as β-blocker) are a class of drugs used for various indications but particularly for the management of Cardiac arrhythmias Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of thecardiovascular system especially Hypertension. Propranolol ( INN) is a non-selective Beta blocker mainly used in the treatment of Hypertension. Tricyclic antidepressants (abbreviation TCAs) are a class of Antidepressant drugs first used in the 1950s Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil Tryptanol Endep Elatrol Tryptizol Trepiline Laroxyl Saroten is a Tricyclic antidepressant The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic Alprazolam, also known under the trade names Xanax and Niravam, is a short-acting drug of the Benzodiazepine class used to treat moderate Diazepam (daɪˈæzɨpæm first marketed as Valium by Hoffmann-La Roche, is a Benzodiazepine derivative Drug. Carbamazepine ("CBZ" is an Anticonvulsant and mood stabilizing drug used primarily in the treatment of Epilepsy and Bipolar disorder Cisapride is a Parasympathomimetic which acts as a Serotonin 5-HT4 receptor Agonist. Clozapine (sold as Clozaril, Leponex, Fazaclo, Froidir; Gen-Clozapine in Canada Clozaril, Denzapine, Ciclosporin (ˌsaɪkləˈspɔrən cyclosporine ( USAN) or cyclosporin (former BAN) is an Immunosuppressant drug widely Haloperidol is a Typical antipsychotic. It is in the Butyrophenone class of Antipsychotic medications and has pharmacological effects similar Phenytoin sodium is a commonly used Antiepileptic. Phenytoin acts to dampen the unwanted runaway brain activity seen in seizure by reducing electrical conductance among brain Pimozide (sold as Orap) is an Antipsychotic drug. It was discovered at Janssen Pharmaceutica in 1963. Theophylline, also known as dimethylxanthine, is a Methylxanthine drug used in therapy for Respiratory diseases such as COPD or Asthma In Chemistry, an alcohol is any Organic compound in which a Hydroxyl group ( - O[[hydrogen H]]) is bound to a Carbon A diuretic is any Drug that elevates the rate of urination ( Diuresis) Monoamine oxidase inhibitors ( MAOIs) are a class of powerful antidepressant drugs prescribed for the treatment of depression. Sympathomimetic drugs are substances that mimic the effects of the Catecholamines Epinephrine (adrenaline Norepinephrine (noradrenaline and/or Pseudoephedrine (commonly abbreviated as PSE is a sympathomimetic Amine commonly used as a Decongestant. Lithium (ˈlɪθiəm is a Chemical element with the symbol Li and Atomic number 3 Sibutramine (trade name Meridia in the US and Canada Reductil in Europe and most other countries usually as sibutramine hydrochloride monohydrate is an orally MDMA ( 34-methylenedioxy- N -methylamphetamine) most commonly known today by the street name Ecstasy (often abbreviated E, X, Zolpidem is a prescription medication used for the short-term treatment of Insomnia, as well as some brain disorders Dextromethorphan ( DXM or DM) is an Antitussive (cough suppressant drug found in many over-the-counter cold and Cough medicines Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons How much an individual will respond to this, however, also depends on genetics. In addition, several other mechanisms are suggested for the desired effect, e. g. neuroprotection and anti-inflammatory and immunomodulatory factors. Taken together, SSRI has several advantages compared with tricyclic antidepressants (TCA)s and 5-HT-prodrugs. Tricyclic antidepressants (abbreviation TCAs) are a class of Antidepressant drugs first used in the 1950s A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form However, the latter might be required in addition to SSRIs in certain situations.

Basic understanding

Further information: Chemical synapse

In the brain, messages are passed between two nerve cells via a synapse, a small gap between the cells. Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands The cell that sends the information releases neurotransmitters (of which serotonin is one) into that gap. See Chemical synapse for an introduction to concepts and terminology used in this article The neurotransmitters are then recognized by receptors on the surface of the recipient (postsynaptic) cell, which upon this stimulation, in turn, relays the signal. In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling About 10% of the neurotransmitters are lost in this process; the other 90% are released from the receptors and taken up again by monoamine transporters into the sending (presynaptic) cell (a process called reuptake). Monoamine transporters are structures in nerve-cell membranes that function as Neurotransmitter transporters transferring Monoamine neurotransmitters

Some theories link depression to a lack of stimulation of the recipient neuron at a synapse. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression To stimulate the recipient cell, SSRIs inhibit the reuptake of serotonin. As a result, the serotonin stays in the synaptic gap longer than it normally would, and may be recognized again (and again) by the receptors of the recipient cell, stimulating it.

Pharmacodynamics

SSRIs inhibit the reuptake of the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) into the presynaptic cell, increasing levels of 5-HT within the synaptic cleft. Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands

But there is one counteracting effect: high serotonin levels will not only activate the postsynaptic receptors, but also flood presynaptic autoreceptors, that serve as a feedback sensor for the cell. Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands An autoreceptor is a receptor located on Presynaptic nerve cell terminals and serves as a part of a feedback loop in Signal transduction. Activation of the autoreceptors (by agonists like serotonin) triggers a throttling of serotonin production. An agonist is a term used to describe a type of ligand or drug that binds and alters the activity of a receptor. The resulting serotonin deficiency persists for some time, as the transporter inhibition occurs downstream to the cause of the deficiency, and is therefore not able to counterbalance it. The body adapts gradually to this situation by lowering (downregulating) the sensitivity of the autoreceptors. WikipediaWikipedia is not a dictionary ---> Downregulation is the process by which

Of greater importance is another adaptive process: the downregulation of postsynaptic serotonin 5-HT_2A receptors. The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor which belongs to the Serotonin receptor family and is a G protein coupled receptor After the use of an SSRI, since there is more serotonin available, the response is to lower (to normal levels or less) the number of postsynaptic receptors over time, and in the long run, this modifies the serotonin/receptor ratio. Since a larger percentage of available receptors become activated by serotonin, transmission is enhanced or restored.

These (slowly proceeding) neurophysiological adaptions of the brain tissue are the reason why usually several weeks of continuous SSRI use are necessary for the antidepressant effect to become fully manifested, and why increased anxiety is a common side effect in the first few days or weeks of use.

Pharmacogenetics

Further information: Pharmacogenetics

Large bodies of research are devoted to using genetic markers to predict whether patients will respond to SSRIs or have side effects which will cause their discontinuation, although these tests are not yet ready for widespread clinical use. The terms Pharmacogenomics and pharmacogenetics tend to be used interchangeably and a precise consensus definition of either remains elusive A genetic marker is a known DNA sequence. It can be described as a variation which may arise due to mutation or alteration in the genomic loci that can be observed Discontinuation is to quit a procedure and has different meanings for a treatment of an individual and a whole brand of a drug product Discontinuation of a treatment is ^[3] Single nucleotide polymorphisms of the 5-HT(2A) gene correlates with increased paroxetine discontinuation, but not mirtazapine (a non-SSRI antidepressant) discontinuation^[4]

Neuroprotection

Studies have suggested that SSRIs may promote the growth of new neural pathways or neurogenesis in rats. A single nucleotide polymorphism ( SNP, pronounced snip) is a DNA sequence variation occurring when a single Nucleotide - A, T Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Paroxetine (trade names Seroxat, Paxil, Parotin, Aropax, Xetanor, ParoMerck, Rexetin) is a Selective serotonin Mirtazapine is an Antidepressant introduced by Organon International in 1994 used for the treatment of moderate to severe depression. A neural pathway is a Neural tract connecting one part of the Nervous system with another usually consisting of bundles of elongated Myelin -insulated Neurogenesis ( birth of Neurons ' is the process by which neurons are created ^[5] Also, SSRIs may protect against neurotoxicity caused by other compounds (for instance MDMA and Fenfluramine) as well as from depression itself. MDMA ( 34-methylenedioxy- N -methylamphetamine) most commonly known today by the street name Ecstasy (often abbreviated E, X, Fenfluramine is a drug that was part of the Fen/Phen anti- Obesity medication (the other drug being Phentermine)

Anti-inflammatory and immunomodulation

Recent studies show pro-inflammatory cytokine processes take place during depression, mania and bipolar disorder, in addition to somatic disease (such as autoimmune hypersensitivity) and is possible that symptoms manifest in these psychiatric illnesses are being attenuated by pharmacological effect of antidepressants on the immune system. Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition "Somatic" redirects here for the musician known as Somatic see Hahn Rowe. Hypersensitivity (also called hypersensitivity reaction refers to undesirable (damaging discomfort-producing and sometimes fatal reactions produced by the normal immune system ^{[6][7][8][9][10]}

SSRI's 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). Selective serotonin reuptake inhibitors ( SSRIs) are a class of Antidepressants used in the treatment of depression, Anxiety disorders Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular Interferon-gamma ( IFN-γ) is a Dimerized soluble Cytokine that is the only member of the type II class of Interferons This interferon was originally Interleukin -10 (IL-10 or IL10 also known as human cytokine synthesis inhibitory factor (CSIF is an anti- Inflammatory Cytokine. Tumor necrosis factor ( TNF, cachexin or cachectin and formally known as Tumor necrosis factor-alpha) is a Cytokine involved in systemic Antidepressants have also been shown to suppress TH1 upregulation. T helper cells (also known as effector T cells or Th cells) are a sub-group of Lymphocytes (a type of White blood cell or ^{[11][12][13][14]}

Future serotonergic 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. ^[15]

SSRIs versus TCAs

SSRIs are described as 'selective' because they affect only the reuptake pumps responsible for serotonin, as opposed to earlier antidepressants, which affect other monoamine neurotransmitters as well. In Biochemistry, a ligand ( latin ligare = to bind is a substance that is able to bind to and form a complex with a Biomolecule Because of this, SSRIs lack some of the side effects of the more general drugs.

There appears to be no significant difference in effectiveness between SSRIs and tricyclic antidepressants, which were the most commonly used class of antidepressants before the development of SSRIs. Tricyclic antidepressants (abbreviation TCAs) are a class of Antidepressant drugs first used in the 1950s ^[16] However, SSRIs have the important advantage that their toxic dose is high, and, therefore, they are much more difficult to use as a means to commit suicide. The term drug overdose (or simply overdose or OD) describes the Ingestion or application of a Drug or other substance in quantities Further, they have fewer and milder side effects. An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted negative consequences Tricyclic antidepressant also have a higher risk of serious cardiovascular side effects which SSRIs lack.

SSRIs versus 5-HT-Prodrugs

Further information: Prodrugs

Serotonin cannot be administered directly because when ingested orally, it will not cross the blood-brain barrier, and therefore would have no effect on brain functions. A prodrug is a pharmacological substance ( drug) that is administered in an inactive (or significantly less active form The blood-brain barrier (BBB is a metabolic or cellular structure in the Central nervous system (CNS that restricts the passage of various chemical substances and microscopic Also, serotonin would activate every synapse it reaches, whereas SSRIs only enhance a signal that is already present, but too weak to come through.

SSRIs together with 5-HT-Prodrugs

Biosynthetically serotonin is made from tryptophan, an amino acid. Biosynthesis is a phenomenon wherein Chemical compounds are produced from simpler Reagents Biosynthesis unlike Chemosynthesis, takes place within living Tryptophan (abbreviated as Trp or W) is one of the 20 standard amino acids, as well as an Essential amino acid in the Human diet In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this If depression is caused by lack of serotonin, rather than insensitivity to it, SSRIs alone will not work well, whereas supplementing with tryptophan will. In 1989, the Food and Drug Administration made tryptophan available by prescription only, in response to an outbreak of eosinophilia-myalgia syndrome caused by impure L-tryptophan supplements sold over-the-counter. A prescription (℞ is a health-care program implemented by a Physician or other medical practitioner in the form of instructions that govern the plan of care for an individual Eosinophilia-myalgia syndrome (EMS is an incurable and sometimes fatal flu-like neurological condition that is believed to have been caused by ingestion of poorly produced L-tryptophan Over-the-counter (OTC drugs are medicines that may be sold without a prescription, in contrast to Prescription drugs The name "over-the-counter" With current standards, L-tryptophan is again available over the counter in the US as well as supplement 5-HTP which is a direct precursor to serotonin. 5-Hydroxytryptophan or 5-HTP is a naturally-occurring Amino acid, a precursor to the Neurotransmitter Serotonin and an intermediate Combining 5-HTP with SSRIs may lead to serotonin syndrome, as a result of too much serotonin activity in the brain. Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use inadvertent interactions between drugs or the recreational A doctor should be consulted before combining the two.

Adverse effects

General side effects

General side effects are mostly present during the first 1-4 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 6-8 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:

• anhedonia
• nausea
• drowsiness or somnolence
• headache
• clenching of teeth
• extremely vivid and strange dreams
• dizziness
• changes in appetite
• weight loss/gain (measured by a change in bodyweight of 7 pounds)
• may result in a double risk of bone fractures and injuries
• changes in sexual behaviour (see the next section)
• increased feelings of depression and anxiety (which may sometimes provoke panic attacks)
• tremors
• autonomic dysfunction including orthostatic hypotension, increased or reduced sweating
• akathisia
• liver or renal impairment
• suicidal ideation (thoughts of suicide)
• Photosensitivity (increased risk of sunburn) (Use protective clothing, such as long sleeves and hats, and sunscreen to decrease the risk of sunburn. Somnolence (or " drowsiness " is a state of near- Sleep, a strong desire for sleep or sleeping for unusually long periods (c A bone fracture (sometimes abbreviated # or Fx or Fx) is a medical condition in which a Bone is cracked or broken Human sexual behavior or different human sexual practices encompass a wide range of activities such as strategies to find or attract partners ( Mating and display Panic attacks are sudden discrete periods of intense anxiety mounting Physiological arousal fear stomach problems and discomfort that are associated with a variety of Orthostatic hypotension (also known as postural hypotension, and colloquially as head rush or a dizzy spell) is a form of Hypotension in which Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain Renal failure or kidney Suicidal ideation is a common medical term for thoughts about Suicide, which may be as detailed as a formulated plan without the suicidal act itself )^[17]

Common gastrointestinal side effects include nausea, vomiting, and diarrhea, which are brought about by the actions of serotonin on the gastrointestinal tract. Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the In Medicine, diarrhea, also spelled diarrhoea (see spelling differences) is frequent loose or liquid Bowel movements Acute diarrhea

Most side effects usually disappear after the adaptation phase, when the antidepressive effects begin to show. However, despite being called general, the side effects and their durations are highly individual and drug-specific. Usually the treatment is begun with a small dose to see how the patient's body reacts to the drug, after that either the dose can be adjusted (eg. Prozac in the UK is begun at a 20mg dose, and then adjusted as necessary to 40mg or 60mg). Should the drug prove not to be effective, or the side effects intolerable to the patient, another common route is to switch treatment to either another SSRI, or an SNRI. Serotonin-norepinephrine reuptake inhibitors (SNRIs are a class of Antidepressant used in the treatment of major depression and other mood disorders ^[18]

Mania or hypomania is a possible side-effect. Mania (from Greek μανία and that from μαίνομαι - mainomai, "to rage to be furious" is a severe medical condition This article is an expansion of a section entitled '''Hypomania''' from within the main article Bipolar disorder. Users with some type of bipolar disorder are at a much higher risk, however SSRI-induced mania in patients previously diagnosed with unipolar depression can trigger a bipolar diagnosis.

Sexual side effects

See also: Post SSRI Sexual Dysfunction

SSRIs can cause various types of sexual dysfunction such as anorgasmia, erectile dysfunction, and diminished libido. Post-SSRI sexual dysfunction (PSSD is an Iatrogenic type of Sexual dysfunction caused directly by the previous use of Selective serotonin reuptake inhibitor Sexual dysfunction or sexual malfunction (see also Sexual function) is difficulty during any stage of the Sexual act (which includes desire, Anorgasmia (often related to Delayed ejaculation in males is a form of Sexual dysfunction sometimes classified as a Psychiatric disorder in which the patient Libido in its common usage means Sexual desire however more technical definitions such as those found in the work of Carl Jung, are more general referring to libido Initial studies found that such side effects occur in less than 10% of patients, but since these studies relied on unprompted reporting, the frequency was probably underestimated. In more recent studies, doctors have specifically asked about sexual difficulties, and found that they are present in between 17%^[19] and 41%^[20] of patients. This dysfunction occasionally disappears spontaneously without stopping the SSRI, and in most cases resolves after discontinuation. In some cases, however, it does not; this is known as Post SSRI Sexual Dysfunction (PSSD). Post-SSRI sexual dysfunction (PSSD is an Iatrogenic type of Sexual dysfunction caused directly by the previous use of Selective serotonin reuptake inhibitor

It is believed that sexual dysfunction is caused by an SSRI induced reduction in dopamine. Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates Stimulation of postsynaptic 5-ht2 and 5-ht3 receptors decreases dopamine release from the Substantia Nigra. The substantia nigra ( Latin for "black substance" Sömmering) or locus niger is a heterogeneous portion of the midbrain, separating A number of drugs are not associated with sexual side-effects (bupropion, mirtazapine (Remeron), maprotiline (Ludiomil), tianeptine (Stablon)^[21][22] (some of these are also not associated with weight gain). Bupropion ( INN, previously known as amfebutamone; sold as Wellbutrin, Zyban, and several other Trade names is an atypical Antidepressant Mirtazapine is an Antidepressant introduced by Organon International in 1994 used for the treatment of moderate to severe depression. Maprotiline (sold as Deprilept, Ludiomil, Psymion) is a Tetracyclic antidepressant. Tianeptine ( INN) (Stablon Coaxil Tatinol is described as a Selective serotonin reuptake enhancer ( SSRE) As a result, sexual dysfunction caused by SSRIs can sometimes be mitigated by several different drugs. These include:

• bupropion (norepinephrine and dopamine reuptake inhibitor)
• buspirone (serotonin receptor agonist)
• methylphenidate (stimulant)
• mirtazapine (noradrenergic and specific serotonergic antidepressant (NaSSA))
• amphetamine (stimulant)
• amantadine (antiviral)
• pramipexole (dopamine agonist) and
• ropinirole (dopamine agonist)

On the other hand, the effect of SSRIs to slow down sexual stimulation may be used as treatment; SSRIs have been proposed as a drug to treat premature ejaculation. Bupropion ( INN, previously known as amfebutamone; sold as Wellbutrin, Zyban, and several other Trade names is an atypical Antidepressant Norepinephrine reuptake inhibitors ( NRIs) also known as noradrenaline reuptake inhibitors ( NARIs) are compounds that elevate the extracellular level of Dopamine Reuptake Inhibitors ( DARI) Dopamine Uptake Inhibitors, Dopamine Transporter Inhibitors are compounds that inhibit the Reuptake of extracellular Buspirone (brand-names Ansial, Ansiced, Anxiron, Axoren, Bespar, BuSpar, Buspimen, Buspinol, A serotonin receptor agonist is a compound that activates Serotonin receptors mimicking the effect of the neurotransmitter Serotonin. Mirtazapine is an Antidepressant introduced by Organon International in 1994 used for the treatment of moderate to severe depression. Noradrenergic and selective serotonergic antidepressants (abbreviated NaSSAs) are a relatively new class of Antidepressants They are thought to work by blocking presynaptic Amphetamine, and related drugs such as Methamphetamine are a group of drugs that act by increasing levels of Norepinephrine, Serotonin, and Dopamine Amantadine is the Organic compound known formally as 1-aminoadamantane Pramipexole ( INN, trade names Mirapex and Sifrol) is a Medication indicated for treating Parkinson's disease and Restless legs A dopamine agonist is a compound that activates Dopamine receptors mimicking the effect of the neurotransmitter Dopamine. Ropinirole (marketed under the brand names Requip and Ropark, in Extended release form as Requip XL) is a non- Ergoline Dopamine A dopamine agonist is a compound that activates Dopamine receptors mimicking the effect of the neurotransmitter Dopamine. Premature ejaculation (PE also known as rapid ejaculation, rapid climax, premature climax or early ejaculation, is the most common sexual ^[23]

Cardiovascular side effects

Cardiovascular side effects are very rare with SSRI use, with a reported incidence of less than 0. Incidence is a measure of the risk of developing some new condition within a specified period of time 0003 percent. ^[24] SSRIs inhibit cardiac and vascular sodium, calcium and potassium channels and prolong QT intervals. Sodium channels are Integral membrane proteins that form Ion channels, conducting sodium ions ( Na+) through a cell's Plasma membrane A Calcium channel is an Ion channel which displays selective permeabiltiy to Calcium ions In the field of Cell biology, potassium channels are the most widely distributed type of Ion channel and are found in virtually all living organisms In medicine specifically Cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's ^[25] However, a number of large studies of patients without known pre-existing heart disease have reported no EKG changes related to SSRI use. ^[26] In overdose, fluoxetine has been reported to cause sinus tachycardia, myocardial infarction, junctional rhythms and trigeminy. Sinus Tachycardia (also colloquially known as sinus tach or sinus tachy) is a rhythm with elevated rate of impulses originating from the Sinoatrial Myocardial infarction ( MI or AMI for acute myocardial infarction) also known as a heart attack, occurs when the blood supply Junctional rhythm is an abnormal heart rhythm where the AV node initiates electrical activity in the heart. Dysrhythmia redirects here For the American band see Dysrhythmia (band. Some authors have suggested electrocardiographic monitoring in patients with severe pre-existing cardiovascular disease who are taking SSRI's. ^[27]

Discontinuation syndrome

Main article: SSRI discontinuation syndrome

SSRIs are not addictive in the conventional medical use of the word (i. SSRI discontinuation syndrome, also known as SSRI withdrawal syndrome or SSRI cessation syndrome is a Withdrawal syndrome that can occur during or following the interruption e. animals given free access to the drug do not actively seek it out and do not seek to increase the dose), but suddenly discontinuing their use is known to produce both somatic and psychological withdrawal symptoms. Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is

Suicidality and aggression

Similarly to other antidepressants, SSRIs can cause suicidality in children. ^[28][29][30] Analyses of the risks of SSRIs by governing bodies in the United States and United Kingdom have produced warnings about suicidality and aggression when the medications are used with children and adolescents. The United States of America —commonly referred to as the The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located

A 2004 Food and Drug Administration (FDA) analysis of clinical trials on children with major depressive disorder found statistically significant increases of the risks of "possible suicidal ideation and suicidal behavior" by about 80%, and of agitation and hostility by about 130%. In health care clinical trials are conducted to allow safety and Efficacy data to be collected for new drugs or devices Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Suicidal ideation is a common medical term for thoughts about Suicide, which may be as detailed as a formulated plan without the suicidal act itself ^[28] An additional analysis by the FDA also indicated 1. 5-fold increase of suicidality in the 18–24 age group. ^[29][30] This resulted in a black box warning on SSRI and other antidepressant medications regarding the increased risk of suicidality in patients younger than 24. In the United States, a black box warning (also sometimes called a black label warning or boxed warning) is a type of warning that appears on the Package ^[31]

In 2004, the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom judged fluoxetine (Prozac) to be the only antidepressant that offered a favorable risk-benefit ratio in children with depression, though it was also associated with a slight increase in the risk of self-harm and suicidal ideation. The Medicines and Healthcare products Regulatory Agency (MHRA is the UK government agency which is responsible for ensuring that Medicines and Medical devices The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located Risk-benefit analysis is the comparison of the Risk of a situation to its related benefits ^[32] Only two SSRIs are licensed for use with children in the UK, sertraline (Zoloft) and fluvoxamine (Luvox), and only for the treatment of obsessive-compulsive disorder. Fluvoxamine ( Luvox) is an Antidepressant which functions as a Selective serotonin reuptake inhibitor. Obsessive-compulsive disorder (OCD is a Chronic Anxiety disorder most commonly characterized by obsessive Distressing Intrusive thoughts Fluoxetine, despite having a favorable risk-benefit ratio for use with depression in adolescents and children, is not licensed for this use. ^[33]

Other studies on SSRIs and suicide among adolescents are equivocal; rates of suicide attempts in high-risk populations appear to be unaffected by SSRI prescriptions in adults. ^[34] There is also evidence that higher rates of SSRI prescriptions are associated with lower rates of suicide in children, though since the evidence is correlational, the true nature of the relationship is unclear. In Probability theory and Statistics, correlation, (often measured as a correlation coefficient) indicates the strength and direction of a linear ^[35] The introduction of a warning regarding the association between SSRIs and suicide led to a decrease in prescriptions for the medications in 2003 and 2004, and these decreases in prescriptions were associated with an increase in actual number of teenage suicide. ^[36]

SSRIs and Pregnancy

The FDA issued a warning on July 19, 2006 stating nursing mothers on SSRIs must discuss treatment with their physicians.

When taken by pregnant women, selective serotonin reuptake inhibitors (SSRIs) cross the placenta and have the potential to affect newborns. Pregnancy ( Latin graviditas) is the carrying of one or more offspring known as a Fetus or Embryo, inside the Uterus of a Female Sertraline and paroxetine have been associated with congenital malformations. Paroxetine (trade names Seroxat, Paxil, Parotin, Aropax, Xetanor, ParoMerck, Rexetin) is a Selective serotonin A congenital disorder is a disease or disorder that is present at birth Some evidence suggests that SSRIs are associated with neonatal complications such as neonatal abstinence syndrome (NAS) and persistent pulmonary hypertension (PPHN). Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is In Medicine, pulmonary hypertension (PH is an increase in blood pressure in the Pulmonary artery, Pulmonary vein, or pulmonary capillaries together known

Neonatal abstinence syndrome

Neonatal abstinence syndrome is a withdrawal syndrome in newborn babies. Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is Withdrawal, also known as withdrawal/abstinence syndrome, refers to the characteristic signs and symptoms that appear when a drug that causes Physical dependence is It has been documented in SSRI treatment. By November 2003, a total of 93 cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome had been reported. Subsequently, the authors of a Lancet study concluded that doctors should avoid or cautiously manage the prescribing of these drugs to pregnant women with psychiatric disorders. This article is about the journal For other uses of the term "lancet" see Lancet (disambiguation. Mental disorder or mental illness is a psychological or behavioral pattern that occurs in an individual and is thought to cause distress or disability that is not expected as ^[37]

Permanent neuropsychological changes

Since the early 80's scientists have used a technique called neonatal clomipramine to produce animals used in depression research. If rats are given the tricyclic antidepressant clomipramine when they are 8-21 days old they will develop behavioural changes in adulthood which resembles depression in humans. Clomipramine (brand-name Anafranil) is a Tricyclic antidepressant. ^[38][39] In 1997 Lundbeck found that treatment with the SSRI LU-10-134-C, which only differs from their product citalopram by two atoms could give similar results as clomipramine. ^[40] Later it was found that neonatal citalopram makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,^[41] which are reversed by treatment with antidepressants. ^[42]

Persistent pulmonary hypertension

Persistent pulmonary hypertension (PPHN) is a serious and life-threatening, but rare, lung condition that occurs soon after birth of the newborn. In Medicine, pulmonary hypertension (PH is an increase in blood pressure in the Pulmonary artery, Pulmonary vein, or pulmonary capillaries together known newborn babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloodstream. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body About 1 to 2 babies per 1000 babies born in the U. S. develop PPHN shortly after birth, and often they need intensive medical care. Health care is the prevention treatment and management of illness and the preservation of mental health through the services offered by the medical, Nursing One study has found that PPHN is six times more common in babies whose mothers take an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers do not take an antidepressant. ^[43]

Interaction with carbohydrate metabolism

Serotonin is also involved in regulation of carbohydrate metabolism. Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of Carbohydrates Few analyses of the role of SSRIs in treating depression cover the effects on carbohydrate metabolism from intervening in serotonin handling by the body.

Overdose

Main article: Serotonin syndrome

SSRIs appear to be safer in overdose when compared with traditional antidepressants such as the tricyclic antidepressants. Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use inadvertent interactions between drugs or the recreational The term drug overdose (or simply overdose or OD) describes the Ingestion or application of a Drug or other substance in quantities This relative safety is supported both by case series and studies of deaths per numbers of prescriptions. ^[44] However, case reports of SSRI poisoning have indicated that severe toxicity can occur^[45] and deaths have been reported following massive single ingestions,^[46] although this is exceedingly uncommon when compared to the tricyclic antidepressants. ^[44]

Because of the wide therapeutic index of the SSRIs, most patients will have mild or no symptoms following moderate overdoses. The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic The most commonly reported severe effect following SSRI overdose is serotonin syndrome; serotonin toxicity is usually associated with very high overdoses or multiple drug ingestion. Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use inadvertent interactions between drugs or the recreational ^[47] Other reported significant effects include coma, seizures, and cardiac toxicity. In Medicine, a coma (from the Greek koma, meaning deep sleep is a profound state of Unconsciousness. An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Cardiotoxicity is the occurrence of heart muscle damage The heart becomes weaker and is not as efficient in pumping and therefore circulating blood ^[44]

Treatment for SSRI overdose is mainly based on symptomatic and supportive care. Medical care may be required for agitation, maintenance of the airways, and treatment for serotonin syndrome. ECG monitoring is usually indicated to detect any cardiac abnormalities.

Criticism

See also: Biopsychiatry controversy and Biological psychiatry

In late 2004 media attention was given to a proposed link between SSRI use and juvenile suicide. The biopsychiatry controversy is the dispute over the scientific basis of Biological psychiatry theory and practice Biological psychiatry, or biopsychiatry is an approach to Psychiatry that aims to understand Mental disorder in terms of the biological function Teenage suicide is the act of self-killing by a Teenager. Although the Suicide rate among youth significantly decreased in the mid-1990s suicide deaths in the For this reason, the use of SSRIs in pediatric cases of depression is now recognized by the United States FDA as warranting a cautionary statement to the parents of children who may be prescribed SSRIs by a family doctor. A general practitioner, or GP is a medical practitioner who provides Primary care and specializes in Family medicine. The FDA's currently required packaging insert for SSRIs includes a warning (known as a "black box warning") that a pooled analysis of placebo controlled trials of 9 antidepressant drugs (including multiple SSRIs) resulted in a risk of suicidality that was twice that of placebo. In the United States, a black box warning (also sometimes called a black label warning or boxed warning) is a type of warning that appears on the Package A randomized controlled trial (RCT is a type of scientific Experiment most commonly used in testing the Efficacy or Effectiveness of Healthcare Placebo is a substance or procedure a patient accepts as medicine or therapy but which has no specific therapeutic activity At the same time, in adults SSRIs do not increase the risk of suicide. ^[48]

Critics of SSRIs claim that the widely-disseminated television and print advertising of SSRIs promotes an inaccurate message, oversimplifying what these medications actually do and deceiving the public. ^[49]

The criticism stems from questions about the validity of claims that SSRIs work by 'correcting' chemical imbalances. Chemical imbalance is a term used as a lay explanation of Mental illness or mental disorders Without accurately measuring patients' neurotransmitter levels to allow for continuous monitoring during treatment, it is impossible to know if one is correctly targeting a deficient neurotransmitter (i. See Chemical synapse for an introduction to concepts and terminology used in this article e. correcting an imbalance), reaching a desirable level, or even introducing too much of a particular neurotransmitter. Thus it has been argued that SSRIs can actually cause chemical imbalances and abnormal brain states. Hence it is purported that when a patient discontinues an SSRI, they may have a chemical imbalance due to the rapid cessation of the drug which is causing the discontinuation syndrome. ^[50]

One possible mechanism is by inhibition of dopaminergic neurotransmission. Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates ^[51]

Biopsychiatrists believe that, among other factors, the balance of neurotransmitters in the brain is a biological regulator of mental health. See Chemical synapse for an introduction to concepts and terminology used in this article The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain Mental health is a term used to describe either a level of cognitive or Emotional wellbeing or an absence of a Mental disorder. In this theory, emotions within a "normal" spectrum reflect a proper balance of neurochemicals, but abnormally extreme emotions, such as clinical depression, reflect an imbalance. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Psychiatrists claim that medications regulate neurotransmitters, and many if not most psychiatrists also claim they treat abnormal personalities by removing a neurochemical excess or replenishing a deficit (though the efficacy of antidepressants and antipsychotics is not undisputed^[52]). An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. On the other hand, Elliot Valenstein, a psychologist and neuroscientist, claims that the broad biochemical assertions and assumptions of mainstream psychiatry are not supported by evidence. Elliot S Valenstein, PhD is a professor emeritus of Psychology and Neuroscience at the University of Michigan. ^[53]

One controversial critic of antidepressants, Peter Breggin, a physician who opposes the overuse of prescription medications to treat patients for mental health issues, predicted iatrogenic issues that SSRIs incur on a significant percentage of patients. Peter Roger Breggin (born May 11, 1936) is an American Psychiatrist, best known as an advocate of Anti-psychiatry and as a critic The terms iatrogenesis and iatrogenic artifact refer to adverse effects or complications caused by or resulting from medical treatment or advice Another prominent SSRI critic is David Healy. David Healy is an Irish Psychiatrist who is currently a professor in Psychological Medicine at Cardiff University College of Medicine Wales.

A widely-reported meta-analysis combined 35 clinical trials submitted to the FDA before licensing of four newer antidepressants (including the SSRIs paroxetine and fluoxetine, and two non-SSRI antidepressants nefazodone and venlafaxine). Paroxetine (trade names Seroxat, Paxil, Parotin, Aropax, Xetanor, ParoMerck, Rexetin) is a Selective serotonin Nefazodone hydrochloride (trade name Serzone, Nefadar) is an Antidepressant drug marketed by Bristol-Myers Squibb. Venlafaxine (Effexor Efexor is an Antidepressant of the Serotonin-norepinephrine reuptake inhibitor (SNRI class first introduced by Wyeth in 1993 The authors found that although the antidepressants were statistically superior to placebo they did not exceed the NICE criteria for a 'clinically significant' effect. Statistics is a mathematical science pertaining to the collection analysis interpretation or explanation and presentation of Data. Placebo is a substance or procedure a patient accepts as medicine or therapy but which has no specific therapeutic activity In particular they found that the effect size was very small for moderate depression but increased with severity reaching 'clinical significance' for very severe depression. The relationship between severity and efficacy was attributed to a reduction of the placebo effect in severely depressed patients, rather than an increase in the effect of the medication. ^{[54] [55] [56] [57] [58]}

A study in the New England Journal of Medicine on a possible publication bias regarding the efficacy of SSRI medications suggests that their effectiveness and risk-benefit ratios may be greatly exaggerated. The New England Journal of Medicine ( N Engl J Med or NEJM) is an English-language Peer-reviewed Medical journal published Publication bias arises from the tendency for Researchers and editors to handle experimental results that are positive (they found something differently from results that are Of 74 studies registered with the United States FDA, 37 with positive results were published in academic journals, while 22 studies with negative results were not published and 11 with negative results were published in a way that conveyed a positive outcome (one positive study was not published and three negative studies were published with results that were portrayed as negative). An academic journal is a peer-reviewed Periodical in which scholarship relating to a particular Academic discipline is published Overall, 94% of studies actually published were positive outcomes; when published and unpublished studies were included for analysis, the percentage of positive outcomes was 51%. ^[59]

Lawsuits

In one of the only three cases to ever go to trial for SSRI indication in suicide, Eli Lilly was caught corrupting the judicial process by making a deal with the plaintiff's attorney to throw the case, in part by not disclosing damaging evidence to the jury. The case, known as the Fentress Case involved a Kentucky man, Joseph Wesbecker, on Prozac, who went to his workplace and opened fire killing 8 people (including Fentress), and injuring 12 others before turning the gun on himself. The Standard Gravure shooting occurred on September 14 1989 when Joseph Wesbecker entered Standard Gravure his workplace and killed eight people injured 12 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 Kentucky Supreme Court was created by a 1975 constitutional amendment and is the State supreme court of the U Bad faith ( Latin: mala fides) is a legal concept in which a malicious motive on the part of a party in a lawsuit undermines their " 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". ^[60]

See also

• Neuropsychopharmacology
• Neuropharmacology
• Neurotoxicology
• Neuropsychotoxicology
• Pharmacology
• Psychoactive drug
• Serotonin/Norepinephrine/Dopamine Reuptake Inhibitor

References and notes

External links

• [5] Notes on Anhedonia and SAD
• MEDLINEplus drug information database at NIH
• The FDA Ban of L-Tryptophan at ceri. The Ballantine Publishing Group, better known as Ballantine Books, is a major American book Publisher founded in 1952 by Ian Ballantine. "NIH" redirects here For other meanings of NIH see NIH (disambiguation. com
• "black box" warning for SSRIs at FDA
• FDA list of SSRIs receiving the black box warning at FDA
• PROZAC Product/Prescribing Information at Eli Lilly and Company
• Barry Yeoman Putting Science in the Dock, The Nation at barryyeoman. In the United States, a black box warning (also sometimes called a black label warning or boxed warning) is a type of warning that appears on the Package Eli Lilly and Company ( is a global Pharmaceutical company and one of the world's largest corporations com
• MeSH Serotonin+uptake+inhibitors