Selective norepinephrine reuptake inhibitor

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Not to be confused with Serotonin–norepinephrine reuptake inhibitor.

Selective norepinephrine reuptake inhibitors (sNRIs) are a class of drugs that have been marketed as antidepressants and are used for various mental disorders, mainly depression and attention deficit hyperactivity disorder (ADHD). The norepinephrine transporter (NET) serves as the fundamental mechanism for the inactivation of noradrenergic signaling because of the NET termination in the reuptake of norepinephrine (NE). The selectivity and mechanism of action for the NRI drugs remain mostly unresolved and, to date, only a limited number of NRI-selective inhibitors are available. The first commercially available selective NRI was the drug reboxetine (Edronax), developed as a first-line therapy for major depressive disorder. Atomoxetine (Strattera) is another potent and selective NRI which is also effective and well tolerated for the treatment of ADHD in adults; it may also be a new treatment option for adults with ADHD, particularly for those patients at risk of substance abuse.

Contents

Medical uses

MedicationBrand nameMedical usesIntroducedChemical structure
Atomoxetine Strattera Attention deficit hyperactivity disorder (ADHD), Cognitive disengagement syndrome (CDS)2002 Atomoxetine structure.svg
Reboxetine Edronax Major depressive disorder 1997 Reboxetine.svg
Viloxazine QelbreeAttention deficit hyperactivity disorder (ADHD), Depression 1974 Viloxazine structure.svg

Adverse effects

Side effects

Selective NRIs are generally well tolerated but the most common side effects reported are headache, dry mouth, abdominal pain, loss of appetite, nausea, vomiting, and drowsiness. An increase in heart rate and blood pressure have been reported but are usually not clinically important. Sexual adverse effects are mostly related to male arousal difficulties and decreased libido in both men and women, but they are significantly less common than with serotonergic drugs. Other side effects are urinary retention, constipation, sweating and insomnia. What can be considered serious side effects are thoughts of suicide, aggressiveness and hallucinations. [5] [6] [7]

Interactions

If people are using sNRI drugs they should not take MAO inhibitors at the same time. That can increase the plasma concentration of NRIs in the body.

Beware of taking atomoxetine in combination with: [8]

  1. CYP2D6 inhibitors (e.g., fluoxetine, paroxetine and quinidine) can increase exposure for atomoxetine and it can also increase atomoxetine steady-state plasma concentration.
  2. Antihypertensive drugs because it can possibly increase the blood pressure
  3. β2-agonist e.g. albuterol because it may increase the efficacy of albuterol on the cardiovascular system.
  4. Medicines that affect norepinephrine (e.g. venlafaxine, imipramine, mirtazapine) should be used with caution when administered with atomoxetine due to possible synergy or synergistic effects on pharmacodynamic effects.

Beware of taking reboxetine in combination with: [9]

  1. Antifungals, e.g. ketoconazole.
  2. Antibiotics, e.g. erythromycin, rifampicin.
  3. Ergot derivatives used to treat migraine or Parkinson's disease may cause an increase in blood pressure.
  4. Any potassium-depleting diuretics (medicines for eliminating water), e.g. thiazides.
  5. Carbamazepine and phenobarbital, medicines used to control fits or seizures.
  6. Herbal medicines that contains St. John's Wort.

Contraindications

A few contraindications should be taken into account for atomoxetine. The first one is hypersensitivity; patients known to be hypersensitive to atomoxetine or other constituents of the product should avoid using it. MAO inhibitors (MAOI) should also be taken into account for contraindications. Atomoxetine should not be taken within 2 weeks after discontinuing an MAOI or completely avoid taking MAOI. The same applies to treatment with an MAOI, that it should not be initiated within 2 weeks after discontinuing atomoxetine. Serious and sometimes fatal reactions may occur when atomoxetine and drugs that affect brain monoamine concentration are given concurrently or in close proximity. Examples of reactions are hyperthermia, inflexibility, myoclonus and altered mental states that include extreme agitation, possibly progressing to delirium and coma. Increased risk of mydriasis was associated with Strattera use in clinical trials. Therefore, the use of Strattera is not recommended in patients with narrow angle glaucoma. Patients with pheochromocytoma or a history of pheochromocytoma should not take Strattera because serious reactions (elevated blood pressure and tachyarrhythmia) have been reported in patients who received Strattera. Last but not least, patients with severe cardiac or vascular disorders should not be using Strattera. [8]

The only contraindication that is reported in the IMB Micromedex database is prior hypersensitivity to the active compound, reboxetine. [10]

Pharmacology

Role of norepinephrine

Norepinephrine (NE), also known as noradrenaline, is a neurotransmitter that is released predominantly from the ends of sympathetic nerve fibers. [11] The sympathetic nervous system is stimulated in fearful situations and elicits the fight-or-flight response both in animals and humans. [12] This stimulus causes the release of catecholamines such as norepinephrine. The chemical class of catecholamines has positive chronotropic, inotropic and dromotropic effects which lead to increased heart rate, blood pressure, and cardiac output. [13] NE is one of the crucial neurotransmitters in the central nervous system (CNS) and plays an important role in regulating blood pressure, energy metabolism and controlling flexor muscles. [14] The substance has involvement in sleep and mood regulation, expression of behavior and the general degree of alertness and arousal. [11] In the face of a threat, whether it's real or perceived, NE being the most prominent receptor modulator activates behavioral adaptions to maintain homeostasis. The physiological responses in these threatening situation creates emotions of stress and acute anxiety. Responses such as dilatation of bronchioles and pupils, increased heart rate and kidney renin secretion, constricted blood vessels and inhibited peristalsis. [12] Norepinephrine is biosynthesized from the amino acid precursor tyrosine and then is sequentially hydroxylated to dihydroxyphenylalanine, also known as Dopa. Decarboxylation on Dopa generates the neurotransmitter dopamine, afterward when hydroxylated it produces norepinephrine. [11]

Role of norepinephrine transporter (NET)

Approximately 90% of released NE from the sympathetic nerve fibers is taken up again by postganglionic adrenergic neurons through the protein NET. The reuptake of NE is either repackaged into vesicles or degraded by the enzyme monoamine oxidase (MAO). [14] [15] The NET is located in the plasma membrane of noradrenergic neurons and serves as the fundamental mechanism by terminating the biological effects of NE in the synapse. The NE inactivation process, when taken up by the NET, is crucial in preventing too much increase in the NE concentration in the synaptic cleft. The reuptake of NE is competitive with various naturally occurring amines and drugs. [11]

Mechanism of action

NET is a target for drugs, that are potent and selective or mixed NET inhibitors (e.g. atomoxetine and reboxetine), named NRI, have been successfully developed to treat various mental disorders, but unfortunately also drugs of abuse (e.g. cocaine). The NRI drugs used medically for mental disorders include attention-deficit hyperactivity disorder (ADHD), depression, anxiety disorders, mood disorders, personality disorders, bipolar disorder, psychosexual disorders and schizophrenia. [11] NRI drugs bind to the NET and inhibit the reuptake of NE. These drugs therefore increase the availability of NE for binding to postsynaptic receptors that regulate adrenergic neurotransmission. [16] Selective NRIs blocks only the monoamine transporter NET, excluding the other two monoamine transporters (DAT and SERT) for dopamine and serotonin. Because if the NRI drug affects those other monoamine transporters they would be called nonselective inhibitors. However, the selectivity and mechanism of action for the NRI drugs remain unknown and, to date, only a very limited number of NRI-selective inhibitors are available. Research has shown that these new ligands vary both in the selectivity and potency at each of these three monoamine transporter sites (NET, DAT and SERT). However, those ligands may be of value in clarifying the pharmacological mechanisms, and in the discovery of new selective NRI drugs with fewer side effects. [11]

Pharmacokinetics

DrugBioavailabilityProtein bindingtmax (hours)t1/2 (hours)
Atomoxetine 63-94%98%14,5-19
Reboxetine 94%96-97%212–12,5
Viloxazine [17] ER relative to IR: 88%76-82%ER: ~5 (3-9)IR: 2-5

ER: 7 ± 4.7

Atomoxetine

The pharmacokinetics of atomoxetine are similar in children, teenagers and adults. Pharmacokinetics of atomoxetine has not been studied in children younger than 6 years old. Pharmacokinetic studies have shown that atomoxetine capsules and oral solutions are equivalent. Atomoxetine is very water soluble so it absorbed rapidly and completely after oral administration. [18] Atomoxetine reaches Cmax 1 to 2 hours after administration. The bioavailability of atomoxetine after oral administration is 63-94%, it is dependent on individual differences in the first-pass metabolism. [18] Atomoxetine is widely distributed and is highly (98%) bound to plasma proteins, mainly albumin. The volume of distribution for atomoxetine is 0.85 L/kg, with limited partitioning into red blood cells. [18] Atomoxetine is mainly metabolized by the cytochrome P4502D6 (CYP2D6) enzyme system. [18] The main metabolite formed is 4-hydroxyatomoxetine, which glucuronate rapidly. 4-hydroxyatomoxetine is equivalent to atomoxetine but is much lower in plasma. [8] The mean elimination half-life of atomoxetine after oral administration is 3.6 hours in individuals in extensive metabolism and 21 hours in those with a slow metabolism. [8] [19] Atomoxetine is excreted mainly as 4-hydroxyatomoxetin-O-glucoronide with urine. [19]

Reboxetine

If 4 mg of reboxetine is taken orally by a healthy adult, the peak levels can be about 130 ng/mL and are achieved within 2 hours after administration. [20] The administration of reboxetine with food delayed the absorption rate by approximately 2 hours while not affecting the extent of absorption. The absolute bioavailability is approximately 94%. Plasma concentrations of reboxetine fell in one exponential phase (monoexponential) with a half-life of about 12 hours. Steady-state is seen within 5 days. [21] [22] Reboxetine is 97% protein bound in young people and 92% in the elderly and is distributed into total body water. [22] Radioactivity excreted in the urine corresponds to 78% of the dose. Even though the drug is mainly unchanged in blood circulation (70% of total radioactivity, as the area under the concentration curve (AUC)), only about 10% of the dose is excreted unchanged in the urine. [20] Reboxetine is almost fully metabolised after oral administration. The drug is mainly metabolised through o-dealkylation and oxidation of the morpholine ring and hydroxylation of the ethoxyphenoxy ring. [20] In vitro studies indicate that the CYP450(3A4) enzyme is primarily responsible for the metabolism of reboxetine. [22] The drug is available as a racemic compound. The RR enantiomer is 10 times less potent than the SS enantiomer. The SS enantiomer (more potent) has a plasma level that is two times lower than the urinary excretion. [21] Elimination of reboxetine is mainly via hepatic metabolism (by cytochrome P450 3A4) with a mean terminal half-life of about 12 hours. [22] No significant difference was observed in the terminal half-lives of the RR and SS diastereomers. About 10% of the dose of reboxetine is cleared renally. [21]

Dosage

For adult patients with attention deficit hyperactivity disorder (ADHD), the initial dose of atomoxetine should be 40 mg daily. The dose should be increased after a minimum of 3 days to a target dose of 80 mg daily as a single dose in the morning. The 80 mg/day can also be taken in two divided doses in the morning and late afternoon. After 2–4 weeks the dose may be increased to 100 mg/day but doses over 100 mg/ day are not suggested. [23]

In the use of atomoxetine in children (6 years or older up to 70 kg) with attention-deficit hyperactivity disorder, acute treatment should be started with approximately 0.5 mg/kg orally daily. The dose should be increased after a minimum of 3 days up to approximately 1.2 mg/kg daily (target dose) as a single or two divided doses (in the morning and late afternoon). For children older than 6 years old, over 70 kg, acute treatment should be started with 40 mg/day orally and increased up to 80 mg/day after a minimum of 3 days. The dose can be taken as a single dose in the morning or in two divided doses (in the morning and late afternoon). After 2–4 weeks the dose can be increased to 100 mg/ daily. [23]

In the use of reboxetine for depression, clinical studies have shown that most patients are treated with an initial dose of reboxetine 8 mg/day, most often as a divided dose. Depending upon patient tolerance and need, the dose can be increased up to 10 mg/day. Doses over 12 mg/day are not recommended. Doses should be adjusted in renal failure, hepatic insufficiency and in geriatric patients. [10]

Structure and function

Structure activity relationship

Aryloxy propylamine moiety of atomoxetine and reboxetine SAR .png
Aryloxy propylamine moiety of atomoxetine and reboxetine

Atomoxetine contains an aryloxy propylamine moiety that has been linked to monoamine reuptake inhibitory activity. It's selectivity to the norepinephrine transporter (NET) is due to its methyl substituent in the 2’ position on the phenyl ring. [24] Research has shown that a methyl group in position 2’ provides more affinity towards NET than a methoxy group in the same position. [25] The amine group of atomoxetine binds to the amino acids of NET with a salt bridge and hydrogen bonds while the phenyl and methylphenyl groups have hydrophobic interactions. [26] Reboxetine has two chiral centers and the active ingredient is a mixture of the (R,R)-(-)- and (S,S)-(+) enantiomers. [27] Reboxetine, like atomoxetine, contains an aryloxy propylamine moiety and has an ethoxy group in position 2’ on the phenyl ring. But the main difference from atomoxetine is the morpholine group instead of a secondary amine. [24] The morpholine group of reboxetine forms a salt bridge and hydrogen bonds with the amino acids of NET. While the phenyl and ethyloxyphenyl groups form hydrophobic interactions. [26]

The aryloxy propylamine moiety is also found in many other monoamine reuptake inhibitors, but the placement of substituents on the phenyl ring determine the selectivity. Compounds with substituents in position 2’ have selectivity for NET. Compounds with substituents in position 4’ are selective serotonin reuptake inhibitors e.g. fluoxetine and paroxetine. Then there is duloxetine which has a phenyl group attached at positions 2’ and 3’ and has a similar affinity for both transporters. [24]

History

In the 1950s, major breakthrough in psychopharmacology occurred around the world. Then throughout the 1960s and 1970s major advances were made in synthesizing and identifying psychoactive drugs which were useful in the treatment of various mental disorders. Here, scientists had realised that these drugs interact with receptors located on neurons that led to changes in neural functioning. The connection was made shortly after the discovery of catecholamines having effects on emotion, relating to depression, and was of wide interest. Discovery was made on the decreased levels of certain neurotransmitters, catecholamines such as norepinephrine, dopamine and serotonin, and their role in the pathogenesis of depression. [28] These past discoveries in psychopharmacology led to the development of antidepressants and a range of drugs with different functions on those neurotransmitters. But a new generation of antidepressants were resulted from the discovery of selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine). Although SSRIs are a group of effective antidepressant drugs with considerably few severe side effects, they are not universally effective and can also have a few unpleasant side effects, such as weight gain, sleep disturbances and anxiety. [11] Pharmacologically and chemically unrelated to SSRIs, the past four decades, norepinephrine has been asserted to play an important, possibly primary, role in the treatment of mental disorders. This was from the notion that depression was primarily due to norepinephrine deficits, partly based on the fact that drugs that relieve depression increase brain norepinephrine levels. [28] To date, a great number of potent and selective and mixed norepinephrine reuptake inhibitors (NRIs) have been marketed as antidepressants. [11] The first commercially available selective norepinephrine reuptake inhibitor (sNRI) was reboxetine (Edronax) and was developed as a first-line therapy for major depressive disorder. [29] The selectivity of reboxetine for the norepinephrine transporter (NET) results in benign side effect profile because the drug is well tolerated. [11] In the laboratories of Chemistry of Farmitalia Carlo Erba (Milan, Italy), reboxetine was synthesized according to the general method described by Melloni et al. [30] In 1993 Kabi Pharmacia, Swedish based pharmaceutical giant, bought Farmitalian and in 2003 Pfizer bought Pharmacia. [31] [32] Atomoxetine (Strattera) is another potent and selective NRI which is also effective and well tolerated treatment for adults with ADHD. This drug was the first ADHD treatment to be specially approved for adult use. Studies showed that atomoxetine is a nonstimulant and carries negligible risk of abuse. This discovery was groundbreaking as a beneficial new treatment option for adults with ADHD, specially those patients at risk of substance abuse. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), and obsessive–compulsive disorder (OCD). SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

<span class="mw-page-title-main">Atomoxetine</span> Medication used to treat ADHD

Atomoxetine, sold under the brand name Strattera among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with stimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Norepinephrine reuptake inhibitor</span> Class of drug

A norepinephrine reuptake inhibitor or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline) by blocking the action of the norepinephrine transporter (NET). This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine and therefore can increase adrenergic neurotransmission.

<span class="mw-page-title-main">Reboxetine</span> NRI antidepressant drug

Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also been used off-label for panic disorder and attention deficit hyperactivity disorder (ADHD). It is approved for use in many countries worldwide, but has not been approved for use in the United States.

<span class="mw-page-title-main">Desipramine</span> Antidepressant

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<span class="mw-page-title-main">Viloxazine</span> Medication used to treat ADHD

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<span class="mw-page-title-main">Norepinephrine transporter</span> Protein-coding gene in the species Homo sapiens

The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.

<span class="mw-page-title-main">Phenyltropane</span> Class of chemical compounds

Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

<span class="mw-page-title-main">Nisoxetine</span> Chemical compound

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<span class="mw-page-title-main">Levoamphetamine</span> CNS stimulant and isomer of amphetamine

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<span class="mw-page-title-main">Norepinephrine–dopamine reuptake inhibitor</span> Drug that inhibits the reuptake of norepinephrine and dopamine

A norepinephrine–dopamine reuptake inhibitor (NDRI) is a drug used for the treatment of clinical depression, attention deficit hyperactivity disorder (ADHD), narcolepsy, and the management of Parkinson's disease. The drug acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of both norepinephrine and dopamine and, therefore, an increase in adrenergic and dopaminergic neurotransmission.

<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

A serotonin–dopamine reuptake inhibitor (SDRI) is a type of drug which acts as a reuptake inhibitor of the monoamine neurotransmitters serotonin and dopamine by blocking the actions of the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. This in turn leads to increased extracellular concentrations of serotonin and dopamine, and, therefore, an increase in serotonergic and dopaminergic neurotransmission.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have application as antidepressants and in the treatment of depression and other psychiatric disorders. SSRIs are therapeutically useful in the treatment of panic disorder (PD), posttraumatic stress disorder (PTSD), social anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder (PMDD), and anorexia. There is also clinical evidence of the value of SSRIs in the treatment of the symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

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