Pharmacology of antidepressants

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The pharmacology of antidepressants is not entirely clear. The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis (which can be traced back to the 1950s), which states that depression is due to an imbalance (most often a deficiency) of the monoamine neurotransmitters (namely serotonin, norepinephrine and dopamine). [1] It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. [1] All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway. [1] Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. [2] [3] Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid (within 2 hours), robust and sustained (lasting for up to a fortnight) antidepressant effects. [3] Monoamine precursor depletion also fails to alter mood. [4] [5] [6] To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. [2] [3] [7] [8] Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases. [9]

Contents

Neurogenic adaptations

The neurogenic hypothesis states that molecular and cellular mechanisms underlying the regulation of adult neurogenesis is required for remission from depression and that neurogenesis is mediated by the action of antidepressants. [10] Chronic use of antidepressant increased neurogenesis in the hippocampus of rats. [11] [12] [13] Other animal research suggests that long term drug-induced antidepressants effects modulate the expression of genes mediated by clock genes, possibly by regulating the expression of a second set of genes (i.e. clock-controlled genes). [14]

The 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). [15]

Hypothalamic-pituitary-adrenal axis

One manifestation of depression is an altered hypothalamic-pituitary-adrenal axis (HPA axis) that resembles the neuro-endocrine (cortisol) response to stress, that of increased cortisol production and a subsequent impaired negative feedback mechanism. It is not known whether this HPA axis dysregulation is reactive or causative for depression. This briefing suggests that the mode of action of antidepressants may be in regulating HPA axis function. [16]

Monoamine hypothesis

In 1965, Joseph Schildkraut postulated the Monoamine Hypothesis when he posited an association between low levels of neurotransmitters and depression. [17] By 1985, the monoamine hypothesis was mostly dismissed until it was revived with the introduction of SSRIs through the successful direct-to-consumer advertising, often revolving around the claim that SSRIs correct a chemical imbalance caused by a lack of serotonin within the brain.

Serotonin levels in the human brain is measured indirectly by sampling cerebrospinal fluid for its main metabolite, 5-hydroxyindole-acetic acid, or by measuring the serotonin precursor, tryptophan. In one placebo controlled study funded by the National Institute of Health, tryptophan depletion was achieved, but they did not observe the anticipated depressive response. [18] Similar studies aimed at increasing serotonin levels did not relieve symptoms of depression. At this time, decreased serotonin levels in the brain and symptoms of depression have not been linked [19]

Although there is evidence that antidepressants inhibit the reuptake of serotonin, [20] norepinephrine, and to a lesser extent dopamine, the significance of this phenomenon in the amelioration of psychiatric symptoms is not known. Given the low overall response rates of antidepressants, [21] and the poorly understood causes of depression, it is premature to assume a putative mechanism of action of antidepressants.

While MAOIs, TCAs and SSRIs increase serotonin levels, others prevent serotonin from binding to 5-HT2Areceptors, suggesting it is too simplistic to say serotonin is a "happy neurotransmitter". In fact, when the former antidepressants build up in the bloodstream and the serotonin level is increased, it is common for the patient to feel worse for the first weeks of treatment. One explanation of this is that 5-HT2A receptors evolved as a saturation signal (people who use 5-HT2A antagonists often gain weight), telling the animal to stop searching for food, a mate, etc., and to start looking for predators. In a threatening situation it is beneficial for the animal not to feel hungry even if it needs to eat. Stimulation of 5-HT2A receptors will achieve that. But if the threat is long lasting the animal needs to start eating and mating again - the fact that it survived shows that the threat was not so dangerous as the animal felt. So the number of 5-HT2A receptors decreases through a process known as downregulation and the animal goes back to its normal behavior. This suggests that there are two ways to relieve anxiety in humans with serotonergic drugs: by blocking stimulation of 5-HT2A receptors or by overstimulating them until they decrease via tolerance.[ medical citation needed ]

Receptor affinity

A variety of monoaminergic antidepressants have been compared below: [1] [22] [23] [24] [25] [26]

Compound SERT NET DAT H1 mACh α1 α2 5-HT1A 5-HT2A 5-HT2C D2 MT1A MT1B
Agomelatine ?????????631?0.10.12
Amitriptyline 3.1322.453801.118246904504.36.151460??
Amoxapine 58164310251000502600?0.5220.8??
Atomoxetine 433.512705500206038008800109001000940>35000??
Bupropion 9100526005266700400004550>35000>35000>10000>35000>35000??
Buspirone ?????138?5.7138174362??
Butriptyline 136051003940??????????
Citalopram 1.3851002800038018001550>10000>10000>10000617???
Clomipramine 0.1445.9260531.23739525>1000035.564.6119.8??
Desipramine 17.60.8331901101961005500>10000113.54961561??
Dosulepin 8.6465310426419124004152????
Doxepin 6829.5121000.2483.323.51270276268.8360??
Duloxetine 0.85.927823003000830086005000504916>10000??
Escitalopram 0.8-1.1780027400200012403900>1000>1000>10002500>1000??
Etoperidone 89020000520003100>35000385708536362300??
Femoxetine 1176020504200184650197022851301905590??
Fluoxetine 1.06604176625020005900139003240019725512000??
Fluvoxamine 1.951892>10000>1000024000012881900>10000>100006700>10000??
Imipramine 1.43783003746323100>10000119120726??
Lofepramine 705.4180003606710027004600200?2000??
Maprotiline 580011.110001.7560919400?51122665??
Mazindol 1001.219.7600?????????
Mianserin 40007194001.05007431.514953.212.592052??
Milnacipran 94.1111>10000??????????
Mirtazapine >100004600>100000.14794608201869395454??
Nefazodone 400490360240001100048640808.672910??
Nisoxetine 6105.1382?5000???620????
Nomifensine 294122.341.12700>10000120067441183937>10000>10000??
Nortriptyline 16.54.37310015.13755203029458.52570??
Oxaprotiline 39004.94340??????????
Paroxetine 0.0856.7574220001084600>10000>35000>100001900032000??
Protriptyline 19.61.41210060251306600?26????
Quetiapine >10,000>10,000>10,0007?223,630376992502245??
Reboxetine 27413.411500312670011900>10000>10000>10000457>10000??
Sertraline 0.2166725.5240006253704100>350001000100010700??
Trazodone 367>10000>10000220>350004232011835.82244142??
Trimipramine 149245037801.45824680??????
Venlafaxine 7.727538474>35000>35000>35000>35000>35000>35000>10000>35000??
Vilazodone 0.1??????2.3?????
Viloxazine 17300155>100000??????????
Vortioxetine 1.6113>1000????15 (Agonist)?180???
Zimelidine 152940011700??????????

The values above are expressed as equilibrium dissociation constants in nanomoles/liter. A smaller dissociation constant indicates more affinity. SERT, NET, and DAT correspond to the abilities of the compounds to inhibit the reuptake of serotonin, norepinephrine, and dopamine, respectively. The other values correspond to their affinity for various receptors.

Anti-inflammatory and immunomodulation

Recent studies show pro-inflammatory cytokine processes take place during clinical depression, mania and bipolar disorder, and it is possible that symptoms of these conditions are attenuated by the pharmacological effect of antidepressants on the immune system. [27] [28] [29] [30] [31]

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. [30] 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. [32] [33] [34] [35] [36]

Antidepressants, specifically TCAs and SNRIs (or SSRI-NRI combinations), have also shown analgesic properties. [37] [38]

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. [39] 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. [40]

Pharmacokinetics

Sources: [41] [42] [43] [44]

DrugBioavailability t1/2 (hr) for parent drug (active metabolite) Vd (L/kg unless otherwise specified)Cp (ng/mL) parent drug (active metabolite)TmaxProtein binding Parent drug (active metabolite(s))ExcretionEnzymes responsible for metabolismEnzymes inhibited [45]
Tricyclic antidepressant (TCAs)
Amitriptyline 30–60%9–27 (26–30)?100–2504 hr>90% (93–95%)Urine (18%)
?
Amoxapine ?8 (30)0.9–1.2200–50090 mins90%Urine (60%), faeces (18%)??
Clomipramine 50%32 (70)17100–250 (230–550)2–6 hr97–98%Urine (60%), faeces (32%) CYP2D6 ?
Desipramine ?30?125–3004–6 hr?Urine (70%) CYP2D6 ?
Doxepin ?18 (30)11930150–2502 hr80%Urine
?
Imipramine High12 (30)18175–3001–2 hr90%Urine
?
Lofepramine 7%1.7–2.5 (12–24)?30–50 (100–150)1 hr99% (92%)UrineCYP450?
Maprotiline High48?200–4008–24 hr88%Urine (70%); faeces (30%)??
Nortriptyline ?28–312150–1507–8.5 hr93–95%Urine, faeces CYP2D6 ?
Protriptyline High80?100–15024–30 hr92%Urine??
Tianeptine 99%2.5–30.5–1?1–2 hr95–96%Urine (65%)??
Trimipramine 41%23–24 (30)17–48100–3002 hr94.9%Urine??
Monoamine oxidase inhibitors (MAOIs)
Moclobemide 55–95%2??1–2 hr50%Urine, faeces (<5%)? MAOA
Phenelzine ?11.6??43 mins?Urine MAOA MAO
Tranylcypromine ?1.5–33.09?1.5–2 hr?Urine MAO MAO
Selective serotonin reuptake inhibitors (SSRIs)
Citalopram 80%35–361275–1502–4 hr80%Urine (15%)
 CYP1A2 (weak)
Escitalopram 80%27–322040–803.5–6.5 hr56%Urine (8%)
 CYP2D6 (weak)
Fluoxetine 72%24–72 (single doses), 96–144 (repeated dosing)12–43100–5006–8 hr95%Urine (15%) CYP2D6
Fluvoxamine 53%1825100–2003–8 hr80%Urine (85%)
Paroxetine ?178.730–1005.2–8.1 (IR); 6–10 hr (CR)93–95%Urine (64%), faeces (36%) CYP2D6
Sertraline 44%23–26 (66)?25–504.5–8.4 hr98%Urine (12–14% unchanged), faeces (40–45%)
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
Desvenlafaxine 80%113.4?7.5 hr30%Urine (69%) CYP3A4 CYP2D6 (weak)
Duloxetine High11–123.4?6 hr (empty stomach), 10 hr (with food)>90%Urine (70%; <1% unchanged), faeces (20%)
 CYP2D6 (moderate)
Levomilnacipran 92%12387–473 L?6–8 hr22%Urine (76%; 58% as unchanged drug & 18% as N-desmethyl metabolite)
?
Milnacipran 85-90%6-8 (L-isomer), 8-10 (D-isomer)400 L?2–4 hr13%Urine (55%)??
Venlafaxine 45%5 (11)7.5?2-3 hr (IR), 5.5–9 hr (XR)27–30% (30%)Urine (87%) CYP2D6 CYP2D6 (weak)
Others
Agomelatine ≥80%1–2 hr35 L?1–2 hr95%Urine (80%)
?
Bupropion ?8–24 (IR; 20, 30, 37), 21±7 (XR)20–4775–1002 hr (IR), 3 hr (XR)84%Urine (87%), faeces (10%) CYP2B6 CYP2D6 (moderate)
Mianserin 20-30%21–61??3 hr95%Faeces (14–28%), urine (4–7%) CYP2D6 ?
Mirtazapine 50%20–404.5?2 hr85%Urine (75%), faeces (15%)
?
Nefazodone 20% (decreased by food)2–40.22–0.87?1 hr>99%Urine (55%), faeces (20–30%) CYP3A4 ?
Reboxetine 94%12–1326 L (R,R diastereomer), 63 L (S,S diastereomer)?2 hr97%Urine (78%; 10% as unchanged) CYP3A4 ?
Trazodone ?6–10?800–16001 hr (without food), 2.5 hr (with food)85–95%Urine (75%), faeces (25%) CYP2D6 ?
Vilazodone 72% (with food)25??4–5 hr96–99%Faeces (2% unchanged), urine (1% unchanged)
?
Vortioxetine ?662600 L?7–11 hr98%Urine (59%), faeces (26%)
?

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Serotonin</span> Monoamine neurotransmitter

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex, touching on diverse functions including mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction. This multifacetedness has led to its study being described as "like the fable of the blind men and the elephant".

<span class="mw-page-title-main">Serotonin syndrome</span> Symptoms caused by an excess of serotonin in the central nervous system

Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild cases include high blood pressure and a fast heart rate; usually without a fever. Symptoms in moderate cases include high body temperature, agitation, increased reflexes, tremor, sweating, dilated pupils, and diarrhea. In severe cases, body temperature can increase to greater than 41.1 °C (106.0 °F). Complications may include seizures and extensive muscle breakdown.

<span class="mw-page-title-main">Psychopharmacology</span> Study of the effects of psychoactive drugs

Psychopharmacology is the scientific study of the effects drugs have on mood, sensation, thinking, behavior, judgment and evaluation, and memory. It is distinguished from neuropsychopharmacology, which emphasizes the correlation between drug-induced changes in the functioning of cells in the nervous system and changes in consciousness and behavior.

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

Mirtazapine, sold under the brand name Remeron amongst others, is an atypical tetracyclic antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is often used in cases of depression complicated by anxiety or insomnia. The effectiveness of mirtazapine is comparable to other commonly prescribed antidepressants. It is taken by mouth.

<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, obsessive–compulsive disorder (OCD), social phobia, attention-deficit hyperactivity disorder (ADHD), chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. 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">Azapirone</span> Drug class of psycotropic drugs

Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs).

<span class="mw-page-title-main">Noradrenergic and specific serotonergic antidepressant</span> Class of antidepressants

Noradrenergic and specific serotonergic antidepressants (NaSSAs) are a class of psychiatric drugs used primarily as antidepressants. They act by antagonizing the α2-adrenergic receptor and certain serotonin receptors such as 5-HT2A and 5-HT2C, but also 5-HT3, 5-HT6, and/or 5-HT7 in some cases. By blocking α2-adrenergic autoreceptors and heteroreceptors, NaSSAs enhance adrenergic and serotonergic neurotransmission in the brain involved in mood regulation, notably 5-HT1A-mediated transmission. In addition, due to their blockade of certain serotonin receptors, serotonergic neurotransmission is not facilitated in unwanted areas, which prevents the incidence of many side effects often associated with selective serotonin reuptake inhibitor (SSRI) antidepressants; hence, in part, the "specific serotonergic" label of NaSSAs.

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

Trimipramine, sold under the brand name Surmontil among others, is a tricyclic antidepressant (TCA) which is used to treat depression. It has also been used for its sedative, anxiolytic, and weak antipsychotic effects in the treatment of insomnia, anxiety disorders, and psychosis, respectively. The drug is described as an atypical or "second-generation" TCA because, unlike other TCAs, it seems to be a fairly weak monoamine reuptake inhibitor. Similarly to other TCAs however, trimipramine does have antihistamine, antiserotonergic, antiadrenergic, antidopaminergic, and anticholinergic activities.

<span class="mw-page-title-main">Serotonin receptor agonist</span> Neurotransmission-modulating substance

A serotonin receptor agonist is an agonist of one or more serotonin receptors. They activate serotonin receptors in a manner similar to that of serotonin, a neurotransmitter and hormone and the endogenous ligand of the serotonin receptors.

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.

<i>N</i>-Acetylserotonin Chemical compound

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.

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

Benzofuranylpropylaminopentane is a drug with an unusual monoamine-release potentiating mechanism of action. It can loosely be grouped with the stimulant or antidepressant drug families, but its mechanism of action is quite different.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

A reuptake inhibitor (RI) is a type of drug known as a reuptake modulator that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons.

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

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

<span class="mw-page-title-main">Selective serotonin reuptake inhibitor</span> Class of antidepressant medication

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.

A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, is a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

Selective serotonin reuptake inhibitors, or serotonin-specific re-uptake inhibitor (SSRIs), are a class of chemical compounds that have contributed to the major advances as antidepressants where they have revolutionised the treatment of depression and other psychiatric disorders. The 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 SSRIs efficiency in the treatment of the negative symptoms of schizophrenia and their ability to prevent cardiovascular diseases.

References

  1. 1 2 3 4 Brunton LL, Chabner B, Knollmann BC, eds. (2011). Goodman & Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN   978-0-07-162442-8.
  2. 1 2 Maes M, Yirmyia R, Noraberg J, Brene S, Hibbeln J, Perini G, et al. (March 2009). "The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression". Metabolic Brain Disease. 24 (1): 27–53. doi:10.1007/s11011-008-9118-1. hdl: 11577/2380064 . PMID   19085093. S2CID   4564675.
  3. 1 2 3 Sanacora G, Treccani G, Popoli M (January 2012). "Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders". Neuropharmacology. 62 (1): 63–77. doi:10.1016/j.neuropharm.2011.07.036. PMC   3205453 . PMID   21827775.
  4. ↑ Oldman AD, Walsh AE, Salkovskis P, Laver DA, Cowen PJ (January 1994). "Effect of acute tryptophan depletion on mood and appetite in healthy female volunteers". Journal of Psychopharmacology. 8 (1): 8–13. doi:10.1177/026988119400800102. PMID   22298474. S2CID   25812087.
  5. ↑ Leyton M, Young SN, Blier P, Ellenbogen MA, Palmour RM, Ghadirian AM, Benkelfat C (April 1997). "The effect of tryptophan depletion on mood in medication-free, former patients with major affective disorder". Neuropsychopharmacology. 16 (4): 294–297. doi: 10.1016/s0893-133x(96)00262-x . PMID   9094147.
  6. ↑ Hughes JH, Dunne F, Young AH (November 2000). "Effects of acute tryptophan depletion on mood and suicidal ideation in bipolar patients symptomatically stable on lithium". The British Journal of Psychiatry. 177 (5): 447–451. doi: 10.1192/bjp.177.5.447 . PMID   11059999.
  7. ↑ Menke A, Klengel T, Binder EB (2012). "Epigenetics, depression and antidepressant treatment". Current Pharmaceutical Design. 18 (36): 5879–5889. doi:10.2174/138161212803523590. PMID   22681167.
  8. ↑ Vialou V, Feng J, Robison AJ, Nestler EJ (January 2013). "Epigenetic mechanisms of depression and antidepressant action". Annual Review of Pharmacology and Toxicology. 53 (1): 59–87. doi:10.1146/annurev-pharmtox-010611-134540. PMC   3711377 . PMID   23020296.
  9. ↑ Outhred T, Hawkshead BE, Wager TD, Das P, Malhi GS, Kemp AH (September 2013). "Acute neural effects of selective serotonin reuptake inhibitors versus noradrenaline reuptake inhibitors on emotion processing: Implications for differential treatment efficacy". Neuroscience and Biobehavioral Reviews. 37 (8): 1786–1800. doi:10.1016/j.neubiorev.2013.07.010. PMID   23886514. S2CID   15469440.
  10. ↑ Warner-Schmidt JL, Duman RS (2006). "Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment". Hippocampus. 16 (3): 239–249. doi:10.1002/hipo.20156. PMID   16425236. S2CID   13852671.
  11. ↑ Malberg JE, Eisch AJ, Nestler EJ, Duman RS (December 2000). "Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus". The Journal of Neuroscience. 20 (24): 9104–9110. doi:10.1523/JNEUROSCI.20-24-09104.2000. PMC   6773038 . PMID   11124987.
  12. ↑ Manev H, Uz T, Smalheiser NR, Manev R (January 2001). "Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro". European Journal of Pharmacology. 411 (1–2): 67–70. doi:10.1016/S0014-2999(00)00904-3. PMID   11137860.
  13. ↑ Carboni L, Vighini M, Piubelli C, Castelletti L, Milli A, Domenici E (October 2006). "Proteomic analysis of rat hippocampus and frontal cortex after chronic treatment with fluoxetine or putative novel antidepressants: CRF1 and NK1 receptor antagonists". European Neuropsychopharmacology. 16 (7): 521–537. doi:10.1016/j.euroneuro.2006.01.007. PMID   16517129. S2CID   32598738.
  14. ↑ 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): 1309–1316. doi:10.1016/j.neuroscience.2005.05.003. PMID   15994025. S2CID   23980582.
  15. ↑ Zhang HT, Huang Y, Mishler K, Roerig SC, O'Donnell JM (October 2005). "Interaction between the antidepressant-like behavioral effects of beta adrenergic agonists and the cyclic AMP PDE inhibitor rolipram in rats". Psychopharmacology. 182 (1): 104–115. doi:10.1007/s00213-005-0055-y. PMID   16010541. S2CID   22214792.
  16. ↑ Pariante CM (August 2003). "Depression, stress and the adrenal axis". Journal of Neuroendocrinology. 15 (8): 811–812. doi:10.1046/j.1365-2826.2003.01058.x. PMID   12834443. S2CID   1359479.
  17. ↑ Schildkraut JJ (1995). "The catecholamine hypothesis of affective disorders: a review of supporting evidence. 1965". The Journal of Neuropsychiatry and Clinical Neurosciences. 7 (4): 524–33, discussion 523–4. doi:10.1176/jnp.7.4.524. PMID   8555758.
  18. ↑ Moreno FA, Parkinson D, Palmer C, Castro WL, Misiaszek J, El Khoury A, et al. (January 2010). "CSF neurochemicals during tryptophan depletion in individuals with remitted depression and healthy controls". European Neuropsychopharmacology. 20 (1): 18–24. doi:10.1016/j.euroneuro.2009.10.003. PMC   2794896 . PMID   19896342.
  19. ↑ Lacasse JR, Leo J (December 2005). "Serotonin and depression: a disconnect between the advertisements and the scientific literature". PLOS Medicine. 2 (12): e392. doi: 10.1371/journal.pmed.0020392 . PMC   1277931 . PMID   16268734.
  20. ↑ Murphy DL, Andrews AM, Wichems CH, Li Q, Tohda M, Greenberg B (1998). "Brain serotonin neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent implications for understanding the actions of serotonergic drugs". The Journal of Clinical Psychiatry. 59 (Suppl 15): 4–12. PMID   9786305.
  21. ↑ Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA (2012). Holscher C (ed.). "A systematic review of comparative efficacy of treatments and controls for depression". PLOS ONE. 7 (7): e41778. Bibcode:2012PLoSO...741778K. doi: 10.1371/journal.pone.0041778 . PMC   3408478 . PMID   22860015.
  22. ↑ Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID   9537821.
  23. ↑ Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". The Journal of Pharmacology and Experimental Therapeutics. 283 (3): 1305–1322. PMID   9400006.
  24. ↑ Cusack B, Nelson A, Richelson E (May 1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–565. doi:10.1007/BF02244985. PMID   7855217. S2CID   21236268.
  25. ↑ Schatzberg AF, Nemeroff CB (2006). Essentials of clinical psychopharmacology. American Psychiatric Pub. p. 7. ISBN   978-1-58562-243-6.
  26. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Oct 4]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: "PDSP Database - UNC". Archived from the original on 2013-11-08. Retrieved 2013-10-26.
  27. ↑ O'Brien SM, Scully P, Scott LV, Dinan TG (February 2006). "Cytokine profiles in bipolar affective disorder: focus on acutely ill patients". Journal of Affective Disorders. 90 (2–3): 263–267. doi:10.1016/j.jad.2005.11.015. PMID   16410025.
  28. ↑ Obuchowicz E, Marcinowska A, Herman ZS (2005). "[Antidepressants and cytokines--clinical and experimental studies]" [Antidepressants and cytokines – clinical and experimental studies](PDF). Psychiatria Polska (in Polish). 39 (5): 921–936. PMID   16358592.
  29. ↑ Hong CJ, Yu YW, Chen TJ, Tsai SJ (2005). "Interleukin-6 genetic polymorphism and Chinese major depression". Neuropsychobiology. 52 (4): 202–205. doi:10.1159/000089003. PMID   16244501. S2CID   19710111.
  30. 1 2 Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP (2005). "Cytokine dysregulation, inflammation and well-being". Neuroimmunomodulation. 12 (5): 255–269. doi:10.1159/000087104. PMID   16166805. S2CID   39185155.
  31. ↑ Kubera M, Maes M, Kenis G, Kim YK, Lasoń W (April 2005). "Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6". Psychiatry Research. 134 (3): 251–258. doi:10.1016/j.psychres.2004.01.014. PMID   15892984. S2CID   28014123.
  32. ↑ Diamond M, Kelly JP, Connor TJ (October 2006). "Antidepressants suppress production of the Th1 cytokine interferon-gamma, independent of monoamine transporter blockade". European Neuropsychopharmacology. 16 (7): 481–490. doi:10.1016/j.euroneuro.2005.11.011. PMID   16388933. S2CID   12983560.
  33. ↑ Kubera M, Lin AH, Kenis G, Bosmans E, van Bockstaele D, Maes M (April 2001). "Anti-Inflammatory effects of antidepressants through suppression of the interferon-gamma/interleukin-10 production ratio". Journal of Clinical Psychopharmacology. 21 (2): 199–206. doi:10.1097/00004714-200104000-00012. PMID   11270917. S2CID   43429490.
  34. ↑ Maes M (January 2001). "The immunoregulatory effects of antidepressants". Human Psychopharmacology. 16 (1): 95–103. doi:10.1002/hup.191. PMID   12404604. S2CID   25926395.
  35. ↑ Maes M, Kenis G, Kubera M, De Baets M, Steinbusch H, Bosmans E (March 2005). "The negative immunoregulatory effects of fluoxetine in relation to the cAMP-dependent PKA pathway". International Immunopharmacology. 5 (3): 609–618. doi:10.1016/j.intimp.2004.11.008. PMID   15683856.
  36. ↑ Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB (June 2006). "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice". International Immunopharmacology. 6 (6): 903–907. doi:10.1016/j.intimp.2005.12.007. PMID   16644475.
  37. ↑ Moulin DE, Clark AJ, Gilron I, Ware MA, Watson CP, Sessle BJ, et al. (2007). "Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society". Pain Research & Management. 12 (1): 13–21. doi: 10.1155/2007/730785 . PMC   2670721 . PMID   17372630.
  38. ↑ Jones CK, Eastwood BJ, Need AB, Shannon HE (December 2006). "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. 51 (7–8): 1172–1180. doi:10.1016/j.neuropharm.2006.08.005. PMID   17045620. S2CID   23871569.
  39. ↑ Kulmatycki KM, Jamali F (2006). "Drug disease interactions: role of inflammatory mediators in depression and variability in antidepressant drug response". Journal of Pharmacy & Pharmaceutical Sciences. 9 (3): 292–306. PMID   17207413.
  40. ↑ O'Brien SM, Scott LV, Dinan TG (August 2004). "Cytokines: abnormalities in major depression and implications for pharmacological treatment". Human Psychopharmacology. 19 (6): 397–403. doi:10.1002/hup.609. PMID   15303243. S2CID   11723122.
  41. ↑ "Therapeutic Goods Administration – Home page". Department of Health (Australia) . Retrieved 27 November 2013.[ full citation needed ]
  42. ↑ "electronic Medicines Compendium – Home page". Datapharm. Retrieved 28 November 2013.[ full citation needed ]
  43. ↑ "Medscape Multispecialty – Home page". WebMD . Retrieved 27 November 2013.[ full citation needed ]
  44. ↑ Brunton LL, Chabner B, Knollmann BC, eds. (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN   978-0-07-162442-8.
  45. ↑ Ciraulo DA, Shader RI, eds. (2011). Pharmacotherapy of Depression. doi:10.1007/978-1-60327-435-7. ISBN   978-1-60327-434-0.{{cite book}}: |work= ignored (help)
  46. ↑ Product Information: ELAVIL(R) oral tablets injection, amitriptyline oral tablets injection. Zeneca Pharmaceuticals, Wilmington, DE, 2000.
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