Tricyclic antidepressant

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.[1] 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.

Tricyclic antidepressant
Drug class
Chemical structure of the prototypical and first marketed tricyclic antidepressant imipramine. Notice its three rings.
Class identifiers
Chemical classTricyclic
External links
MeSHD000929
In Wikidata

Although TCAs are sometimes prescribed for depressive disorders, they have been largely replaced in clinical use in most parts of the world by newer antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and norepinephrine reuptake inhibitors (NRIs). Adverse effects have been found to be of a similar level between TCAs and SSRIs.[2]

History

The TCAs were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s.[3] Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic.[4] Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, a dibenzazepine analogue of chlorpromazine code-named G22355. It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania led to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Roland Kuhn in 1957.[3] Some testing of Geigy's imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz.[4] Geigy later became Ciba-Geigy and eventually Novartis.

Dibenzazepine derivatives are described in U.S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. The compounds described share a tricyclic backbone different from the backbone of the TCA amitriptyline.

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961.[4] This compound has a different three-ring structure than imipramine.

Medical uses

The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), neurological disorders such as attention-deficit hyperactivity disorder (ADHD),[5] Parkinson's disease[6] as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, or migraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE),[7] narcolepsy, insomnia, pathological crying and/or laughing, chronic hiccups, ciguatera poisoning, and as an adjunct in schizophrenia.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression. Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI moclobemide. However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes.[8] Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethal overdose (see therapeutic index) are far wider in comparison.

Nonetheless, the TCAs are commonly prescribed for treatment-resistant depression that has failed to respond to therapy with newer antidepressants, they also tend to have fewer emotional blunting and sexual side effects than SSRI antidepressants.[9] They are not considered addictive and are somewhat preferable to the monoamine oxidase inhibitors (MAOIs). The side effects of the TCAs usually come to prominence before the therapeutic benefits against depression and/or anxiety do, and for this reason, they may potentially be somewhat dangerous, as volition can be increased, possibly giving the patient a greater desire to attempt or commit suicide.[10]

Attention-deficit hyperactivity disorder

The TCAs were used in the past in the clinical treatment of ADHD,[11] though they are not typically used anymore, having been replaced by more effective agents with fewer side effects such as atomoxetine (Strattera, Tomoxetin) and stimulants like methylphenidate (Ritalin, Focalin, Concerta), and amphetamine (Adderall, Attentin, Dexedrine, Vyvanse). ADHD is thought to be caused by an insufficiency of dopamine and norepinephrine activity in the prefrontal cortex of the brain.[12] Most of the TCAs inhibit the reuptake of norepinephrine, though not dopamine, and as a result, they show some efficacy in remedying the disorder.[13] Notably, the TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits, as they help limit hyperactivity and impulsivity, but have little to no benefits on attention.[14]

Chronic pain

The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia.[15][16] The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties.[17][18][19] They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack. They may also be effective to prevent chronic tension headaches.

Side effects

Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.

Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia), confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose.[20] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[21]

Tolerance to these adverse effects of these drugs often develops if treatment is continued. Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

TCAs can behave like class 1A antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle. Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications like TCAs and dementia.[22] Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.[23] Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system. In the brain, acetylcholine is involved in learning and memory.

Discontinuation

Antidepressants in general may produce withdrawal. However, since the term "withdrawal" has been linked to addiction to recreational drugs like opioids, the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[24] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[25] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[26]

Overdose
Main article: Tricyclic antidepressant overdose

TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[27] and the availability of these in the home when prescribed for bed-wetting and depression. In the event of a known or suspected overdose, medical assistance should be sought immediately.

A number of treatments are effective in a TCA overdose.

An overdose on TCA is especially fatal as it is rapidly absorbed from the GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying.

Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:[28]

  1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
  2. Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals)
  3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
  4. Pulmonary effects: hypoventilation resulting from CNS depression
  5. Gastrointestinal effects: decreased or absent bowel sounds

Treatment of TCA overdose depends on severity of symptoms:

Initially, gastric decontamination of the patient is achieved by administering, either orally or via a nasogastric tube, activated charcoal pre-mixed with water, which adsorbs the drug in the gastrointestinal tract (most useful if given within 2 hours of drug ingestion). Other decontamination methods such as stomach pumps, gastric lavage, whole bowel irrigation, or (ipecac induced) emesis, are not  recommended in TCA poisoning.

If there is metabolic acidosis, intravenous infusion of sodium bicarbonate is recommended by Toxbase.org, the UK and Ireland poisons advice database (TCAs are protein bound and become less bound in more acidic conditions, so by reversing the acidosis, protein binding increases and bioavailability thus decreases – the sodium load may also help to reverse the Na+ channel blocking effects of the TCA).

Interactions

The TCAs are highly metabolised by the cytochrome P450 (CYP) hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.[29] The major factor that distinguishes SSRI's amongst one another is the inhibition of select CYP enzymes .[29] Drugs that prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

Pharmacology

The majority of the TCAs act primarily as SNRIs by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[30][31] Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[30] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[32]

In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[33] (5-HT2A[34] and 5-HT2C[34]), 5-HT6,[35] 5-HT7,[36] α1-adrenergic,[33] and NMDA receptors,[37] and as agonists at the sigma receptors[38] (σ1[38] and σ2[39]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[40] The TCAs also have varying but typically high affinity for antagonising the H1[33] and H2[41][42] histamine receptors, as well as the muscarinic acetylcholine receptors.[33] As a result, they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.[43]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[44][45] The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[46] It may also be involved in their efficacy as analgesics, however.[47]

In summary, tricyclic antidepressants can act through NMDA antagonism, opioidergic effects, sodium, potassium and calcium channel blocking, through interfering with the reuptake of serotonin and acting as antagonists to SHAM (serotonin, histamine, alpha, muscarinic) receptors.  Thus their dangerous side effect profile limits their use in daily practice.

Binding profiles
See also: Tetracyclic antidepressant § Binding profiles

The binding profiles of various TCAs and some metabolites in terms of their affinities (Ki, nM) for various receptors and transporters are as follows:[48]

CompoundSERTNETDAT5-HT1A5-HT2A5-HT2C5-HT65-HT7α1α2D2H1H2mAChσ1σ2
Amineptine>100,00010,0001,000–1,400>100,00074,000NDNDND>100,000>100,000>100,000≥13,000ND>100,000NDND
Amitriptyline2.8–4.319–353,250≥45018–234.065–14193–1234.4–24114–690196–1,4600.5–1.1669.6300ND
Amoxapine58164,310ND0.52.06.0–5041502,6003.6–1607.9–25ND1,000NDND
Butriptyline≥1,3605,1003,9407,000380NDNDND5704,800ND1.1ND35NDND
Clomipramine0.14–0.2838–54≥2,190≥7,00027–3665541273.2–38≥53578–19013–3120937546ND
Desipramine18–1630.63–3.53,190≥6,400115–350244–748ND>1,00023–130≥1,3793,40060–1101,55066–198≥1,990≥1,610
DibenzepinNDND>10,000>10,000≥1,500NDNDND>10,000>10,000>10,000231,9501,750NDND
Dosulepin8.6–7846–705,3104,000152NDNDND4192,400ND3.6–4.0ND25–26NDND
Doxepin68–21013–58≥4,60027611–278.8–200136ND2428–1,2703600.09–1.2317423–80NDND
Imipramine1.3–1.420–378,500≥5,80080–150120190–209>1,000323,100620–7267.6–3755046332–520327–2,100
Iprindole≥1,6201,2606,5302,800217–280206NDND2,3008,6006,300100–130200–8,3002,100>10,000ND
Lofepramine705.4>10,0004,600200NDNDND1002,7002,000245–3604,270672,520ND
Maprotiline5,80011–121,000ND51122ND50909,400350–6650.79–2.0776570NDND
Norclomipramine400.452,10019,000130NDNDND1901,8001,200450ND92NDND
Northiaden192252,5392,623141NDNDND950NDND25ND110NDND
Nortriptyline15–181.8–4.41,1402945.0–418.5148ND552,0302,5703.0–15646372,000ND
Opipramol≥2,200≥700≥3,000>10,000120NDNDND2006,100120–3006.04,4703,3000.2–50110
Protriptyline19.61.412,1003,80070NDNDND1306,6002,3007.2–2539825NDND
Tianeptine>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000>10,000
Trimipramine149–2,110≥2,450≥3,7808,00032537NDND24680143–2100.27–1.54158NDND
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. For assay species and references, see the individual drug articles. Most but not all values are for human proteins.

With the exception of the sigma receptors, the TCAs act as antagonists or inverse agonists of the receptors and as inhibitors of the transporters. Tianeptine is included in this list due to it technically being a TCA, but with a vastly different pharmacology.

Therapeutic levels of TCAs are generally in the range of about 100 to 300 ng/mL, or 350 to 1,100 nM.[49] Plasma protein binding is generally 90% or greater.[49]

Chemistry

There are two major groups of TCAs in terms of chemical structure, which most, but not all, TCAs fall into.[50][51][52] The groupings are based on the tricyclic ring system.[50][51][52] They are the dibenzazepines (imipramine, desipramine, clomipramine, trimipramine, lofepramine) and the dibenzocycloheptadienes (amitriptyline, nortriptyline, protriptyline, butriptyline).[50][51] Minor TCA groups based on ring system include the dibenzoxepins (doxepin), the dibenzothiepines (dosulepin), and the dibenzoxazepines (amoxapine).[50][51] In addition to classification based on the ring system, TCAs can also be usefully grouped based on the number of substitutions of the side chain amine.[52][53] These groups include the tertiary amines (imipramine, clomipramine, trimipramine, amitriptyline, butriptyline, doxepin, dosulepin) and the secondary amines (desipramine, nortriptyline, protriptyline).[52][53] Lofepramine is technically a tertiary amine, but acts largely as a prodrug of desipramine, a secondary amine, and hence is more similar in profile to the secondary amines than to the tertiary amines.[53] Amoxapine does not have the TCA side chain and hence is neither a tertiary nor secondary amine, although it is often grouped with the secondary amines due to sharing more in common with them.[54]

Society and culture

Recreational use

A very small number of cases involving non-medical use of antidepressants have been reported over the past 30 years.[55] According to the US government classification of psychiatric medications, TCAs are "non-abusable"[56] and generally have low abuse potential.[57] Nonetheless due to their atypical MOA, amineptine and tianeptine (dopamine reuptake inhibition and μ-opioid receptor agonism, respectively) are the two TCAs with the highest addiction and abuse potential. Despite tianeptine’s recreational value, many people use it as a nootropic and follow other countries’ usage guidelines, such as France, as a way to treat their depression if other antidepressants don’t work. Their prescription guidelines are 12.5 mg three times a day, and not to exceed 50 mg in one day. Tianeptine has no recreational value when taken at that dosage and kept under 50 mg a day. Many people report that tianeptine has treated their depression when SSRI’s or SNRI’s haven’t. Several cases of the misuse[58] of amitriptyline alone[59][60] or together with methadone[58][61] or in other drug dependent patients[62][63] and of dosulepin with alcohol[64] or in methadone patients[65] have been reported.

List of TCAs

Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

Whereas either fairly balanced reuptake inhibitors of serotonin and norepinephrine or unspecified inhibitors include:

And the following are TCAs that act via main mechanisms other than serotonin or norepinephrine reuptake inhibition:

Legend:

  • † indicates products which have been withdrawn from the market worldwide.
  • ‡ indicates products which are not available in any country in which English is an official language.
  • § indicates products which are not available in the United States, but are available in other English-speaking countries such as Australia, Canada, United Kingdom, etc.
  • Bolded names indicates products which are available in at least three countries in which English is an official language.

References
  1. Carson VB (2000). Mental health nursing: the nurse-patient journey W.B. Saunders. ISBN 978-0-7216-8053-8. pp. 423
  2. Trindade, E.; Menon, D.; Topfer, L. A.; Coloma, C. (November 1998). "Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis". Canadian Medical Association Journal. 159 (10): 1245–1252. PMC 1229819. PMID 9861221.
  3. A Guide to the Extrapyramidal Side-Effects of Antipsychotic Drugs, D. G. Cunningham Owens, http://assets.cambridge.org/97805216/33536/excerpt/9780521633536_excerpt.pdf
  4. Rose, Nikolas (2004). "Becoming Neurochemical Selves". In Stehr, Nico (ed.). Biotechnology: Between Commerce and Civil Society. New Brunswick, NJ: Transaction Publishers. pp. 90–91. ISBN 978-0-7658-0224-8.
  5. "Nonstimulant Therapy (Strattera) and Other ADHD Drugs - MedicineNet". MedicineNet.
  6. Paumier, K. L.; Siderowf, A. D.; Auinger, P; Oakes, D; Madhavan, L; Espay, A. J.; Revilla, F. J.; Collier, T. J.; Parkinson Study Group Genetics Epidemiology Working Group (2012). "Tricyclic antidepressants delay the need for dopaminergic therapy in early Parkinson's disease". Movement Disorders. 27 (7): 880–7. doi:10.1002/mds.24978. PMID 22555881.
  7. Glazener C, Evans J, Peto R (2016). Glazener, Cathryn MA (ed.). "Tricyclic and related drugs for nocturnal enuresis in children". Cochrane Database Syst. Rev. (1): CD002117. doi:10.1002/14651858.CD002117.pub2. PMID 26789925.CS1 maint: multiple names: authors list (link)
  8. Mitchell PB, Mitchell MS (September 1994). "The management of depression. Part 2. The place of the new antidepressants". Aust Fam Physician. 23 (9): 1771–3, 1776–81. PMID 7980178.
  9. Broquet K (1999). "Status of treatment of depression". South Med J. 92 (9): 846–56. doi:10.1097/00007611-199909000-00001. PMID 10498158.
  10. Teicher M, Glod C, Cole J (1993). "Antidepressant drugs and the emergence of suicidal tendencies". Drug Saf. 8 (3): 186–212. doi:10.2165/00002018-199308030-00002. PMID 8452661.
  11. Biederman J, Baldessarini R, Wright V, Knee D, Harmatz J (1989). "A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy". J Am Acad Child Adolesc Psychiatry. 28 (5): 777–84. doi:10.1097/00004583-198909000-00022. PMID 2676967.CS1 maint: uses authors parameter (link)
  12. Blum K, Chen AL, Braverman ER, Comings DE, Chen TJ, Arcuri V, Blum SH, Downs BW, Waite RL, Notaro A, Lubar J, Williams L, Prihoda TJ, Palomo T, Oscar-Berman M. (2008). "Attention-deficit-hyperactivity disorder and reward deficiency syndrome". Neuropsychiatr Dis Treat. 4 (5): 894–913. doi:10.2147/NDT.S2627. PMC 2626918. PMID 19183781.CS1 maint: uses authors parameter (link)
  13. Biederman J, Spencer T (1999). "Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder". Biol Psychiatry. 46 (9): 1234–42. doi:10.1016/S0006-3223(99)00192-4. PMID 10560028.CS1 maint: uses authors parameter (link)
  14. Popper C (1997). "Antidepressants in the treatment of attention-deficit/hyperactivity disorder". J Clin Psychiatry. 58 (Suppl 14): 14–29, discussion 30–1. PMID 9418743.
  15. Micó J, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain". Trends Pharmacol Sci. 27 (7): 348–54. doi:10.1016/j.tips.2006.05.004. PMID 16762426.
  16. McQuay H, Tramèr M, Nye B, Carroll D, Wiffen P, Moore R (1996). "A systematic review of antidepressants in neuropathic pain". Pain. 68 (2–3): 217–27. doi:10.1016/S0304-3959(96)03140-5. PMID 9121808.
  17. Botney M, Fields H (1983). "Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system". Ann Neurol. 13 (2): 160–4. doi:10.1002/ana.410130209. PMID 6219612.
  18. Benbouzid M; Gavériaux-Ruff C; Yalcin I; et al. (March 2008). "Delta-opioid receptors are critical for tricyclic antidepressant treatment of neuropathic allodynia". Biological Psychiatry. 63 (6): 633–6. doi:10.1016/j.biopsych.2007.06.016. PMID 17693391.
  19. de Gandarias JM, Echevarria E, Acebes I, Silio M, Casis L (July 1998). "Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain". Arzneimittel-Forschung. 48 (7): 717–9. PMID 9706370.
  20. Gelder, M, Mayou, R. and Geddes, J. 2005. Psychiatry. 3rd ed. New York: Oxford. pp243.
  21. Chabria SB (2006). "Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity". J Occup Med Toxicol. 1: 16. doi:10.1186/1745-6673-1-16. PMC 1540431. PMID 16846511.
  22. Gray, Shelly L.; Anderson, Melissa L.; Dublin, Sascha; Hanlon, Joseph T.; Hubbard, Rebecca; Walker, Rod; Yu, Onchee; Crane, Paul K.; Larson, Eric B. (1 March 2015). "Cumulative Use of Strong Anticholinergics and Incident Dementia". JAMA Internal Medicine. 175 (3): 401–7. doi:10.1001/jamainternmed.2014.7663. PMC 4358759. PMID 25621434.
  23. "Strong Link Found Between Dementia, Common Anticholinergic Drugs". Drug Discovery & Development.
  24. Shelton RC (2006). "The nature of the discontinuation syndrome associated with antidepressant drugs". J Clin Psychiatry. 67 Suppl 4: 3–7. PMID 16683856.
  25. van Broekhoven F, Kan CC, Zitman FG (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Progress in Neuro-psychopharmacology & Biological Psychiatry. 26 (5): 939–43. doi:10.1016/S0278-5846(02)00209-9. PMID 12369270.
  26. Kent Kunze MD. "Somatic Therapies in Psychiatry". Des Moines University Psychiatry Class.
  27. Rosenbaum T, Kou M (2005). "Are one or two dangerous? Tricyclic antidepressant exposure in toddlers". J Emerg Med. 28 (2): 169–74. doi:10.1016/j.jemermed.2004.08.018. PMID 15707813.
  28. California Poison Control 1-800-876-4766
  29. "Clinical Pharmacology of SSRI's: Why Are CYP Enzymes Important When Considering SSRIs?". preskorn.com.
  30. Tatsumi M, Groshan K, Blakely RD, Richelson E (1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". Eur J Pharmacol. 340 (2–3): 249–258. doi:10.1016/S0014-2999(97)01393-9. PMID 9537821.
  31. Gillman PK (July 2007). "Tricyclic antidepressant pharmacology and therapeutic drug interactions updated". British Journal of Pharmacology. 151 (6): 737–48. doi:10.1038/sj.bjp.0707253. PMC 2014120. PMID 17471183.
  32. Rénéric JP, Lucki I (March 1998). "Antidepressant behavioral effects by dual inhibition of monoamine reuptake in the rat forced swimming test". Psychopharmacology. 136 (2): 190–7. doi:10.1007/s002130050555. PMID 9551776.
  33. Cusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–565. doi:10.1007/BF02244985. PMID 7855217.
  34. Sánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology. 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID 10379421.
  35. Branchek TA, Blackburn TP (2000). "5-ht6 receptors as emerging targets for drug discovery". Annual Review of Pharmacology and Toxicology. 40: 319–34. doi:10.1146/annurev.pharmtox.40.1.319. PMID 10836139.
  36. Stam NJ, Roesink C, Dijcks F, Garritsen A, van Herpen A, Olijve W (August 1997). "Human serotonin 5-HT7 receptor: cloning and pharmacological characterisation of two receptor variants". FEBS Letters. 413 (3): 489–94. doi:10.1016/S0014-5793(97)00964-2. PMID 9303561.
  37. Sills MA, Loo PS (July 1989). "Tricyclic antidepressants and dextromethorphan bind with higher affinity to the phencyclidine receptor in the absence of magnesium and L-glutamate". Molecular Pharmacology. 36 (1): 160–5. PMID 2568580.
  38. Narita N, Hashimoto K, Tomitaka S, Minabe Y (June 1996). "Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain". European Journal of Pharmacology. 307 (1): 117–9. doi:10.1016/0014-2999(96)00254-3. PMID 8831113.
  39. Volz HP, Stoll KD (November 2004). "Clinical trials with sigma ligands". Pharmacopsychiatry. 37 Suppl 3: S214–20. doi:10.1055/s-2004-832680. PMID 15547788.
  40. "Differences between tricyclic antidepressants and SNRIs mechanism of action | Pharmacology Corner".
  41. Green JP, Maayani S; Maayani (September 1977). "Tricyclic antidepressant drugs block histamine H2 receptor in brain". Nature. 269 (5624): 163–5. Bibcode:1977Natur.269..163G. doi:10.1038/269163a0. PMID 20581.
  42. Tsai BS, Yellin TO (November 1984). "Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa". Biochemical Pharmacology. 33 (22): 3621–5. doi:10.1016/0006-2952(84)90147-3. PMID 6150708.
  43. Uher R.; Farmer A.; Henigsberg N.; Rietschel M.; Mors O.; Maier W.; Aitchison K. J. (2009). "Adverse reactions to antidepressants". The British Journal of Psychiatry. 195 (3): 202–210. doi:10.1192/bjp.bp.108.061960. PMID 19721108.
  44. Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C (January 1998). "Inhibition of neuronal Na+ channels by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 284 (1): 208–14. PMID 9435180.
  45. Zahradník I, Minarovic I, Zahradníková A (March 2008). "Inhibition of the cardiac L-type calcium channel current by antidepressant drugs". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 977–84. doi:10.1124/jpet.107.132456. PMID 18048694.
  46. Harrigan RA, Brady WJ (July 1999). "ECG abnormalities in tricyclic antidepressant ingestion". The American Journal of Emergency Medicine. 17 (4): 387–93. doi:10.1016/S0735-6757(99)90094-3. PMID 10452441.
  47. Brian E. Cairns (1 September 2009). Peripheral Receptor Targets for Analgesia: Novel Approaches to Pain Management. John Wiley & Sons. pp. 66–68. ISBN 978-0-470-52221-9.
  48. Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  49. Alan F. Schatzberg; Charles B. Nemeroff (2009). The American Psychiatric Publishing Textbook of Psychopharmacology. American Psychiatric Pub. pp. 267–271. ISBN 978-1-58562-309-9.
  50. K. Ghose (11 November 2013). Antidepressants for Elderly People. Springer. pp. 182–. ISBN 978-1-4899-3436-9.
  51. J. K. Aronson (2009). Meyler's Side Effects of Psychiatric Drugs. Elsevier. pp. 7–. ISBN 978-0-444-53266-4.
  52. Patricia K. Anthony (2002). Pharmacology Secrets. Elsevier Health Sciences. pp. 39–. ISBN 978-1-56053-470-9.
  53. Philip Cowen; Paul Harrison; Tom Burns (9 August 2012). Shorter Oxford Textbook of Psychiatry. OUP Oxford. pp. 532–. ISBN 978-0-19-162675-3.
  54. Alan F. Schatzberg, M.D.; Charles B. Nemeroff, M.D., Ph.D. (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology, Fifth Edition. American Psychiatric Pub. pp. 306–. ISBN 978-1-58562-523-9.CS1 maint: multiple names: authors list (link)
  55. Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. p. 213. ISBN 978-0-85369-582-0.
  56. "Exhibit 4-3 Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. Retrieved 2007-05-25.
  57. "Figure 3-4: Abuse Potential of Common Psychiatric Medications". Health Services/Technology Assessment Text (HSTAT). U.S. National Library of Medicine. Retrieved 2007-05-25.
  58. Wills, Simon (2005). Drugs Of Abuse, 2nd Edition. London: Pharmaceutical Press. pp. 215–216. ISBN 978-0-85369-582-0.
  59. Wohlreich MM, Welch W (1993). "Amitriptyline abuse presenting as acute toxicity". Psychosomatics. 34 (2): 191–3. doi:10.1016/S0033-3182(93)71918-0. PMID 8456167. The patient denied any alcohol or substance abuse, and no signs of withdrawal were noted in the hospital...On examination, Ms. B. denied suicidal ideation or intent but did admit to taking over 800 mg of amitriptyline per day for the past 3 years after being started on the drug for depression. She clearly described a euphoria associated with amitriptyline, noting that it gave her a “buzz” and that she felt “numbed up” and calm about 30 minutes after ingestion. The patient expressed fears of being addicted to the amitriptyline and desired inpatient hospitalization for medication adjustment and education.
  60. Singh GP, Kaur P, Bhatia S (June 2004). "Dothiepin dependence syndrome". Indian J Med Sci. 58 (6): 253–4. PMID 15226578.
  61. Cohen MJ, Hanbury R, Stimmel B (September 1978). "Abuse of amitriptyline". JAMA. 240 (13): 1372–3. doi:10.1001/jama.240.13.1372. PMID 682328.
  62. Delisle JD (October 1990). "A case of amitriptyline abuse". Am J Psychiatry. 147 (10): 1377–8. doi:10.1176/ajp.147.10.1377b. PMID 2400006. Ms. A, a 24-year-old abuser of alcohol and cannabis, consulted her family physician because of anxiety, depression, and insomnia. Unaware of her drug abuse, he prescribed amitriptyline, 200 mg. About 30 minutes after taking each dose, she would experience relief from her symptoms that lasted about 2 hours. By increasing the dose, she found she could intensify these effects and prolong them for up to several hours. Her “high” consisted of feelings of relaxation, giddiness, and contentment.Frequently, this progressed to incoordination, slurred speech, and confusion. Sometimes she would forget how much she had taken and ingest up to 2 g.
  63. Sein Anand J, Chodorowski Z, Habrat B (2005). "Recreational amitriptyline abuse". Prz. Lek. 62 (6): 397–8. PMID 16225078.
  64. Lepping P, Menkes DB (July 2007). "Abuse of dosulepin to induce mania". Addiction. 102 (7): 1166–7. doi:10.1111/j.1360-0443.2007.01828.x. PMID 17567406.
  65. Dorman A, Talbot D, Byrne P, O'Connor J (December 1995). "Misuse of dothiepin". BMJ. 311 (7018): 1502. doi:10.1136/bmj.311.7018.1502b. PMC 2543748. PMID 8520352.

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