The most common side effects are dry mouth, drowsiness, dizziness, constipation, and weight gain.
Glaucoma, liver toxicity and
abnormal heart rhythms are rare but serious side effects. Blood levels of amitriptyline vary significantly from one person to another,[17] and amitriptyline interacts with many other medications potentially aggravating its side effects.
Amitriptyline is effective for depression,[23] but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability.[24] It can be tried for depression as a second-line therapy, after the failure of other treatments.[13] For
treatment-resistant adolescent depression[25] or for cancer-related depression[26] amitriptyline is no better than placebo, however the number of treated patients in both studies was small. It is sometimes used for the treatment of depression in
Parkinson's disease,[27] but supporting evidence for that is lacking.[28]
Pain
Amitriptyline alleviates painful
diabetic neuropathy. It is recommended by a variety of guidelines as a first or second line treatment.[14] It is as effective for this indication as
gabapentin or
pregabalin but less well tolerated.[29] Amitriptyline is as effective at relieving pain as
duloxetine.
Combination treatment of amitriptyline and pregabalin offers additional pain relief for people whose pain is not adequately controlled with one medication, and is safe.[30][31] Amitriptyline in certain formulations may also induce the level of
sciatic-nerve blockade needed for local
anesthesia therein.[32] Here, it has been demonstrated to be of superior potency to
bupivacaine, a customary long-acting local anesthetic.
There is some (low-quality) evidence that amitriptyline may reduce pain in cancer patients. It is recommended only as a second line therapy for non-chemotherapy-induced neuropathic or mixed neuropathic pain, if
opioids did not provide the desired effect.[35]
Moderate evidence exists in favor of amitriptyline use for
atypical facial pain.[36] Amitriptyline is ineffective for HIV-associated neuropathy.[29]
In multiple sclerosis it is frequently used to treat painful paresthesias in the arms and legs (e.g., burning sensations, pins and needles, stabbing pains) caused by damage to the pain regulating pathways of the brain and spinal cord.[37]
Headache
Amitriptyline is probably effective for the prevention of periodic
migraine in adults. Amitriptyline is similar in efficancy to
venlafaxine and
topiramate but carries a higher burden of adverse effects than topiramate.[16] For many patients, even very small doses of amitriptyline are helpful, which may allow for minimization of side effects.[38] Amitriptyline is not significantly different from placebo when used for the prevention of migraine in children.[39]
Amitriptyline may reduce the frequency and duration of chronic
tension headache, but it is associated with worse adverse effects than
mirtazapine. Overall, amitriptyline is recommended for tension headache
prophylaxis, along with lifestyle advice, which should include avoidance of analgesia and caffeine.[40]
Other indications
Amitriptyline is effective for the treatment of
irritable bowel syndrome; however, because of its side effects, it should be reserved for select patients for whom other agents do not work.[41][42][43] There is insufficient evidence to support its use for abdominal pain in children with functional gastrointestinal disorders.[44]
Tricyclic antidepressants decrease the frequency, severity, and duration of
cyclic vomiting syndrome episodes. Amitriptyline, as the most commonly used of them, is recommended as a first-line agent for its therapy.[45]
Amitriptyline may improve pain and urgency intensity associated with
bladder pain syndrome and can be used in the management of this syndrome.[46][47] Amitriptyline can be used in the treatment of nocturnal
enuresis in children. However, its effect is not sustained after the treatment ends. Alarm therapy gives better short- and long-term results.[48]
In the US, amitriptyline is commonly used in children with
ADHD as an adjunct to stimulant medications without any evidence or guideline supporting this practice.[49] Many physicians in the UK (and the US also) commonly prescribe amitriptyline for
insomnia;[50] however,
Cochrane reviewers were not able to find any randomized controlled studies that would support or refute this practice.[51] Similarly, a major
systematic review and
network meta-analysis of medications for the treatment of insomnia published in 2022 found little evidence to inform the use of amitriptyline for insomnia.[52] The well-known sedating effects of amitriptyline, however, bear understanding on and arguable justification for this practice. It may function similarly to
doxepin in this regard, although the evidence for
doxepin is more robust.[53]Trimipramine may be a more novel alternative, especially given its tendency to not suppress; indeed, rather, brighten; R.E.M. sleep.[54][55][56]
Contraindications and precautions
The known contraindications of amitriptyline are:[12]
CYP2D6 poor metabolizers should avoid amitriptyline due to increased side effects. If it is necessary to use it, half dose is recommended.[57] Amitriptyline can be used during pregnancy and lactation when SSRIs have been shown not to work.[58]
Side effects
The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8 kg[59]).[23] Other common side effects are headache problems (
amblyopia, blurred vision),
tachycardia, increased appetite,
tremor, fatigue/
asthenia/feeling slowed down, and
dyspepsia.[23]
A less common side effect of amitriptyline is urination problems (8.7%).[23]
Amitriptyline can increase suicidal thoughts and behavior in people under the age of 24 and was black boxed by the FDA for these qualifiers due to this potential side effect.[60]
Amitriptyline-associated
sexual dysfunction (occurring at a frequency of 6.9%) seems to be mostly confined to males with depression and is expressed predominantly as
erectile dysfunction and low
libido disorder, with lesser frequency of ejaculatory and orgasmic problems. The rate of sexual dysfunction in males treated for indications other than depression and in females is not significantly different from placebo.[61]
Liver tests abnormalities occur in 10–12% of patients on amitriptyline, but are usually mild, asymptomatic and transient,[62] with consistently elevated
alanine transaminase in 3% of all patients.[63][64] The increases of the enzymes above the 3-fold threshold of liver toxicity are uncommon, and cases of clinically apparent liver toxicity are rare;[62] nevertheless, amitriptyline is placed in the group of antidepressants with greater risks of hepatic toxicity.[63]
The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of
serotonin syndrome and adverse cardiac effects. The
British National Formulary notes that amitriptyline can be particularly dangerous in overdose,[68] thus it and other TCAs are no longer recommended as first-line therapy for depression.
The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Cardiac monitoring is advised for at least five days after the overdose.
Benzodiazepines are recommended to control seizures.
Dialysis is of no use due to the high degree of
protein binding with amitriptyline.[7]
Interactions
Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes
CYP2D6 and
CYP2C19 (see
Amitriptyline#Pharmacology), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with
CYP2D6 inhibitors may increase the plasma level of amitriptyline.[12] However, the results in the other literature are inconsistent:[9] the co-administration of amitriptyline with a potent CYP2D6 inhibitor
paroxetine does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold,[69] but combination with less potent CYP2D6 inhibitors
thioridazine or
levomepromazine does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold;[70] a moderate CYP2D6 inhibitor fluoxetine does not seem to have a significant effect on the levels of amitriptyline or nortriptyline.[71][72] A case of clinically significant interaction with potent CYP2D6 inhibitor
terbinafine has been reported.[73]
A potent inhibitor of
CYP2C19 and other cytochromes
fluvoxamine increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline.[71] Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes
cimetidine: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%.[74]CYP3A4 inhibitor
ketoconazole elevates amitriptyline level by about a quarter.[10] On the other hand,
cytochrome P450 inducers such as
carbamazepine and
St. John's Wort decrease the levels of both amitriptyline and nortriptyline[70][75]
Oral contraceptives may increase the blood level of amitriptyline by as high as 90%.[76] Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism.[77]
The prescribing information warns that the combination of amitriptyline with
monoamine oxidase inhibitors may cause potentially lethal
serotonin syndrome;[12] however, this has been disputed.[78] The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate.[79] However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%.[80]
Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of
serotonin and
norepinephrine. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline.[79]
Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the
posterior gray column of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of
alpha-2 adrenergic receptors, which mediate an analgesic effect by increasing
gamma-aminobutyric acid transmission among
spinal interneurons. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions.[6]
Pharmacokinetics
Amitriptyline is readily absorbed from the gastrointestinal tract (90–95%).[6] Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours.[5] Extensive metabolism on the
first pass through the liver leads to average
bioavailability of about 50% (45%[5]-53%[6]). Amitriptyline is metabolized mostly by
CYP2C19 into
nortriptyline and by
CYP2D6 leading to a variety of
hydroxylated metabolites, with the principal one among them being (E)-10-hydroxynortriptyline[9] (see metabolism scheme),[6] and to a lesser degree, by
CYP3A4.[10]
Nortriptyline, the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the
blood plasma than the parent drug amitriptyline and 40% greater
area under the curve, and its action is an important part of the overall action of amitriptyline.[5][9]
Another active metabolite is (E)-10-hydroxynortriptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (E)-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its
cerebrospinal fluid level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptyline's. Based on this, (E)-10-hydroxynortriptyline was suggested to significantly contribute to antidepressant effects of amitriptyline.[119]
Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with
clearance difference of up to 10-fold, vary widely between individuals.[120] Variability of the area under the curve
in steady state is also high, which makes a slow upward
titration of the dose necessary.[17]
In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (E)-10-hydroxynortiptyline is about 60% bound.[7][121][119]
Amitriptyline has an elimination half life of 21 hours,[5] nortriptyline – 23–31 hours,[122] and (E)-10-hydroxynortiptyline - 8–10 hours.[119] Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites.[8] 2% of the unchanged drug is excreted in the urine.[123] Elimination in the feces, apparently, have not been studied.
Therapeutic levels of amitriptyline range from 75 to 175 ng/mL (270–631 nM),[124] or 80–250 ng/mL of both amitriptyline and its metabolite nortriptyline.[125]
Pharmacogenetics
Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body.[126] Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy.[127][128][129][130]
Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers,[57] and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure.[127][128][57][130]
The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments.[57] The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are
CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are
CYP2D6 intermediate metabolizers.[131]
Chemistry
Amitriptyline is a highly lipophilic molecule having an
octanol-water partition coefficient (pH 7.4) of 3.0,[132] while the
log P of the free base was reported as 4.92.[133] Solubility of the free base amitriptyline in water is 14 mg/L.[134] Amitriptyline is prepared by reacting
dibenzosuberane with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with
hydrochloric acid to
eliminate water.[6]
History
Amitriptyline was first developed by the American pharmaceutical company
Merck in the late 1950s. In 1958, Merck approached a number of clinical investigators proposing to conduct clinical trials of amitriptyline for schizophrenia. One of these researchers,
Frank Ayd, instead, suggested using amitriptyline for depression. Ayd treated 130 patients and, in 1960, reported that amitriptyline had antidepressant properties similar to another, and the only known at the time, tricyclic antidepressant
imipramine.[135] Following this, the US
Food and Drug Administration approved amitriptyline for depression in 1961.[18]
In Europe, due to a quirk of the patent law at the time allowing patents only on the chemical synthesis but not on the drug itself,
Roche and
Lundbeck were able to independently develop and market amitriptyline in the early 1960s.[136]
According to research by the historian of psychopharmacology
David Healy, amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors. First, amitriptyline has much stronger anxiolytic effect. Second, Merck conducted a marketing campaign raising clinicians' awareness of depression as a clinical entity.[136][135]
Society and culture
In the 2021 film The Many Saints of Newark, amitriptyline (referred to by the brand name Elavil) is part of the plot line of the movie.[137]
Names
Amitriptyline is the English and French
generic name of the drug and its
INNTooltip International Nonproprietary Name,
BANTooltip British Approved Name, and
DCFTooltip Dénomination Commune Française, while amitriptyline hydrochloride is its
USANTooltip United States Adopted Name,
USPTooltip United States Pharmacopeia,
BANMTooltip British Approved Name, and
JANTooltip Japanese Accepted Name.[138][139][140][141] Its generic name in Spanish and Italian and its
DCITTooltip Denominazione Comune Italiana are amitriptilina, in German is Amitriptylin, and in
Latin is amitriptylinum.[139][141] The
embonate salt is known as amitriptyline embonate, which is its BANM, or as amitriptyline pamoate unofficially.[139]
Prescription trends
Between 1998 and 2017, along with
imipramine, amitriptyline was the most commonly prescribed first antidepressant for children aged 5–11 years in England. It was also the most prescribed antidepressant (along with
fluoxetine) for 12 to 17-year olds.[142]
Research
The few randomized controlled trials investigating amitriptyline efficacy in
eating disorder have been discouraging.[143]
^
abSchulz P, Balant-Gorgia AE, Kubli A, Gertsch-Genet C, Garrone G (1983). "Elimination and pharmacological effects following single oral doses of 50 and 75 mg of amitriptyline in man". Archiv Fur Psychiatrie und Nervenkrankheiten. 233 (6): 449–455.
doi:
10.1007/BF00342785.
PMID6667101.
S2CID20844722.
^
abcdBreyer-Pfaff U (October 2004). "The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man". Drug Metabolism Reviews. 36 (3–4): 723–746.
doi:
10.1081/dmr-200033482.
PMID15554244.
S2CID25565048.
^
abcVenkatakrishnan K, Schmider J, Harmatz JS, Ehrenberg BL, von Moltke LL, Graf JA, et al. (October 2001). "Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies". Journal of Clinical Pharmacology. 41 (10): 1043–1054.
doi:
10.1177/00912700122012634.
PMID11583471.
S2CID27146286.
^
abHitchings A, Lonsdale D, Burrage D, Baker E (2015). Top 100 drugs : clinical pharmacology and practical prescribing. Churchill Livingstone. p. 50.
ISBN978-0-7020-5516-4.
^
abTfelt-Hansen P, Ågesen FN, Pavbro A, Tfelt-Hansen J (May 2017). "Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine". CNS Drugs. 31 (5): 389–403.
doi:
10.1007/s40263-017-0430-3.
PMID28405886.
S2CID23560743.
^
abFangmann P, Assion HJ, Juckel G, González CA, López-Muñoz F (February 2008). "Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics". Journal of Clinical Psychopharmacology. 28 (1): 1–4.
doi:
10.1097/jcp.0b013e3181627b60.
PMID18204333.
S2CID31018835.
^Organization WH (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.
hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^"Amitriptyline Hydrochloride". Drugs.com. The American Society of Health-System Pharmacists.
Archived from the original on 24 September 2014. Retrieved 25 September 2014.
^
abcdLeucht C, Huhn M, Leucht S (December 2012). "Amitriptyline versus placebo for major depressive disorder". The Cochrane Database of Systematic Reviews. 12: CD009138.
doi:
10.1002/14651858.CD009138.pub2.
PMID23235671.
^Rossi S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.
ISBN978-0-9805790-9-3.
^Riblet N, Larson R, Watts BV, Holtzheimer P (2014). "Reevaluating the role of antidepressants in cancer-related depression: a systematic review and meta-analysis". General Hospital Psychiatry. 36 (5): 466–473.
doi:
10.1016/j.genhosppsych.2014.05.010.
PMID24950919.
^"Parkinson's disease". merckmanuals.com. Merck Sharp & Dohme Corp. August 2007. Archived from
the original on 18 November 2013. Retrieved 22 December 2013.
^van den Beuken-van Everdingen MH, de Graeff A, Jongen JL, Dijkstra D, Mostovaya I, Vissers KC (March 2017). "Pharmacological Treatment of Pain in Cancer Patients: The Role of Adjuvant Analgesics, a Systematic Review". Pain Practice. 17 (3): 409–419.
doi:
10.1111/papr.12459.
PMID27207115.
S2CID37418010.
^Do TM, Unis GD, Kattar N, Ananth A, McCoul ED (June 2021). "Neuromodulators for Atypical Facial Pain and Neuralgias: A Systematic Review and Meta-Analysis". The Laryngoscope. 131 (6): 1235–1253.
doi:
10.1002/lary.29162.
PMID33037835.
S2CID222256076.
^Loder E, Rizzoli P (November 2018). "Pharmacologic Prevention of Migraine: A Narrative Review of the State of the Art in 2018". Headache. 58 (Suppl 3): 218–229.
doi:
10.1111/head.13375.
PMID30137671.
S2CID52071815.
^Klein T, Woo TM, Panther S, Odom-Maryon T, Daratha K (2019). "Somnolence-Producing Agents: A 5-Year Study of Prescribing for Medicaid-Insured Children With Attention Deficit Hyperactivity Disorder". Journal of Pediatric Health Care. 33 (3): e1–e8.
doi:
10.1016/j.pedhc.2018.10.002.
PMID30630642.
S2CID58577978.
^Riemann D, Voderholzer U, Cohrs S, Rodenbeck A, Hajak G, Rüther E, et al. (September 2002). "Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study". Pharmacopsychiatry. 35 (5): 165–74.
doi:
10.1055/s-2002-34119.
PMID12237787.
^Berger M, Gastpar M (1996). "Trimipramine: a challenge to current concepts on antidepressives". European Archives of Psychiatry and Clinical Neuroscience. 246 (5): 235–9.
doi:
10.1007/BF02190274.
PMID8863001.
^Nielsen RE, Damkier P (June 2012). "Pharmacological treatment of unipolar depression during pregnancy and breast-feeding--a clinical overview". Nordic Journal of Psychiatry. 66 (3): 159–166.
doi:
10.3109/08039488.2011.650198.
PMID22283766.
S2CID11327135.
^
abAmitriptyline. National Institute of Diabetes and Digestive and Kidney Diseases. 6 January 2012.
PMID31643729.
Archived from the original on 21 January 2022. Retrieved 6 January 2021 – via PubMed.
^
abVoican CS, Corruble E, Naveau S, Perlemuter G (April 2014). "Antidepressant-induced liver injury: a review for clinicians". The American Journal of Psychiatry. 171 (4): 404–415.
doi:
10.1176/appi.ajp.2013.13050709.
PMID24362450.
^Holmberg MB (1962). "A study of blood count and serum transaminase in prolonged treatment with amitriptyline". The Journal of New Drugs. 2 (6): 361–365.
doi:
10.1177/009127006200200606.
PMID13961401.
^Hefner G, Hahn M, Hohner M, Roll SC, Klimke A, Hiemke C (January 2019). "QTc Time Correlates with Amitriptyline and Venlafaxine Serum Levels in Elderly Psychiatric Inpatients". Pharmacopsychiatry. 52 (1): 38–43.
doi:
10.1055/s-0044-102009.
PMID29466824.
S2CID3447931.
^Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R (January 2000). "Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients". Psychopharmacology. 147 (4): 378–383.
doi:
10.1007/s002130050006.
PMID10672631.
S2CID22476829.
^
abJerling M, Bertilsson L, Sjöqvist F (February 1994). "The use of therapeutic drug monitoring data to document kinetic drug interactions: an example with amitriptyline and nortriptyline". Therapeutic Drug Monitoring. 16 (1): 1–12.
doi:
10.1097/00007691-199402000-00001.
PMID7909176.
S2CID1428027.
^
abVandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, et al. (June 1995). "Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients". Pharmacological Research. 31 (6): 347–353.
doi:
10.1016/1043-6618(95)80088-3.
PMID8685072.
^Vandel S, Bertschy G, Bonin B, Nezelof S, François TH, Vandel B, et al. (1992). "Tricyclic antidepressant plasma levels after fluoxetine addition". Neuropsychobiology. 25 (4): 202–207.
doi:
10.1159/000118838.
PMID1454161.
^Castberg I, Helle J, Aamo TO (October 2005). "Prolonged pharmacokinetic drug interaction between terbinafine and amitriptyline". Therapeutic Drug Monitoring. 27 (5): 680–682.
doi:
10.1097/01.ftd.0000175910.68539.33.
PMID16175144.
^Curry SH, DeVane CL, Wolfe MM (1985). "Cimetidine interaction with amitriptyline". European Journal of Clinical Pharmacology. 29 (4): 429–433.
doi:
10.1007/BF00613457.
PMID3912187.
S2CID25430195.
^Johne A, Schmider J, Brockmöller J, Stadelmann AM, Störmer E, Bauer S, et al. (February 2002). "Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort ( Hypericum perforatum )". Journal of Clinical Psychopharmacology. 22 (1): 46–54.
doi:
10.1097/00004714-200202000-00008.
PMID11799342.
S2CID25670895.
^Berry-Bibee EN, Kim MJ, Simmons KB, Tepper NK, Riley HE, Pagano HP, et al. (December 2016). "Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review". Contraception. 94 (6): 650–667.
doi:
10.1016/j.contraception.2016.07.011.
PMID27444984.
^Wong SL, Cavanaugh J, Shi H, Awni WM, Granneman GR (July 1996). "Effects of divalproex sodium on amitriptyline and nortriptyline pharmacokinetics". Clinical Pharmacology and Therapeutics. 60 (1): 48–53.
doi:
10.1016/S0009-9236(96)90166-6.
PMID8689811.
S2CID37720622.
^Meyer JF, McAllister CK, Goldberg LI (August 1970). "Insidious and prolonged antagonism of guanethidine by amitriptyline". JAMA. 213 (9): 1487–1488.
doi:
10.1001/jama.1970.03170350053016.
PMID5468457.
^Maany I, Hayashida M, Pfeffer SL, Kron RE (June 1982). "Possible toxic interaction between disulfiram and amitriptyline". Archives of General Psychiatry. 39 (6): 743–744.
doi:
10.1001/archpsyc.1982.04290060083018.
PMID7092508.
^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.
Archived from the original on 27 August 2021. Retrieved 14 August 2017.
^
abcTatsumi 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.
PMID9537821.
^
abcOwens 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.
PMID9400006.
^
abcdCusack 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.
PMID7855217.
S2CID21236268.
^
abPeroutka SJ (May 1988). "Antimigraine drug interactions with serotonin receptor subtypes in human brain". Annals of Neurology. 23 (5): 500–504.
doi:
10.1002/ana.410230512.
PMID2898916.
S2CID41570165.
^Peroutka SJ (August 1986). "Pharmacological differentiation and characterization of 5-HT1A, 5-HT1B, and 5-HT1C binding sites in rat frontal cortex". Journal of Neurochemistry. 47 (2): 529–540.
doi:
10.1111/j.1471-4159.1986.tb04532.x.
PMID2942638.
S2CID25108290.
^Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H (May 1996). "Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache?". The European Journal of Neuroscience. 8 (5): 959–967.
doi:
10.1111/j.1460-9568.1996.tb01583.x.
PMID8743744.
S2CID19578349.
^Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, et al. (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology. 126 (3): 234–240.
doi:
10.1007/bf02246453.
PMID8876023.
S2CID24889381.
^
abcSánchez 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): 467–489.
doi:
10.1023/a:1006986824213.
PMID10379421.
S2CID19490821.
^Kohen R, Metcalf MA, Khan N, Druck T, Huebner K, Lachowicz JE, et al. (January 1996). "Cloning, characterization, and chromosomal localization of a human 5-HT6 serotonin receptor". Journal of Neurochemistry. 66 (1): 47–56.
doi:
10.1046/j.1471-4159.1996.66010047.x.
PMID8522988.
S2CID35874409.
^Hirst WD, Abrahamsen B, Blaney FE, Calver AR, Aloj L, Price GW, et al. (December 2003). "Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling". Molecular Pharmacology. 64 (6): 1295–1308.
doi:
10.1124/mol.64.6.1295.
PMID14645659.
S2CID33743899.
^Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR (March 1993). "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs". Molecular Pharmacology. 43 (3): 320–327.
PMID7680751.
^
abNojimoto FD, Mueller A, Hebeler-Barbosa F, Akinaga J, Lima V, Kiguti LR, et al. (2010). "The tricyclic antidepressants amitriptyline, nortriptyline and imipramine are weak antagonists of human and rat alpha1B-adrenoceptors". Neuropharmacology. 59 (1–2): 49–57.
doi:
10.1016/j.neuropharm.2010.03.015.
PMID20363235.
S2CID207225294.
^
abcFallarero A, Pohjanoksa K, Wissel G, Parkkisenniemi-Kinnunen UM, Xhaard H, Scheinin M, et al. (December 2012). "High-throughput screening with a miniaturized radioligand competition assay identifies new modulators of human α2-adrenoceptors". European Journal of Pharmaceutical Sciences. 47 (5): 941–951.
doi:
10.1016/j.ejps.2012.08.021.
PMID22982401.
^Bylund DB, Snyder SH (July 1976). "Beta adrenergic receptor binding in membrane preparations from mammalian brain". Molecular Pharmacology. 12 (4): 568–580.
PMID8699.
^
abcdefvon Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H (January 2009). "Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics". Bioorganic & Medicinal Chemistry Letters. 19 (2): 538–542.
doi:
10.1016/j.bmcl.2008.09.012.
PMID19091563.
^
abcdAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology. 385 (2): 145–170.
doi:
10.1007/s00210-011-0704-0.
PMID22033803.
S2CID14274150.
^Ghoneim OM, Legere JA, Golbraikh A, Tropsha A, Booth RG (October 2006). "Novel ligands for the human histamine H1 receptor: synthesis, pharmacology, and comparative molecular field analysis studies of 2-dimethylamino-5-(6)-phenyl-1,2,3,4-tetrahydronaphthalenes". Bioorganic & Medicinal Chemistry. 14 (19): 6640–6658.
doi:
10.1016/j.bmc.2006.05.077.
PMID16782354.
^
abcdeStanton T, Bolden-Watson C, Cusack B, Richelson E (June 1993). "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochemical Pharmacology. 45 (11): 2352–2354.
doi:
10.1016/0006-2952(93)90211-e.
PMID8100134.
^
abcBymaster FP, Nelson DL, DeLapp NW, Falcone JF, Eckols K, Truex LL, et al. (May 1999). "Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro". Schizophrenia Research. 37 (1): 107–122.
doi:
10.1016/s0920-9964(98)00146-7.
PMID10227113.
S2CID19891653.
^Werling LL, Keller A, Frank JG, Nuwayhid SJ (October 2007). "A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder". Experimental Neurology. 207 (2): 248–257.
doi:
10.1016/j.expneurol.2007.06.013.
PMID17689532.
S2CID38476281.
^Yamakawa Y, Furutani K, Inanobe A, Ohno Y, Kurachi Y (February 2012). "Pharmacophore modeling for hERG channel facilitation". Biochemical and Biophysical Research Communications. 418 (1): 161–166.
doi:
10.1016/j.bbrc.2011.12.153.
PMID22244872.
^Nau C, Seaver M, Wang SY, Wang GK (March 2000). "Block of human heart hH1 sodium channels by amitriptyline". The Journal of Pharmacology and Experimental Therapeutics. 292 (3): 1015–1023.
PMID10688618.
^Swen JJ, Nijenhuis M, de Boer A, Grandia L, Maitland-van der Zee AH, Mulder H, et al. (May 2011). "Pharmacogenetics: from bench to byte--an update of guidelines". Clinical Pharmacology and Therapeutics. 89 (5): 662–673.
doi:
10.1038/clpt.2011.34.
PMID21412232.
S2CID2475005.
^The Pharmaceutical Codex. 1994. Principles and practice of pharmaceutics, 12th edn. Pharmaceutical press
^Hansch C, Leo A, Hoekman D. 1995. Exploring QSAR.Hydrophobic, electronic and steric constants. Washington, DC: American Chemical Society.
^Box KJ, Völgyi G, Baka E, Stuart M, Takács-Novák K, Comer JE (June 2006). "Equilibrium versus kinetic measurements of aqueous solubility, and the ability of compounds to supersaturate in solution--a validation study". Journal of Pharmaceutical Sciences. 95 (6): 1298–1307.
doi:
10.1002/jps.20613.
PMID16552741.
^
abHealy D (1997). The Antidepressant Era. Harvard University Press. pp. 74–76.
ISBN0674039572.
^Press J (10 January 2021).
"The Sopranos Fan's Guide to The Many Saints of Newark". Vanity Fair.
Archived from the original on 1 October 2021. Retrieved 10 January 2021. Livia is already troubled enough in the yesteryear of Many Saints that her doctor wants to prescribe her the antidepressant Elavil, but she rejects it. "I'm not a drug addict!" she sneers. Tony pores over the Elavil pamphlet with great interest and even schemes with Dickie Moltisanti to get his suffering mother to take it: "It could make her happy."