Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs have decreased in use in recent decades due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which have fewer side effects and are safer in overdose.
Imipramine is used in the treatment of depression and certain anxiety disorders. It is similar in efficacy to the antidepressant drug moclobemide. It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150-250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.
Imipramine affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.
The mechanisms of imipramine's actions include, but are not limited to, effects on:
Acetylcholine: imipramine is an anticholinergic, specifically an antagonist of the muscarinic acetylcholine receptors. Thus, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population.
BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.
In the late 1950s, imipramine was the first TCA to be developed (by Ciba). At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression. It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania. Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.
Before the advent of selective serotonin reuptake inhibitors (SSRIs), its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since the 1990s, it has no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression . It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome. Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome. In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.
^Heck HA, Buttrill SE Jr, Flynn NW, Dyer RL, Anbar M, Cairns T, Dighe S, Cabana BE (June 1979). "Bioavailability of imipramine tablets relative to a stable isotope-labelled internal standard: increasing the power of bioavailability tests". Journal of Pharmacokinetics and Biopharmaceutics. 7 (3): 233–248. doi:10.1007/bf01060015. PMID480146.CS1 maint: multiple names: authors list (link)
^Delini-Stula, A; Mikkelsen, H; Angst, J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". Journal of Affective Disorders. 35 (1–2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID8557884.
^Skidmore-Roth, L., ed. (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier.
^ abRoth, 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.
^ abcTatsumi 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): 249–58. doi:10.1016/s0014-2999(97)01393-9. PMID9537821.
^ abcdOwens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". J. Pharmacol. Exp. Ther. 283 (3): 1305–22. PMID9400006.
^ abcdefCusack B, Nelson A, Richelson E (1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–65. doi:10.1007/bf02244985. PMID7855217.
^ abcdefToll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS (1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Res. Monogr. 178: 440–66. PMID9686407.
^ abWander TJ, Nelson A, Okazaki H, Richelson E (1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". Eur. J. Pharmacol. 132 (2–3): 115–21. doi:10.1016/0014-2999(86)90596-0. PMID3816971.
^Monsma FJ, Shen Y, Ward RP, Hamblin MW, Sibley DR (1993). "Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs". Mol. Pharmacol. 43 (3): 320–7. PMID7680751.
^Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR (1993). "Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype". J. Biol. Chem. 268 (24): 18200–4. PMID8394362.
^ abcdefgRichelson E, Nelson A (1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". J. Pharmacol. Exp. Ther. 230 (1): 94–102. PMID6086881.
^Sánchez C, Hyttel J (1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cell. Mol. Neurobiol. 19 (4): 467–89. doi:10.1023/A:1006986824213. PMID10379421.
^ abcdAppl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn Schmiedebergs Arch. Pharmacol. 385 (2): 145–70. doi:10.1007/s00210-011-0704-0. PMID22033803.
^ abcdeStanton T, Bolden-Watson C, Cusack B, Richelson E (1993). "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochem. Pharmacol. 45 (11): 2352–4. doi:10.1016/0006-2952(93)90211-e. PMID8100134.
^Arias HR, Targowska-Duda KM, Feuerbach D, Sullivan CJ, Maciejewski R, Jozwiak K (2010). "Different interaction between tricyclic antidepressants and mecamylamine with the human alpha3beta4 nicotinic acetylcholine receptor ion channel". Neurochem. Int. 56 (4): 642–9. doi:10.1016/j.neuint.2010.01.011. PMID20117161.
^ abHindmarch I, Hashimoto K (2010). "Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered". Hum Psychopharmacol. 25 (3): 193–200. doi:10.1002/hup.1106. PMID20373470.
^ abRobson MJ, Elliott M, Seminerio MJ, Matsumoto RR (2012). "Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo". Eur Neuropsychopharmacol. 22 (4): 308–17. doi:10.1016/j.euroneuro.2011.08.002. PMID21911285.
^Tsankova, N. M.; Berton, O; Renthal, W; Kumar, A; Neve, R. L.; Nestler, E. J. (April 2006). "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action". Nature Neuroscience. 9 (4): 519–25. doi:10.1038/nn1659. PMID16501568.
^Jørgensen, Tine Krogh; Andersen, Knud Erik; Lau, Jesper; Madsen, Peter; Huusfeldt, Per Olaf (1999). "Synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines; key synthons in syntheses of pharmaceutically active compounds". Journal of Heterocyclic Chemistry. 36 (1): 57–64. doi:10.1002/jhet.5570360110. ISSN0022-152X.
^Healy, David (1997). The Antidepressant Era. Harvard University Press. p. 211.
^Bottlender, R; Rudolf, D; Strauss, A; Möller, H. J. (1998). "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience. 248 (6): 296–300. doi:10.1007/s004060050053. PMID9928908.