Of imipramine

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Fig 1 Chromatogram of imipramine and phenothiazine derivatives after staining with Forrest reagent [4] 1 = imipramine, 2 = desipramine, 3 = clomipramine, 4 = lofepramine, 5 = trimipramine, 6 = thioridazine, 7 = chlorphenethazine, 8 = periciazine, 9 = promazine, 10 = promethazine. 

The detection limits of imipramine and its derivatives were 100 ng substance per chromatogram zone. 

Set against this background is the finding that the inhibition of [ H]noradrenaline uptake by the neuroleptic, chlorpromazine, is even greater than that of imipramine and yet chlorpromazine has no apparent antidepressant effects. This serves as a testimony... 

Salama, A.I., and Goldberg, M.E. Neurochemical effects of imipramine and amphetamine in aggressive mouse-killing (muricidal) rats. Biochem Pharmacol 19 2023-2032, 1970. 

Compared to antipsychotics, there are even fewer studies on the prescribing patterns of antidepressants done in Asian countries. Pi etal. (1985) conducted a survey of psychotropic prescribing practices reported by psychiatrists in 29 medical schools in 9 Asian countries. Daily dose range of tricyclic antidepressants (TCAs) such as amitriptyline, imipramine, and nortriptyline in Asian countries was comparable to the practice in USA. This is despite differences found between Asian and non-Asian populations in the pharmacokinetics of TCAs (Pi et al, 1993). A questionnaire on the practical prescribing approaches in mood disorders administered to 298 Japanese psychiatrists was reported by Oshima et al. (1999). As first-line treatment, the majority of respondents chose newer TCAs or non-TCAs for moderate depression and older TCAs for severe depression. Combination of antidepressants and anxiolytics was preferred in moderate depression, while an antidepressant and antipsychotic combination was common in severe psychotic depression. Surprisingly, sulpiride was the most favored drug for dysthymia. In a naturalistic, prospective follow-up of 95 patients with major depression in Japan, the proportion of patients receiving 125 mg/day or less of imipramine was 69% at one month and 67% at six months (Furukawa et al., 2000). 

It is important to note that claims for the effectiveness of iproniazid and imipramine were not based on placebo-controlled clinical trials. Instead, they were based on clinical impressions.6 In discovering the antidepressant effects of imipramine, Kuhn did not even use precise measurement, rating scales or statistics. His claim was that precise measurement led to stagnation rather than progress in medicine, and he preferred to rely on his extensive medical experience and artistic imagination instead.7... 

Axelrod s discovery provided an answer to the question of why imipramine might alleviate depression, even if it did not inhibit the destruction of neurotransmitters in the brain. With the problem of imipramine solved, the chemical-imbalance theory seemed to work. Two different types of drugs relieve depression, the theory went,... 

List the side effects of imipramine that result from its blockade of muscarinic acetylcholine receptors. 

Desipramine An active metabolite of imipramine that is more selective for inhibiting noradrenaline reuptake into the presynaptic neuron. 

Adjunctive use of imipramine, valproic acid, or buspirone can help to reduce withdrawal symptoms during the BZ taper. 

Isenberg, G. and Tamargo, J. (1985) Effect of imipramine on calcium and potassium currents in isolated bovine ventricular myocytes. European Journal of Pharmacology, 108, 121—131. 

Delpon, E., Tamargo, J. and Sanchez-Chapula, J. (1991) Further characterization of the effects of imipramine on plateau membrane currents in guinea-pig ventricular myocytes, hiaunyn-Schmiedeberg s Archives of Pharmacology, 344, 645-652. 

Mehendale HM. 1977b. Effect of preexposure to Kepone on the biliary excretion of imipramine and sulfobromophthalein. Toxicol Appl Pharmacol 40 247-259. 

Mehendale HM. 1977c. Mirex-induced impairment of hepatobiliary function Suppressed biliary excretion of imipramine and sulfobromophthalein. Drug Metab Dispos 5 56-62. 

Drew R, Siddik Z, Mimnaugh EG, Gram TE (1981) Species and dose differences in the accumulation of imipramine by mammalian lungs. Drug Metab Dispos 9 322-326. 

Lumb AB. (1994). Effect of dried ginger on human platelet function. Thromb Haemost. 71(1) 110-1. Maione S, Palazzo E, Pallotta M, Leyva J, Berrino L, Rossi F. (1997). Effects of imipramine on raphe nuclei and prefrontal cortex extracellular serotonin levels in the rat. Psychopharmacology (Berlin). 134(4) 401-5. 

Rickels K, Downing R, Schweizer E, Hassman H. (1993). Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam. Arch Gen Psychiatry. 50(11) 884-95. 

Sussman N. (1998). Anxiolytic antidepressant augmentation. J Clin Psychiatry. 59(suppl 5) 42-48. Tadokoro C, Kiuchi Y, Yamazaki Y, Oguchi K, Kamijima K. (1998). Effects of imipramine and sertraline on protein kinase activity in rat frontal cortex. Eur J Pharmacol. 342(1) 51-4. 

Coutts RT, Su P, Baker GB, Daneshtalab M. 1993. Metabolism of imipramine in vitro by isozyme CYP2D6 expressed in a human cell line, and observations on metabolite stability. J Chromatogr B Biomed Appl 615 265. 

This conclusion is supported by the mechaiusm of action of imipramine. Once a neurotransmitter has been released into the synapse, there are two ways to terminate its action. The first is to degrade it to inactive products, by MAO for example. The second is to remove the neurotransmitter through reuptake into the presynaptic neuron. This mechaiusm is the predominant one for clearing the synapse of serotonin, norepinephrine, and dopamine. Specific proteins embedded in the neuronal plasma membrane mediate the reuptake of these monoamine neurotransmitters. Imipramine is a nonspecific monoamine reuptake inhibitor that is, it slows the reuptake of aU three of these monoamines, which enhances the activity of these neurotransmitters. This also suggests that a deficit in the activity of one or more of the monoamines underlies the problem of depression. 

A breakthrough in the treatment of major depression was the discovery of fluoxetine, marketed as Prozac. Fluoxetine has a mechanism of action similar to that of imipramine with an important exception. It is a selective serotonin reuptake inhibitor, an SSRI. This strongly suggests that, in some sense, the symptoms of major depression result from a deficit in serotonin specifically. By inhibiting its reuptake from the synapse, the activity of serotonin is enhanced. Two other important drugs for major depression, sertraline (Zoloft) and paroxetine (Paxil), among several others,... 

After checking a baseline EKG to rule out undetected heart rhythm abnormalities, many clinicians use a low dose of imipramine or protriptyline to treat the auxiliary symptoms of narcolepsy. Either of these can be started at 10 mg taken once a day and then slowly increased over several weeks as needed until the symptoms... 

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