Imipramine depression from

In several antidepressant tests, (46) is very active the oral EDso in reserpine and tetrabenazine tests is 03-1 mg kg" [133,134]. Compound (46), and also its meta-MeO analogue, with 5biogenic amine uptake mechanisms in mouse and rat heart were half as potent as, and of shorter duration than, those of imipramine (I). Uptake of NA in rat medulla or hypothalamus was not inhibited by (46), but alteration of the NA-metabolite pattern was similar to that associated with (I) [136]. Ginically a rapid onset of action of (46) in depressed patients was claimed [ 137], but in subsequent trials only a minority adhered to this view in general no difference from imipramine was demonstrated in various double-blind trials [132]. It appeared to have less peripheral anticholinergic and possibly a lower intrinsic activity in blocking the monoamine uptake process than (1). In depressed patients with clear anxiety components, (46) showed also favourable results [138]. 

Kleber HD, Weissman MM, Rounsaville BJ, et al Imipramine as treatment for depression in addicts. Arch Gen Psychiatry 40 649-633, 1983 Kleber HD, Riordan CE, Rounsaville BJ, et al Clonidine in outpatient detoxification from methadone maintenance. Arch Gen Psychiatry 42 391-394, 1983 Kleber HD, Topazian M, Gaspari J, et al Clonidine and naltrexone in the outpatient treatment of heroin withdrawal. Am J Drug Alcohol Abuse 13 1-17, 1987 Kornetsky C. Brain stimulation reward, morphine-induced stereotypy, and sensitization implications for abuse. Neurosci Biobehav Rev 27 777-786, 2004 Kosten TR, Kleber HD Buprenorphine detoxification from opioid dependence a pilot study. Life Sci 42 633-641, 1988... 

The tricyclic antidepressants (TCAs) derive their name from their three-ringed molecular structure (Fig. 20.3) and emerged, in 1958, from a search for better neuroleptics than chlopromazine among the phenothiazines. The prototype, imipramine, turned out to be ineffective in treating the positive symptoms experienced by schizophrenics but it did relieve their depression (negative symptoms). In fact, imipramine is still the standard agent against which novel antidepressants are compared in clinical trials. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

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,... 

Of greater concern is the safety of the TCAs. Toxic levels of these medications can produce lethal cardiac arrhythmias, seizures, and suppression of breathing. An overdose of a 1-2 week supply of most TCAs is often fatal, a serious consideration when prescribing medication to depressed patients with suicidal thoughts. Children taking imipramine for treatment of ADHD have died from sudden cardiac death consequently, child psychiatrists seldom use TCAs. Likewise, patients with heart disease or seizure disorders are more likely to have dangerous complications from TCAs and should avoid them. 

Tricyclic Antidepressants (TCAs). TCAs were introduced in the 1950s and over the years have become the mainstay of treatment for cataplexy and the other REM-related symptoms. The doses used are usually less than the doses required in the treatment of depression. Imipramine (Tofranil) is the most widely used TCA for narcolepsy and is usually effective at doses from 10 to 75 mg given once a day. Some doctors prefer the TCA protriptyline (Vivactil) because it has mild stimulant effects, but it has not been as widely used or as thoroughly studied in narcolepsy. The common side effects of TCAs are drowsiness, dry mouth, and constipation, but these are usually not a problem at the lower doses used for narcolepsy. Patients should receive a baseline electrocardiograph (EKG) before starting a TCA and should have blood levels of the medication checked periodically. 

Imipramine (Tofranil) [Antidepressant/TCA] WARNING Close observation for suicidal thinking or unusual changes in behavior Uses Depres-sion, enuresis, panic attack, chronic pain Action TCA t CNS synaptic serotonin or norepinephrine Dose Adults. Hospitalized Initial 100 mg/24 h PO in doses T over several wk 300 mg/d max Output Maint 50-150 mg PO hs, 300 mg/24 h max Peds. Antidepressant 1.5-5 mg/kg/24 h daUy-qid Enuresis >6 y 10-25 mg PO qhs T by 10-25 mg at 1-2-wk int vals (max 50 mg for 6-12 y, 75 mg for >12 y) Rx for 2-3 mo, then tap Caution [D, /-] Contra Use w/ MAOIs, NAG, acute recovery from MI, PRG, CHF, angina, CVD, arrhythmias Disp Tabs, caps SE CV Sxs, dizziness, xerostomia, discolored urine Interactions t Effects W/ amiodarone, anticholinergics, BBs, cimetidine, diltiazem, Li, OCPs, quinidine, phenothiazines, ritonavir, verapamil, EtOH, evening primrose oil t effects OF CNS depressants, hypoglycemics, warfarin T risk of serotonin synd W/MAOIs 4-... 

Some questions have been raised about the relative efficacy of the SSRls, particularly in severe depression. The pooled analyses of the data from blinded, controlled trials have tended to find similar levels of efficacy between the SSRls and the comparator TCA, imipramine. Paroxetine and fluvoxamine were both found in subanalyses of patients with severe depression included in large placebo- and imipramine-controlled studies to be more effective than imipramine in severe depression (S. A. Montgomery 1992a Ottevanger 1991 Tignol et al. 1992 Wakelin 1988]. However, imipramine may not be the TCA that is most effective in severe depression or may not have been used in the trials at an adequate dose. 

Reifler BV, Teri L, Raskind M, et al Double-bhnd trial of imipramine in Alzheimer s disease patients with and without depression. Am J Psychiatry 146 45-49, 1989 Reisberg B, Ferris SH, DeLean MJ, et al The Global Deterioration Scale for Assessment of Primary Degenerative Dementia. Am J Psychiatry 139 1136-1139, 1982 Reisine T, Zatz M Interactions between lithium, calcium, diacylglycerides and phorbol esters in the regulation of ACTEl release from AtT-20 cells. J Neurochem 49 884-889, 1987... 

According to Kuhn s observations, the effect of imipramine became apparent in some cases after a few days in other cases several weeks passed before any therapeutic effect could be seen. He estimated his failure rate at 20 25%, but regarded his sample as too small for any reliable estimate to be made. If the medicament was discontinued too soon, there was said to be a danger of relapse. It was also not possible to ascertain from his observations whether imipramine shortened the natural duration of the depressive phase. The best therapeutic successes were recorded in endogenous depression and in cases of depression which first appeared at the menopause, in cases where vital symptoms were clearly in the foreground". Kuhn also provided a comprehensive list of side effects of imipramine. which nevertheless in his view did not appreciably restrict use of the medicament. (None of the claims regarding the clinical pattern of action of imipramine made by Kuhn on the basis of open... 

Significantly decreased H-labeled imipramine binding sites in platelets from depressed and obsessive-compulsive patients... 

The antidepressant properties of these earlier antidepressants were chance discoveries. Imipramine was first developed as a potential antipsychotic, but when Kuhn (2) tested the clinical efficacy of this agent, he found that it only benefited depressed schizophrenic patients. This observation prompted him to test it in patients who were suffering from melancholia. Iproniazid was developed as an antitubercular drug, but the observation that euphoria was a side effect led George Crane ( 3) to conduct clinical trials, which found it useful in purely depressed patients. A year later, Nathan Kline ( 4), following up on this observation, reported positive results when he administered iproniazid to another depressed group. 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

Therapeutic plasma concentrations of TCAs have clinically significant antiarrhythmic activity (420). Imipramine and nortriptyline (and probably other TCAs) share electrophysiological properties characteristic of type I (A, B) compounds (e.g., quinidine, procainamide, disopyramide) and can even be used in cardiac patients free from depression, exclusively for the control of arrhythmia (421). 

Berzewski H, Van-Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacoi 1997 7 S37-S47... 

Two studies have indicated that the tricyclic antidepressant (TCA) imipramine may be as effective as BZDs in the treatment of GAD ( 58, 59). No studies longer than 8 weeks duration have been conducted, however, and imipramine s onset of anxiolytic action may be even slower than that of buspirone. Aithough adverse effects also may limit usefulness, its lack of dependence liability may make it an appropriate alternative in chronically anxious patients who also suffer from panic and depression. 

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