Desipramine

INTRODUCTION

Recent studies suggest that desipramine is useful for treatment of cocaine abuse [1-3]. Desipramine's efficacy is being further assessed in a series of double blind studies with cocaine abusers including methadone-maintained opioid addicts who also abuse cocaine [2, 4, 5]. Methadone maintenance is one of our most effective treatments for opioid dependence, but it is not a treatment for cocaine abuse and adjunctive treatments are needed for these dually addicted opioid and cocaine abusers [6, 7]. Desipramine has been suggested as a treatment adjunct, although recent controlled studies have found no difference from placebo in efficacy of desipramine [4, 5, 7]. This lack of efficacy among methadone-maintained patients in particular may be related to alterations in the metabolism of desipramine.

Desipramine (DMI) metabolism involves an initial hydroxylation of the aromatic ring that may be inhibited by several medications including neuroleptics, quinidine, and possibly opiods [8-10]. This metabolic step may also be clinically significant, since unconjugated 2-hydroxy-desipramine (OHDMI) blocks reuptake of norepinephrine and has behavioral effects in animals similar to the parent compound [11-15]. These effects may include antidepressant efficacy in man [16]. Not only is OHDMI pharmacologically active, but it is also present in both plasma and cerebrospinal fluid at substantial levels that are commonly about half those of the parent drug [17-19]. Increased DMI levels resulting from reduced hydroxylation may make toxicity and side effects more likely at the standard DMI dosages that have been recommended for treatment of melancholia [20]. In summary, medications that affects its metabolic disposition might impact on the clinical effects of DMI.

In the current study we examined DMI and OHDMI concentrations in a group of methadone-maintained patients undergoing treatment with DMI for cocaine abuse, and compared them with depressed patients and nonmethadone-treated cocaine abusers. In a pilot study, methadone patients complained of substantial side effects at relatively low dosages of DMI, averaging 141 mg daily [7]. In our previous studies of depressed patients and nonmethadone-treated cocaine abusers, a mean daily DMI dosage that had been 20 to 30% higher was associated with minimal side effects [2, 20]. In spite of this lower dosage in the methadone patients, clinical efficacy in our open pilot study was generally similar to that in nonmethadone-treated cocaine abusers [2, 5]. Detailed analysis of treatment outcome in relationship to blood levels of DMI and its metabolites were not undertaken in that pilot study, however. In the current study, assessment of both DMI and OHDMI plasma levels have been made and compared among methadone-maintained patients, nondrug-abusing depressives, and nonmethadone-treated cocaine abusers.

METHODS

A. Subjects

Three groups of patients were compared: 39 with major depressive disorder, 22 nonmethadone-treated cocaine abusers, and 11 methadone-maintained cocaine abusers. The 39 depressed patients were all under 60 years old with a mean age of 38 years (SD = 12.3). The two cocaine-abusing groups were somewhat younger with mean ages of 30.2 (SD = 7.3) and 31.3 years (SD = 4.5) for the methadone and nonmethadone patients, respectively. Fewer males were included among the depressed (28%) than among the cocaine-abusing patients (67%) ([X.sup.2] = 9; P < .01), but sex had no association with DMI dosage or blood levels within either the cocaine or noncocaine abuser samples. The methadone patients had been taking methadone for 4 months (SD = 2) at a dose of 64 mg daily (SD = 8) and had been on stable methadone doses for at least a month before starting DMI. None of the depressives were either drug or alcohol abusers, and in all three groups patients with current alcoholism, active medical illness, organic brain syndromes, or schizophrenia were excluded. Six of the nonmethadone cocaine and none of the methadoen patients met DSM III-R criteria for major depressive disorder using the Structured Clinical Interview for DSM III-R (methadone patients) or the Schedule for Affective Disorders and Schizophrenia (nonmethadone patients). Liver function testing (SGOT and SGPT) was also done in all of the drug abusers, and values were within the normal range before starting DMI. During treatment, the cocaine abusers were monitored randomly three times per week in the methadone group and biweekly in the "pure" cocaine group. Written informed consent was obtained from all three study samples.

B. Dosing and Drug Level Analysis

The patients received a 3-week fixed dose DMI trial at a daily dosage of 2.5 mg/kg for the depressed patients and the nonmethadone cocaine abusers and 150 mg (about 2.5 mg/kg) for the methadone patients. Single daily dosing was used, and for the methadone patients the medication was administered under the observation of the nursing staff. Dosage was gradually increased over the first week starting at 50 mg, and adjustments were made for side effects, particularly among the methadone patients whose dose was reduced to 100 mg daily in two patients.

Steady-state plasma concentrations were determined from blood samples drawn during the second through fourth weeks of medication treatment. Blood samples were drawn in heparinized glass tubes at 15 hours after the last daily dose from the depressed patients and at 18 to 24 hours from the two cocaine abuse groups. Plasma concentrations of DMI were determined using a modification of a published HPLC technique [21]. Concentrations of unconjugated OHDMI were determined in the same sample with an HPLC method described previously [18].

RESULTS

While the plasma concentration of DMI was not significantly different among the three patient groups, as shown in Table 1, the dose of DMI was significantly lower in the methadone patients compared to the other two groups. To adjust for this difference we determined the ratio of the DMI dose to blood level, and found it to be significantly lower in the methadone group (Table 1). Since the methadone patients had higher dose corrected plasma concentrations than either of the other two groups, we directly examined OHDMI levels.

The unconjugated OHDMI levels were significantly lower in the methadone patients, but there was no difference between the depressed patients and the nonmethadone-treated cocaine abusers (Table 1). Table 1 shows the mean and standard deviation for the dose and blood levels. Both dosage and blood levels

had a relative normalized distribution, particularly among the methadone patients. Thus, the differences among the groups were not due to outlaying values.

The relationship between the DMI and OHDMI plasma levels was then examined. The ratio of metabolite to parent drug was significantly different among the three groups. The methadone-maintained cocaine abusers had a substantially lower ratio, as shown in Table 1. Because of somewhat lower DMI dose in the methadone patients, we also performed covariance analyses using dosage, but the difference between the groups in OHDMI to DMI ratio remained significant (F = 4.4; df = 3,71; P < .01). Demographic (sex, age) adjustments did not affect these ratio differences among the groups. Furthermore, within the methadone group, the DMI and OHDMI levels did not significant differ for cocaine abstinent versus nonabstinent patients.

DISCUSSIONS

Chronic methadone treatment appeared to affect the disposition of desipramine in patients being treated with DMI for cocaine abuse. The ratio of DMI dose to blood level, and of OHDMI to its parent compound, were substantially different in the methadone patients than in the nonmethadone-treated cocaine abusers or in the depressed patients. Since these values did not differ between the nonmethadone cocaine abusers and the nonabuser depressives, the alteration in DMI disposition was not due to the cocaine abuse. The methadone and nonmethadone cocaine abusers were also comparable in age, sex, and lack of alcohol abuse and major medical disorders, suggesting that the definitive difference was maintained on methadone. An interactive effect of cocaine with methadone on DMI disposition also appeared to be unlikely, since among the methadone patients, the DMI and OHDMI levels did not differ in patients who were abstinent compared to those with cocaine in their urine toxicologies.

Methadone is extensively metabolized by the hepatic microsomal enzymes with production of N-demethylated cyclic metabolites of methadone which are then hydroxylated and excreted in bile and urine as water-soluble glucuronide conjugates [22-25]. Hydroxylation is also a key metabolic step in DMI metabolism. However, inhibition of hydroxylation of DMI by methadone, as an explanation for our data, must be considered conjectural. More definite pharmacokinetic studies on this mechanism, including urinary studies of DMI and its metabolites and an assessment of conjugation, would require impatients who could be administered DMI while on and off methadone. The need to maintain opioid abusers on methadone and the undesirability of administering methadone to nondrug abusers are logistic and ethical obstacles to the performance of such studies.

While it is possible that factors associated with a history of opioid abuse such as hepatitis in the past, rather than the methadone, were responsible for our findings, several of these factors seem unlikely. Current liver toxicity was unlikely, since liver function tests were performed before starting DMI and were within normal limits for all subjects. Furthermore, consideration of the large number of medications that inhibit hydroxylation of DMI suggests a metabolic interactions as the most plausable explanation for the higher dose corrected DMI concentrations and reduced metabolite to parent ratios seen in this population. A wide variety of drugs have been reported to inhibit the hydroxylation of DMI. These drugs include quinidine [10], neuroleptics [8, 26, 27], and tyramine [28]. Neuroleptics have also been shown to elevate DMI blood levels in patients receiving combined therapy [8, 27]. Thus, an interaction between methadone and DMI would be consistent both with the shared metabolic pathways and with previous findings regarding other nonopioid drugs.

Studies in rats have shown increased analgesis and alterations in the distribution and metabolism of methadone by DMI [9]. In addition to potentiating analgesia, DMI increased the toxic symptoms and reduced the [LD.sub.50] of methadone. This last study has direct relevance to the current findings in humans. Further work on the mechanics of interaction between methadone and DMI is needed in humans to specify the details of the altered disposition and any treatment implications [16, 20, 29]. The smaller standard deviation and normal distribution of DMI levels within the methadone sample suggests that these patients may have been converted to a more homogenous group of metabolizers, perhaps by inhibition of the more rapid hydroxylation of DMI found in most individuals [29].

Regardless of the mechanicm, patients concurrently receiving methadone and DMI shows higher dose-corrected DMI plasma concentrations. As a consequence, such patients should probably receive lower dosages in order to reduce the probability of side effects and possibly to increase the likelihood of treatment response. Since among our nonmethadone-treated cocaine abusers treatment response appears more likely below DMI blood levels that many of our methadone sample exceeded (Gawin, personal communication), we will be addressing this treatment response question in our methadone sample as it gets larger.

REFERENCES

[1] Grabowski, J. (ed.), cocaine: Pharmacology, Effects, and Treatment of Abuse, NIDA Research Monograph 50, U.S. Government Printing Office, Washington, D.C., 1984.

[2] Gawin, F. H., Byck, R., Rounsaville, B. J., Kosten, T. R., Jatlow, P. I., and Morgan, C., Despiramine facilitation of initial cocaine abstinence, Arch. Gen. Psychiatry 46:117-121 (1989).

[3] Kosten, T. R., Pharmacotherapeutic interventions for cocaine abuse: Matching patients to treatments, J. Nerv. Ment. Dis. 177:379-389 (1989).

[4] Arndt, I., Dorozynsky, L., McLellan, A. T., Woody, G., and O'Brien, C. P., Desipramine treatment of cocaine abuse in methadone maintained patients, in Proceedings of the Committee on Problems of Drug Dependence, 1989, In Press.

[5] Weddington, W. W., Brown, B. S., Haertzen, C. A., Hess, J. M., Mahaffey, J. R., Kolar, A. F., and Jaffee, J. H., Amantadine and desipramine for treatment of cocaine dependence, in Proceedings of the Committee on Problems of Drug Dependence, 1989, In Press.

[6] Kosten, T. R., Rounsaville, B. J., and Kleber, H. D., A 2.5 year follow-up of cocaine use among treated opioid addicts: Have our treatments helped?, Arch. Gen. Psychiatry 44:281-284 (1987).

[7] Kosten, T. R., Schumann, B., Wright, D. R., Carney, M. K., and Gawin, F. H., A pilot study using desipramine for cocaine abusing methadone maintenance patients, J. Clin. Psychiatry 48(11):442-444 (1987).

[8] Nelson, J. C., and Jatlow, P. U., Neuroleptic effect on desipramine steady-state plasma concentrations, Am. J. Psychiatry 137:1232-1234 (1980).

[10] Liu, S. J., and Wang, R. I., Increased analgesia and alterations in distribution and metabolism of methadone by desipramine in the rat, J. Pharm. Exp. Ther. 195:94-104 (1975).

[11] Steiner, E., Dumont, E., Spina, E., and Dahlqvist, R., Inhibition of desipramine 2-hydroxylantion by quinidine and quinine, Clin. Pharmacol. Ther. 43:577-581 (1988).

[12] Jandhyala, B. S., Steenberg, M. L., Perel, J. M., et a., Effects of several trycyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs, Eur. J. Pharmacol. 42:403-410 (1977).

[13] Potter, W. Z., Calil, H. M., Manian, A. A., et a., Hydroxylated metabolites of tricyclic antidepressant: Preclinical assessment of activity, Biol. Psychiatry 14:601-613 (1979).

[14] Javaid, J. L., Perel, J. M., and Davis, J. M., Inhibitation of biogenic amines uptake by imipramine, desipramine, 2-OH-imipramine and 2-OH-desipramine in rat brain, Life Sci. 24:21-28 (1979).

[15] Wilkerson, R. D., Antiarrhytmic effects of tricyclic antidepressant drugs in ouabain-induced arrhythmias in the dog, J. Pharmacol. Exp. Ther. 205:666-674 (1978).

[16] Nelson, J. C., Mazure, C., and Jatlow, P. I., Antidepressant activity of 2-hydroxydesipramine, Clin. Pharm. Ther. 44:283-288 (1988).

[17] Potter, W. Z., Calil, H. M., Suffin, T. A., et al., Active metabolites of imipramine and desipramine in man, Clin. Pharmacol. Ther. 31:393-401 (1982).

[18] Bock, J. L., Nelson, J. C., Gray, S., and Jatlow, P. I., Desipramine hydroxylation: Variability and effect of antipsychotic drugs, Clin. Pharmacol. Ther. 33:190-197 (1983).

[19] DeVane, C. L., Savett, M., and Jusko, W. J., Desirpamine and 2-hydroxydesirpramine pharmacokinetics in normal volunteers, Eur. J. Clin. Pharmacol. 19:61-64 (1981).

[20] Nelson, J. C., Jatlow, P. I., Quinlan, D. M., et al., Desipramine plasma concentration and antidepressant response, Arch. Gen. Psychiatry 39:1419-1422 (1982).

[21] Proelss, H. F., Logman, H. J., and Miles, D. G., High performance liquid chromatographic simultaneous determination of commonly used antidepressants, Clin. Chem. 24:1948-1953 (1978).

[22] Beckett, A. H., Taylor, J. F., Casey A. F., and Hassan, M. M. A., The biotransformation of methadone in man: Synthesis and identification of a major metabolite, J. Pharm. Pharmacol. 20:754-762 (1968).

[23] Pohland, A., Boaz, H. E., and Sullivan, H. R., Synthesis and identification of metabolites resulting from the biotransformation of d,l-methadone in man and in the rat, J. Med. Chem. 14:194-197 (1971).

[24] Baselt, R. C., and Casrett, L. J., Biliary and urinary elimination of methadone and its metabolites in the rat, Biochem. Pharmacol. 21:2705-2712 (1972).

[25] Baselt, R. C., and Bickel, M. H., Biliary excretion of methadone by the rat: Identification of a parahydroxylated major metabolite, Biochem. Pharmacol. 22:3117-3120 (1973).

[26] Gram, L. F., and Overo, K. F., Drug interaction: Inhibitory effect of neuroleptics on metabolism of trycyclic antidepressants in man, Br. J. Med. 1:463-465 (1972).

[27] Nelson, J. C., Price, L. H., and Jatlow, P. I., Neuroleptic dose and desipramine concentrations during combined treatment of unipolar delusional depression, Am. J. Psychiatry 143:1151-1154 (1986).

[28] Lemberger, L., Kuntzman, R., Conney, A. H., and Burns, J. J., Metabolism of tyramine to dopamine by liver microsomes, J. Pharmacol. Exp. Ther. 150:292-297 (1965).

[29] Nelson, J. C. and Jatlow, P. I., Nonlinear desipramine kinetics: Prevalience and importance, Clin. Pharmacol. Ther. 41:666-670 (1987).

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