Dothiepin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Dothiepin is a tricyclic antidepressant that is structurally related to amitriptyline. It appears that the antidepressant activity of dothiepin is mediated through facilitation of noradrenergic neurotransmission by uptake inhibition and possibly also by enhancement of serotoninergic neurotransmission. The overall therapeutic efficacy of dothiepin is very similar to that of amitriptyline. In addition, dothiepin appears to be comparable to imipramine, doxepin, maprotiline, mianserin, fluoxetine, fluvoxamine and trazodone. Dry mouth is the most commonly reported side effect of therapeutic doses but the incidence of this and other anticholinergic side effects is less among patients treated with dothiepin than with amitriptyline. However, the sedative/anxiolytic activity of dothiepin is similar to that of amitriptyline. Dothiepin has not been associated with cardiotoxicity at therapeutic doses. Thus, many years of extensive clinical use have shown that dothiepin is now an established and effective antidepressant in both inpatients and outpatients with depressive symptoms of varying severity and coexisting anxiety. Its therapeutic equivalence to other tricyclics ensures its place as a treatment alternative in these disorders.     

Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluvoxamine is a new antidepressant which potently and specifically inhibits neuronal reuptake of serotonin. In the absence of other major pharmacological effects it appears that its antidepressant activity stems from facilitation of serotoninergic neurotransmission as a result of reuptake inhibition. Studies suggest that fluvoxamine has overall therapeutic efficacy comparable with that of imipramine and clomipramine in depressive illness. It causes fewer anticholinergic-type and cardiovascular side effects than the tricyclic antidepressants but it is associated with a higher incidence of nausea and vomiting. Elderly patients also respond well to fluvoxamine. Studies are now required to compare fluvoxamine with other second generation antidepressants and to establish whether some types of depressive illness respond more readily to fluvoxamine than other agents. Thus, in patients with depressive illness, fluvoxamine offers a suitable alternative to tricyclic antidepressants and may be especially valuable in patients with concomitant cardiovascular disease, and those unresponsive to or unable to tolerate tricyclic antidepressants.     

Pharmacokinetics of lofepramine in man: Relationship to inhibition of noradrenaline uptake

Summary The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desmethylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rat irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimpramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formedin vivo in man affect neuronal uptake of this amine. Lofepramine belongs to the group of tricyclic anti-depressants which preferentially inhibit noradrenaline uptake.Lofepramine = Leo 640 = N-methyl-N-[4-Chlorobenzoyl-methyl-3-(10.11-dihydro-5H-dibenz (b, t) azepin-5-yl]-propylamine     

Effect of lofepramine and other antidepressants on the uptake of 5-hydroxytryptamine and noradrenaline into rat brain monoaminergic neurons.

Lofepramine, (N-methyl-N-[4-chlorobenzoylmethyl]-3-[10,11-dihydro-5H-dibenz(b,f)-azepin-5-yl]-propylamine hydrochloride), is a new antidepressant with low toxicity and no peripheral anticholinergic activity. Its effect on 5-hydroxytryptamine (5-HT) and noradrenaline uptake into rat brain monoaminergic neurons was studied and compared with that of other antidepressants, particularly with that of imipramine and desipramine. Lofepramine inhibited both 5-HT and noradrenaline uptake into synaptosomal fractions in vitro but was 4 times more potent in inhibiting noradrenaline than 5-HT uptake, indicating the effect resembles that of desipramine. Noradrenaline uptake was also preferentially inhibited in synaptosomes from brain of rats treated previously with lofepramine or desipramine (i.p.). Pretreatment with SKF 525A (i.p.) did not diminish the effect of lofepramine, but rather potentiated it. Therefore it is suggested that the formation of desipramine is not necessary for lofepramine to exhibit, the effect on amine uptake in vivo. Both lofepramine and desipramine inhibited intraventricular noradrenaline uptake into synaptosomes without any effect on 5-HT uptake. These results suggest that lofepramine is qualitatively similar to desipramine with respect to preferential inhibition of noradrenaline uptake into central noradrenergic neurons.     

Effect of lofepramine and other antidepressants on the uptake of 5-hydroxytryptamine and noradrenaline into rat brain monoaminergic neurons

Lofepramine, (N-methyl-N-[4-chlorobenzoylmethyl]-3-[10, 11-dihydro-5H-dibenz(b,f)-azepin-5-yl]-propylamine hydrochloride), is a new antidepressant with low toxicity and no peripheral anticholinergic activity. Its effect on 5-hydroxytryptamine (5-HT) and noradrenaline uptake into rat brain monoaminergic neurons was studied and compared with that of other antidepressants, particularly with that of imipramine and desipramine. Lofepramine inhibited both 5-HT and noradrenaline uptake into synaptosomal fractions in vitro but was 4 times more potent in inhibiting noradrenaline than 5-HT uptake, indicating the effect resembles that of desipramine. Noradrenaline uptake was also preferentially inhibited in synaptosomes from brain of rats treated previously with lofepramine or desipramine (i.p.). Pretreatment with SKF 525A (i.p.) did not diminish the effect of lofepramine but rather potentiated it. Therefore it is suggested that the formation of desipramine is not necessary for lofepramine to exhibit the effect on amine uptake in vivo. Both lofepramine and desipramine inhibited intraventricular noradrenaline uptake into synaptosomes without any effect on 5-HT uptake. These results suggest that lofepramine is qualitatively similar to desipramine with respect to preferential inhibition of noradrenaline uptake into central noradrenergic neurons.     

Fluoxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

Fluoxetine is a new antidepressant which enhances serotoninergic neurotransmission through potent and selective inhibition of neuronal reuptake of serotonin. Metabolism by N-desmethylation occurs in man yielding desmethylfluoxetine, which also inhibits serotonin reuptake. Both the parent compound and metabolite possess elimination half-lives of several days facilitating the maintenance of steady-state plasma concentrations during long term treatment. Fluoxetine has overall therapeutic efficacy comparable with imipramine, amitriptyline and doxepin in patients with unipolar depression treated for 5 to 6 weeks, although it may be less effective than tricyclic antidepressants in relieving sleep disorders in depressed patients. Geriatric patients also responded as well to fluoxetine as to doxepin. The symptomatic improvement in patients with unipolar depression during short term fluoxetine treatment has been satisfactorily maintained when therapy was extended for at least 6 months: the relapse rate was low and similar to that of imipramine. Preliminary data have shown that patients with bipolar depression gained similar therapeutic benefit from fluoxetine or imipramine. Other preliminary trials have indicated that fluoxetine may be useful in obsessive-compulsive disorders. Usual doses of fluoxetine cause significantly fewer anticholinergic-type side effects than tricyclic antidepressants. Nausea, nervousness and insomnia are the most frequently reported fluoxetine-related adverse effects, but these have usually not been severe. Therapeutic doses of fluoxetine do not affect cardiac conduction intervals in patients without pre-existing cardiovascular disease and fluoxetine has been relatively safe in the small number of patients who have taken overdoses. It has not been clearly established whether some types of depression may respond more readily to fluoxetine than other antidepressants, and its overall therapeutic efficacy has not been compared with other second generation antidepressants. Thus, with its different and perhaps improved side effect profile compared with older tricyclic antidepressants, fluoxetine offers properties that could be used to advantage in many patients with depression.     

Citalopram. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Citalopram is an antidepressant belonging to a new class of drugs which enhance serotoninergic neurotransmission through potent and selective inhibition of serotonin reuptake. Preliminary trials suggest that its short term therapeutic efficacy is significantly greater than that of placebo and mianserin, and comparable to that of amitriptyline, maprotiline and imipramine. It appears to be a weaker antidepressant agent than clomipramine, but better tolerated. Its elimination half-life of 33 hours permits once daily oral administration. Symptomatic improvement obtained with short term treatment has been maintained when therapy has been extended for up to 1 year; in the few patients studied for this extended period, the relapse rate was lower than with fluvoxamine, fluoxetine or imipramine. Compared to standard antidepressant agents, citalopram is well tolerated. It does not appear to be cardiotoxic, has not been associated with seizures in humans, and is relatively nonsedating. Unlike the tricyclic antidepressants, citalopram has minimal anticholinergic effects. Mild and transient nausea, with or without vomiting, is the most frequent adverse effect--occurring in 20% of patients--and increased perspiration, headache, dry mouth, tremor and insomnia are experienced by 15 to 18% of patients. Citalopram thus offers similar therapeutic efficacy and a more favourable tolerability profile than the tricyclic antidepressants. Preliminary data suggest that it may be particularly useful in patients who cannot tolerate the anticholinergic or cardiovascular side effects of tricyclic antidepressants and in those for whom sedation is not indicated.     

Experimental investigation of psychophysiological effect of a new antidepressant (lofepramine) as compared to imipramine and placebo (author's transl)

Using 24 non-selected healthy male students the effects of imipramine (single dose of 100 mg orally) and 4'-chloro-2-[3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-propyl]-methylamino]-acetophenone-hydrochloride (lofepramine, Gamonil) (single dose of 140 mg orally) in comparison to placebo (doubleblind) on subjective, physiological and performance variables were examined. All subjects (Ss) received the three drugs in a completely counterbalanced sequence. On the basis of their scores on the Depression Scale of the Freiburger Personality Inventory (FPI, Fahrenberg) Ss were divided into two groups of 12 Ss each, "high depression" and "low depression" group. Two-way analyses of variance were computed. Imipramine and Lofepramine elevate scores in the mood scale, but only for the "high depression" group. For the Ss scoring lower in depression no such effect can be demonstrated. The physiological effects are similar. Reported side effects are less for lofepramine than for imipramine.     

A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review

The effects of the novel tricyclic antidepressant lofepramine were compared with that of its principal metabolite desipramine. In double-bind clinical trials, lofepramine has been shown to be as effective as desipramine and other comparator tricyclic antidepressants in the treatment of endogenous and reactive depression, but there are some differences between them. Thus the acute toxicity of lofepramine is approximately one-fifth that of its metabolite; lofepramine is a less potent muscarinic receptor antagonist than desipramine (verified by clinical studies in volunteers and depressed patients); lofepramine is less likely to produce conduction defects than desipramine. Neurochemical studies show that both lofepramine and its metabolite are potent noradrenaline uptake inhibitors in vitro and evidence is presented to suggest that lofepramine may release this amine following chronic administration in vivo; both drugs slightly increase serotonin turnover under these conditions and down-regulate cortical beta-adrenoceptor function. Unlike desipramine and most clinically effective antidepressants, lofepramine was inactive in attenuating the hyperactivity of olfactory bulbectomized rats in the "open field" apparatus, and in reversing acute clonidine induced hypomotility. From such tests it appears unlikely that the active metabolite, desipramine, is formed in the brain in sufficient concentrations after chronic lofepramine administration to make a substantial contribution towards the pharmacological activity of the parent compound.     

A double-blind comparison of the pharmacodynamic effects of single doses of lofepramine,amitryptyline and placebo in elderly subjects

Summary In a double-blind five-way cross-over study, six drug free healthy elderly subjects received single oral doses of lofepramine (70 mg, 105 mg and 140 mg), amitriptyline (50 mg) and matched placebo tablets.A dose related increase in plasma drug levels and pharmacological effects of lofepramine was observed. Lofepramine (140 mg) improved psychomotor performance (choice reaction time and letter cancellation), but no such change was seen with lower dose regimes or placebo. No significant differences between lofepramine and placebo were observed in other parameters measured.Amitriptyline, as expected, reduced salivary volume, produced drowsiness and impaired psychomotor performance. These changes correlated with plasma amitriptyline levels. The incidence of subjective side-effects with amitryptyline was also higher than that of lofepramine or placebo.In the dosage used, lofepramine exhibited no deleterious effect on the peripheral cholinergic system or psychomotor performance. This drug therefore is likely to be a relatively safe antidepressant for the elderly, but further investigations during long-term medication are required to verify these observations.     

Chemistry,Pharmacology, Pharmacokinetics,Adverse Effects,and Efficacy of the Antidepressant Maprotiline Hydrochloride

Maprotiline, a tetracyclic antidepressant with sedative properties, exhibits strong inhibitory effects on norepinephrine uptake across nerve cell membranes but interferes relatively little with serotoninergic mechanisms. The biological half-life of unchanged maprotiline in blood averages 43 hours. Though several studies suggest a more rapid onset of antidepressant effects with maprotiline than with amitriptyline or imipramine, this issue remains unresolved. The adverse effect profile of maprotiline is similar to that of the tricyclic antidepressants, except that rashes are about twice as frequent with maprotiline as with amitriptyline or imipramine. The most frequent adverse reactions are anticholinergic effects and sedation. Data suggest less frequent and severe anticholinergic side effects with maprotiline than with amitriptyline. Maprotiline may be less likely to induce orthostatic hypotension and tachycardia than standard tricyclic antidepressants, but clinically important differences in cardiovascular effects remain to be conclusively demonstrated. Many patients benefit from the convenience of once daily dosing. Maprotiline is comparable in antidepressant efficacy to the tricyclic antidepressants.     

Cardiovascular effects of imipramine and bupropion in depressed patients with congestive heart failure

There has been a long-standing concern over the cardiovascular effects of tricyclic antidepressants, particularly in patients with preexisiting cardiac disease. Recent studies have demonstrated that imipramine causes no deleterious effect on ejection fraction as determined by radionuclide angiography in patients with impaired left ventricular function (LVF). However, the high rate of severe orthostatic hypotension induced by imipramine makes use of the drug problematic in these patients. Bupropion is a new antidepressant of the aminoketone class which is structurally unrelated to the tricyclics and which is relatively free of cardiac side effects in healthy depressed patients. We compared imipramine and bupropion in 10 depressed patients with impaired LVF in a random, double-blind crossover study. Neither imipramine nor bupropion adversely affected ejection fraction or other indices of LVF. However, as previously reported, severe orthostatic hypotension requiring discontinuation of drug developed in 50% of patients on imipramine. This difficulty did not occur with bupropion. From a cardiac perspective, bupropion may offer a safe alternative to imipramine in depressed patients with congestive heart failure.     

Paroxetine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.

Paroxetine is a potent and selective inhibitor of the neuronal reuptake of serotonin, thereby facilitating serotoninergic transmission; this action appears to account for the antidepressant activity observed with this drug. A mean terminal elimination half-life of approximately 24 hours permits once daily administration. Results of short term clinical trials have shown paroxetine to be significantly superior to placebo, and comparable to amitriptyline, clomipramine, imipramine, dothiepin and mianserin in relieving symptoms associated with major depressive disorders. Paroxetine has shown some preliminary promise in the treatment of depressive illness resistant to tricyclic antidepressant therapy but further studies are required before any conclusions can be drawn. Paroxetine in therapeutic doses has been very well tolerated, and the favourable tolerability profile of this agent appears to be its primary advantage over traditional antidepressant agents. Paroxetine causes minimal anticholinergic-type adverse effects, and unlike tricyclic antidepressants, it does not precipitate cardiovascular effects or provoke cardiac conduction disturbances. Nausea has been the most frequently reported adverse event during short term use of paroxetine, but it is generally mild and transient and subsides with continued use. With longer term use headache, sweating and constipation were the most frequently reported side effects but the incidence rate was not significantly different from that noted for comparator antidepressants. Furthermore, the frequency of withdrawal due to adverse effects is less with paroxetine than with tricyclic antidepressant agents. Overall, available data appear to indicate that while the efficacy of paroxetine is similar to that of traditional antidepressant drugs, the newer agent possesses much improved tolerability. In addition, the wide therapeutic index of paroxetine may be beneficial when treating patients with an increased risk of suicide. Thus, paroxetine clearly looks to become a valuable addition to the range of drugs currently available to treat depressive illness. Future research may help to further define the relative place of this newer agent in antidepressant therapy and determine how its overall therapeutic efficacy compares with that of other related antidepressant agents such as fluoxetine.     

Doxepin up-to-date: a review of its pharmacological properties and therapeutic efficacy with particular reference to depression.

Doxepin is closely related in structure and general pharmacological properties to other tricyclic antidepressant drugs such as amitriptyline and imipramine. It combines antidepressant activity with a sedative effect and in this respect resembles amitriptyline, with which it shares a similar profile of clinical action. The mood elevating effect of doxepin appears to be similar to that of amitriptyline but is probably less marked than that of imipramine and in some studies has been slower to take effect than imipramine. At dosages which have achieved a similar overall response rate, doxepin tends to cause fewer or less troublesome side-effects than imipramine, amitriptyline or amitriptyline-prephenazine. The more marked sedative properties of doxepin make it more useful than imipramine in depressed patients with sleep distrubances and in depression associated with anxiety. The benzodiazepines remain the drugs of choice in anxiety states. but when anxiety is accompained by significant depression, doxepin is more effective than chlordiazepoxide or diazepam. Doxepin is usually well tolerated, and in particular by the elderly and those with cardiovascular disease. Side-effects are similar in nature to those of other tricyclic antidepressants, with dry mouth, drowsiness and constipation being the most common. Postural hypotension is uncommon. Although doxepin appears to cause fewer cardiovascular side-effects in usual therapeutic doses, it has an intrinsic cardiotoxicity on overdosage similar to other tricyclics.     

The effect of lofepramine and other related agents on the motility of Tetrahymena pyriformis

Tricyclic antidepressants (TCAs) were introduced almost 50 years ago. Whilst there is no doubt that TCAs are effective in treating depression, they are also more cardiotoxic when taken in overdose than other antidepressant groups. Lofepramine is a more recently introduced modified TCA, which in animals and man has low toxicity when compared to older TCAs. Paradoxically, lofepramine is extensively metabolised to desipramine, which has considerable toxicity, both experimentally and in overdose. The toxicity of such compounds is attributed, in part, to a membrane stabilising effect (MSA) on cell membranes. This MSA causes gross effects to the cell structure and in turn, normal cell activity. The aim of this study was to compare the MSA of lofepramine with that of desipramine and amitriptyline in order to see if this might help to explain the low toxicity of lofepramine. The local anaesthetic agent lignocaine was also studied for comparison. Each compound was enclosed in a beta-cyclodextrin to increase its solubility in aqueous medium. The extent of MSA was determined as a measure of the effect on the swimming speed of the protozoan Tetrahymena pyriformis using a video image analysis system. The IC50s for the various drugs were then correlated with their respective octanol-water partition coefficient values (Pow). Amitriptyline had an IC50 of 1.26+/-0.29 mM, desipramine 75.99+/-14.40 mM, while lofepramine had an IC50 of 357.40+/-25.00 mM. Lignocaine had an IC50 of 85.73+/-18.30 mM. There was also a significant correlation between the IC50 values and the Pow values.     

Effect of tricyclic antidepressants on taste responses in humans and gerbils

One of the side effects of antidepressant pharmacotherapy reported clinically is impairment of the sense of taste. In this study, the taste effects of four tricyclic antidepressant compounds (clomipramine HCl, desipramine HCl, doxepin HCl, and imipramine HCl) were evaluated experimentally by topical application of the drugs to the tongue. Taste detection threshold concentrations for all four medications ranged from 0.1 mM to 0.2 mM in young persons but were elevated by as much as 7.71 times that in elderly individuals who were taking no concurrent medications. Each compound had a predominantly bitter taste with other qualities including metallic, sour, and sharp-pungent. In addition, each tricyclic antidepressant at concentrations from 1 mM to 5 mM blocked responses to a wide range of taste stimuli in both humans and gerbils. The differential suppression of other tastes by tricyclic antidepressants at the level of the taste receptors may contribute to the clinical reports of dysgeusia and hypogeusia.     

Effects of quinupramine on the central monoamine uptake systems and involvement of pharmacokinetics in its pharmacological activities

The effects of a new tricyclic antidepressant drug, quinupramine, on the monoamine uptake of rat brain homogenate preparations were studied in comparison with imipramine. Pharmacokinetic studies on quinupramine and imipramine in plasma and brain were also performed in rats after a single oral administration. Quinupramine had few effects on the noradrenaline and serotonin uptake both in in vitro and ex vivo models. After the administration of [3H]quinupramine, the unchanged drug was estimated as 60-75% of the total radioactivity in the cerebral cortex. Imipramine and desipramine preferentially inhibited the uptake of serotonin and noradrenaline, respectively, in vitro. After the administration, imipramine showed a marked inhibitory effect on noradrenaline uptake. A considerable amount of desipramine but not imipramine could be detected in the brain and plasma after the administration of [3H]imipramine. These results demonstrate that 1) the antidepressant activity of quinupramine cannot be attributed to inhibition of monoamine uptake, 2) unchanged quinupramine penetrates into the CNS and affects some of the processes of neurotransmission and 3) the pharmacological activities of imipramine, when administered orally, may be attributed to desipramine, the metabolite formed.     

Comparative cardiovascular toxicity of trazodone and imipramine in the rat.

Several authors have associated the cardiotoxicity of the tricyclic antidepressants with their capacity to potentiate the response to catecholamines. Trazodone is a psychotropic drug with a clinically proven antidepressant activity. It differes from the tricyclic antidepressants under several aspects (chemistry, pharmacology, mode and mechanism of action, etc.), including interactions with catecholamines. Contrary to the tricyclic antidepressants, it does not potentiate the response to catecholamines, but, instead, has an adrenolytic activity. We therefore decided to compare the cardiotoxicity of trazodone and of a tricyclic antidepressant, i.e. imipramine in the rat. The experiments were conducted on anaesthetized Long Evans rats, the drugs being administered by i.v. infusion until cardiac arrest occurred; ECG (lead II) and blood pressure (BP) were recorded at the same time. The primary effect of trazodone was its hypotensive action. ECG changes, consisting of a lengthening of the PR interval, were observed only when there was a marked drop in BP. The primary effect of imipramine, instead, consisted of disturbances in cardiac conduction. It is concluded that trazodone and imipramine produce different cardiovascular effects.     

Regulation of rat cortical 5-hydroxytryptamine2A receptor-mediated electrophysiological responses by repeated daily treatment with electroconvulsive shock or imipramine.

Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT(2A) receptor binding sites. However, the effects of antidepressants on 5-HT(2A) receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT(2A) receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT(2A) receptors were consistent with 5-HT(2A) receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT(2A) receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex.     

The relationship between antidepressant response and tricyclic antidepressant plasma concentrations. A retrospective analysis of the literature using logistic regression analysis

The relationship between the antidepressant effect of the tricyclic antidepressants and their plasma concentrations was reviewed. Logistic regression was utilised as an analytical tool to facilitate the evaluation. The currently available literature allowed the construction of 4 tricyclic data sets of sufficient size to warrant statistical analysis. Inspection of the distribution of the data and the logistic regression analyses resulted in several conclusions regarding the existence of 'therapeutic windows' for these drugs. Firstly, no relationship between amitriptyline plasma concentrations and therapeutic response was apparent. Secondly, curvilinear relationships were apparent for 2 of the other tricyclic antidepressants studied. The currently recommended therapeutic range of 60 to 150 micrograms/L for nortriptyline was found to be the range most likely to produce a positive antidepressant effect. Desipramine concentrations between 108 and 158 micrograms/L were most commonly associated with beneficial therapeutic responses. Finally, a linear relationship was noted for imipramine in which an imipramine therapeutic plasma concentration threshold of 244 micrograms/L and above was most commonly associated with a beneficial response to the drug.