Effects of selective serotonin reuptake inhibitors on platelet serotonin parameters in major depressive disorder.

The effects of treatment with serotonin (5-HT) reuptake inhibitors on platelet 5-HT2 receptors, 5-HT reuptake sites an 5-HT uptake were studied in a double-blind trial comparing two selective serotonin reuptake inhibitors (SSRI), paroxetine, and fluoxetine, for the treatment of major depression. Hamilton Depression Rating Scale (HAM-D) scores and platelet 5-HT parameters were determined in 21 depressed patients at baseline, after 4 and 8 weeks of treatment, and were compared to 21 healthy controls. Antidepressant treatment did not significantly alter the density of 5-HT reuptake sites, labelled with [3H]paroxetine, or 5-HT2 receptors, labelled with [3H]LSD. However, a strong correlation was observed between the HAM-D suicidality item and 5-HT2 receptor density at baseline. A marked increase in platelet 5-HT2 receptors at baseline was observed in suicidal depressed patients compared to those with no suicidal ideation and healthy controls. Changes in [3H]paroxetine Bmax and in [3H]5-HT uptake significantly correlated with change in HAM-D score at 4 and 8 weeks respectively. These results confirm previous reports of an association between suicidality and platelet 5-HT2 receptor upregulation. Our data also lends support to the use of platelet 5-HT parameters as indicators of antidepressant efficacy, particularly in suicidal depressed patients.

Frequency of long allele in serotonin transporter gene is increased in depressed suicide victims.

BACKGROUND: There is evidence indicating that serotonin uptake and density of 5-HT2A receptors are altered in brain regions of depressed suicide victims and in platelets of depressed suicidal subjects. The present investigation tested the hypothesis that these changes in the serotonergic system in depressed suicide victims are trait rather than state markers and associated with a polymorphism in respective candidate genes. METHODS: Two polymorphic variants (102T/C polymorphism and His452Tyr functional polymorphism) of the 5-HT2A receptor gene and a functional polymorphism in the 5' regulatory region of the 5-HT transporter gene, have been determined in genomic DNA obtained from postmortem brain samples of 24 depressed suicide victims and 31 control subjects of the same ethnic background. In a subset of subjects, density (Bmax) of 5-HT uptake sites (labeled with 3H-paroxetine) and of 5-HT2A receptors (labeled with 3H-ketanserin) was also determined in prefrontal cortex samples. RESULTS: The major finding of this study was a significantly higher frequency of the 5-HT transporter gene long (L) allele (chi 2 = 3.9, df = 1; p = .048) in depressed suicides. No significant differences between suicides and controls were observed for the 102T/C polymorphism and His452Tyr polymorphism of 5-HT2A receptor gene. The density of 3H-paroxetine binding sites tended to be higher in subjects expressing the short (S) allele of 5-HT transporter gene. Furthermore, there was a significant difference in serotonin transporter binding sites between the genotype S/S and combined genotypes S/L and L/L. CONCLUSIONS: Our finding provides the first evidence suggesting that a functional polymorphism in the regulatory region of serotonin transporter gene may be associated with suicide in depressed subjects.

Synthesis and characterization of an aryl-azidoparoxetine. A novel photo-affinity probe for serotonin-transporter.

Paroxetine is an effective antidepressant drug and potent serotonin (5-HT) uptake inhibitor. It selectively labels 5-HT transporter on platelets and neurons. We report here the synthesis of an aryl-azido derivative of paroxetine, which is a novel photoactive and irreversible ligand for the [3H]paroxetine binding site on the platelet 5-HT transporter. The compound inhibited [3H]paroxetine binding (IC50, 55 nM) and 5-HT uptake (IC50, 12 nM) at equilibrium conditions and inactivated 10-20% of [3H]paroxetine binding sites upon irradiation at 320 nm. SDS-PAGE of platelet protein extract labelled with the radioactive analogue of the synthesized probe revealed the presence of four radioactive bands of which the 71-kDa one was the most prominent.

Association of polymorphism of serotonin 2A receptor gene with suicidal ideation in major depressive disorder.

There is evidence indicating that density of 5-HT2A receptors is altered in brain regions of depressed suicide victims and in platelets of suicidal subjects with major depression or schizophrenia. Recent studies have also shown an association between the allele C of 102T/C polymorphism in the 5-HT2A receptor gene and schizophrenia. The present investigation tested the hypothesis that the observed changes in 5-HT2A receptor density in platelets of patients with major depression are a trait rather than state phenomenon and are associated with the 102 C allele in 5-HT2A receptor gene in a sample of 120 patients with major depression and a group of 131 control subjects comparable with respect to age, sex, and ethnic background. The allele and genotype frequencies of 102T/C polymorphism in 5-HT2A receptor gene were compared between patients and control subjects and between suicidal and non-suicidal patient groups. The major finding of this study was a significant association between the 102 C allele in 5-HT2A receptor gene and major depression, chi(2) = 4.5, df = 1, P = 0.03, particularly in patients with suicidal ideation, chi(2) = 8.5, df = 1, P < 0.005. Furthermore, we found that patients with a 102 C/C genotype had a significantly higher mean HAMD item 3 score (indication of suicidal ideation) than T/C or T/T genotype patients. Our results suggest that the 102T/C polymorphism in 5-HT2A receptor gene is primarily associated with suicidal ideation in patients with major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:56-60, 2000.

New standard of depression treatment: remission and full recovery.

Major depressive disorder (MDD) is a chronic disorder that substantially impairs a patient's psychosocial and occupational functioning. Lifetime prevalence rates for MDD vary widely, ranging from 4.4% to approximately 20%, and it is predicted to become the second leading cause of disability by the year 2020. The magnitude of this public health problem, with its associated decreased quality of life, increased risk of suicide, loss of productivity, and increased health care use, underscores the importance of treating depressed patients to full remission. The presence of residual depressive symptoms due to partial or incomplete remission is associated with significant morbidity and mortality. Hence, complete remission should be the goal in the treatment of patients with MDD because it leads to a symptom-free state and a return to premorbid levels of functioning. Full remission and improved long-term prognosis can be achieved with long-term antidepressant therapy with newer agents that work through multireceptor mechanisms, especially through the serotonergic and noradrenergic systems (i.e., dual action). Robust efficacy and greater remission rates have been associated with dual-action agents.

The patient with comorbid depression and anxiety: the unmet need.

Major depression and anxiety occur concomitantly in general practice, occur in more patients than either depression or anxiety alone, and are associated with significant morbidity. When depression and anxiety occur together, they are associated with more severe symptoms, increased impairment, a more chronic course and poorer outcome, and a higher incidence of suicide. As many as 80% of patients with generalized anxiety disorder (GAD) have symptoms of depression. Patients with depression and comorbid anxiety present special treatment challenges with selection of drugs that have demonstrated efficacy for both depression and anxiety. A range of effective pharmacotherapeutic strategies are available, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, the 5-HT2 blocker nefazodone, and the serotonin-norepinephrine reuptake inhibitor venlafaxine. Venlafaxine has been extensively evaluated for the treatment of depression and symptoms of anxiety in post hoc analyses. The efficacy of venlafaxine extended release (XR) has been demonstrated in patients with depression and concomitant anxiety. Further, venlafaxine XR is the first antidepressant that has demonstrated significant pure anxiolytic effects in prospective clinical trials of patients with GAD. The spectrum of pure depression, comorbid depression and anxiety disorders, and pure anxiety presents a treatment challenge. Venlafaxine offers a unique pharmacologic approach for the entire spectrum of these disorders.

Combined SSRI-moclobemide treatment of psychiatric illness.

BACKGROUND: To determine the efficacy and safety of a serotonin selective reuptake inhibitor (SSRI) combined with moclobemide in the treatment of 11 patients with various DSM-III-R diagnoses. METHOD: Subjects received moclobemide in doses of 150 to 800 mg/day together with sertraline (N = 5) in doses of 25 to 200 mg/day or fluvoxamine (N = 6) in doses of 50 to 200 mg/day. Patients were carefully monitored for side effects and for clinical response at the end of the trial, which lasted a minimum of 5 weeks. RESULTS: The combination was tolerated extremely well. Insomnia was the most common side effect, occurring in 5 of 11 subjects. A marked or complete therapeutic response was noted in 8 of 11 subjects. CONCLUSION: This open clinical trial suggests that combined SSRI-moclobemide treatment appears to be safe and well tolerated. It may also have therapeutic effects in treatment-refractory patients.

A comparison of moclobemide, amitriptyline and placebo in depression: a Canadian multicentre study.

In a 7-week prospective multicentre study, the efficacy, tolerability and safety of moclobemide were compared to those of amitriptyline and placebo in parallel groups of out-patients (n = 173) fulfilling the DSM III-R criteria for a major depressive episode. Participants were required to have a minimum baseline total score of 18 on the 17-item Hamilton Depression Rating Scale (HAMD). After a 1-week placebo washout, patients were randomly allocated to the three treatment groups. Assessment of efficacy, as judged by the number of responders achieving a 50% reduction in HAMD score by the end of treatment, showed that both moclobemide and amitriptyline were significantly superior to placebo, but that they were not significantly different from each other. Both treatments differed significantly from placebo with respect to the Physician's Global Assessment of Efficacy ('very good' or 'good' response: moclobemide 57%, amitriptyline 60% and placebo 35%). Assessment of tolerance as judged by the spontaneous reporting of adverse events showed a significant superiority of moclobemide over amitriptyline, but there was no significant difference between moclobemide and placebo. At termination of the study, amitriptyline patients showed a significant elevation of heart rate both supine (10.8 beats/min) and standing (15.5 beats/min), as well as significant weight gain (1.7 kg), but no changes were seen in the moclobemide or placebo groups. In conclusion, both moclobemide and amitriptyline were found to be more effective than placebo in the treatment of depression, while moclobemide had fewer side effects.

Gender differences in association between serotonin transporter gene polymorphism and personality traits.

Since Lesch and colleagues reported an association between anxiety-related traits (Neuroticism) and a functional polymorphism in the serotonin transporter gene regulatory region (5-HTTLPR), there have been several reports on 5-HTTLPR and personality traits with both positive and negative results. The present study was a further attempt to replicate the original findings of Lesch et al. in a population of well-defined normal healthy subjects. In addition, a variable number tandem repeat polymorphism in the second intron was included in this study because it has recently been shown to act as a transcriptional regulator. Personality traits were evaluated in 186 unrelated normal subjects by the NEO Five Factor Inventory. The most important and novel finding of this study was a significant association of mean Neuroticism scores with the short allele of 5-HTTLPR in male subjects (t = 2.4, P = 0.018). We were thus able to replicate the finding of Lesch et al. of an association between serotonin transporter gene polymorphism (5-HTTLPR) and Neuroticism, but only in a male population. We also found a significant effect of gender on mean scores of Neuroticism [F = 3.9, degrees of freedom (df) = 1, 180, P = 0.05] and Agreeableness (F = 6.8, df = 1, 180, P = 0.01), but no significant effect of 5-HTTLPR genotype on Neuroticism (F = 0.87, df= 2, 180, P = 0.42) or Agreeableness (F = 0.35, df = 2, 180, P = 0.7). These findings suggest that gender differences exist in contribution of genetic factors to behavioural phenotypes. They may also explain the inconsistencies in previous reports on association of Neuroticism with 5-HTTLPR from studies using different proportions of male and female subjects.

Mixed Anxiety and Depression : Diagnosis and Treatment Options.

Symptoms of anxiety and depression often appear together in patients, either as 2 discrete disorders, such as major depressive disorder and panic disorder, or as a combination of symptoms not meeting criteria for specific disorders. The social, economic, occupational and medical costs of such comorbid anxiety and depression can be enormous, affecting both the individual and society.The clinician must be creative when treating patients with mixed anxiety and depressive symptoms; psychopharmacological treatment can involve the use of a variety of mono- and polytherapies. Benzodiazepines can be effective in treating anxiety symptoms, but unwanted adverse effects limit their use to the short term. Tricyclic antidepressants, although proven to be effective in treating both anxiety and depressive symptoms, have numerous adverse effects, making them a second-choice therapy. Traditional monoamine oxidase inhibitors have proven efficacy in atypical depression, and the newer reversible and selective inhibitors of monoamine oxidase-A may prove to be very effective in treating both sets of symptoms. Of particular importance in the treatment of patients with anxiety and depressive symptoms are the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors, nefazodone and the azapirones (including buspirone).

Platelet 3H imipramine binding: a possible predictor of response to antidepressant treatment.

No significant difference in the density (Bmax) of platelet 3H imipramine recognition sites were found between the group of 20 unmedicated depressed patients and 10 healthy volunteers. The mean KD value was significantly higher in the population of depressives than in controls. Non-responders (after 2 weeks of treatment with antidepressants) had significantly lower initial Bmax values than responders or control subjects. Density of platelet 3H imipramine site may thus be a predictor of early response to antidepressant therapy. No significant sex differences were found in KD or Bmax values in the depressed group or in control subjects. There was, however, a seasonal variation in Bmax but not in KD values of platelet 3H imipramine binding.

Preparatory brain potentials in major depressive disorder.

1. Psychomotor slowing in depression is frequently reflected by delayed reaction times (RT). 2. The role of central arousal mechanisms in response slowing was examined by comparing scalp-recorded slow negative potentials of depressed patients with normal controls in two separate studies. 3. Varying fore-warned RT conditions elicited contingent negative variation (CNV) waveforms and the resultant mid-point amplitudes of these waveforms together with orienting (O-wave), expectancy (E-wave) and post-imperative negative variation (PINV) component amplitudes and sensory evoked responses (N1, P2) were compared between groups. 4. RTs were significantly slowed in depressed patients and the patient group exhibited consistently larger PINV amplitudes. Depending on the RT condition, patients also exhibited larger mid-point CNV amplitudes and smaller N1 and P2 amplitudes.

Tryptophan hydroxylase gene 218A/C polymorphism is associated with somatic anxiety in major depressive disorder.

BACKGROUND: Abnormalities in functioning of the central serotonergic system have been implicated in the pathogenesis of depressive illness and suicidal behavior. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the biosynthesis of serotonin, therefore, it may play an important role in regulation or control of serotonin functions. The aim of the present investigation was to determine whether there is an association between TPH gene polymorphism and major depression. particularly in patients with suicidal ideation. METHODS: A total of 135 unrelated patients suffering from major depressive disorder and 196 normal unrelated controls were included in the study. All controls and patients were Caucasian. A biallelic polymorphism at the tryptophan hydroxylase locus was genotyped. RESULTS: No significant difference between controls and depressed subjects in TPH gene polymorphism was detected. There was no association between TPH gene polymorphism and suicidal ideation. Total HAMD scores were not different between the genotypes or alleles in patients. However, among the HAMD clusters, somatic anxiety was significantly associated with TPH genotypes and alleles in that patients with 218A/A genotype had a significantly higher somatic anxiety scores compared to other genotypes. LIMITATION: Potential confounding effect of population stratification can not be excluded. The functional relevance of the TPH gene 218A/C polymorphism is, at present, uncertain. CONCLUSION: The polymorphism in serotonergic system related genes may be associated with depressive symptoms in major depressive disorder. The results suggest that analysis of clusters that narrow down the phenotype may be more suitable in genetic studies of major depressive illness.

Event-related potentials and selective attention in major depressive illness.

Depressive episodes have been frequently characterized by deficits in information processing efficiency which are particularly evident when required to sustain or focus attention. As cerebral event-related potentials (ERPs) have been shown to reflect various aspects of selective attention and attentional dysfunction, this study attempted to examine ERPs in depressed patients performing a selective auditory attention task. Twenty-nine patients with a diagnosis of major depressive disorder (DSM-III) and 15 normal, non-psychiatric controls served as experimental subjects. Auditory potentials were recorded from the vertex of subjects who listened selectively to a series of tone pips in one ear and ignored concurrent tone pips to the other ear. Tone pips were delivered at short (320-500 ms) interstimulus intervals and subjects were required to detect, within the attended ear, rare 'target' tones of a different pitch than the more frequent 'standard' tones. In addition to behavioral indices of 'hits' and 'false alarms', ERP-derived measures included N1 amplitudes to attended and ignored stimuli, 'coefficients of attention' as calculated from N1 amplitude ratios and the latency onset and amplitude of the 'negative difference' (Nd) wave resulting from the subtraction of attended and ignored waveforms. Behavioral measures indicated that depressed patients were as efficient as controls in task performance and in fact they exhibited a significant left ear advantage in the additional task. Although a significant 'N1 effect' was observed with attended tones eliciting larger amplitudes than unattended tones, ERP measures of selective attention did not tend to differentiate the two groups.

A Canadian multicentre placebo-controlled study of a fixed dose of brofaromine, a reversible selective MAO-A inhibitor, in the treatment of major depression.

In a 6-week double-blind study, 220 patients with major depression (mostly outpatients) were randomly assigned to receive a fixed dose of brofaromine 150 mg daily (n = 111) or placebo (n = 109) after a 1-week single-blind placebo washout. Except for the HAM-D sleep items, brofaromine was superior to placebo on measures of depression as determined by the four methods of assessing drug efficacy: (1) psychiatric symptom rating (HAM-D 17-item less the three sleep items); (2) self-rating scale (Beck Depression Inventory); (3) Clinical Global Assessment of Efficacy; and (4) drop-out rate due to lack of efficacy. Most commonly reported adverse events with brofaromine were: headache, nausea, dizziness and sleep disturbance. Brofaromine was found to be an effective antidepressant, superior to placebo with a good tolerability profile.

A Canadian multicenter, double-blind study of paroxetine and fluoxetine in major depressive disorder.

BACKGROUND: Recent studies have suggested clinical differences among selective serotonin reuptake inhibitors. In a 12-week randomized, multicenter, double-blind trial, the antidepressant and anxiolytic efficacy of the selective serotonin reuptake inhibitors paroxetine and fluoxetine was compared in patients with moderate to severe depression. METHODS: A total of 203 patients were randomized to fixed doses (20 mg/day) of paroxetine or fluoxetine for the first six weeks of therapy. From week 7-12, dosing could be adjusted biweekly, as required (paroxetine 20-50 mg/day, and fluoxetine 20-80 mg/day). The mean prescribed doses were paroxetine 25.5 mg/day (range 20.0-40.2 mg/day), and fluoxetine 27.5 mg/day (range 20.0-59.5 mg/day). Emergence of motor nervousness or restlessness was assessed using the ESRS scale for akathisia. RESULTS: Both active treatments demonstrated comparable antidepressant efficacy (HAM-D, CGI). Anxiolytic activity of the two drugs (COVI, STAI, HAM-D) was also comparable. However, paroxetine was found to be superior to fluoxetine on two subscore measures at week 1 of therapy (HAM-D Agitation item, p < 0.05; Psychic Anxiety item, p < 0.05), with no differences detected after week 2. The overall incidence of adverse effects was comparable in the two treatment groups. Constipation, dyspepsia, tremor, sweating and abnormal ejaculation were more common in paroxetine-treated subjects, whereas nausea and nervousness were more frequent in fluoxetine-treated patients. Weight loss was more common in the fluoxetine versus paroxetine group (11.88% versus 2.94%, respectively). ESRS scores for akathisia were low throughout the study and showed little change. LIMITATIONS: Differences observed between the two drugs in antianxiety effects were limited to two measures of anxiety among several others. DISCUSSION: The data indicate that paroxetine and fluoxetine have comparable antidepressant and anxiolytic efficacy. Paroxetine appears to produce an earlier improvement in agitation and psychic anxiety symptoms compared with fluoxetine.

Reversible monoamine oxidase-A inhibitors in panic disorder.

Monoamine oxidase (MAO) inhibitors are known to be effective in panic disorder, but a high incidence of adverse reactions have limited their use. The new, selective, and reversible MAO-A inhibitors exemplified by brofaromine and moclobemide do not require dietary restrictions, have fewer drug interactions, and are better tolerated. This paper reports a randomized, double-blind, 8-week trial in which the efficacy and safety of brofaromine was compared to clomipramine in patients with panic disorder with or without agoraphobia. Both treatments achieved a significant and comparable reduction in the number of panic attacks, and were equally effective in all the parameters measured. Side effects were typical of the drug class. Further trials are required to evaluate this promising new treatment.

Brofaromine in depression: a Canadian multicenter placebo trial and a review of standard drug comparative studies.

Brofaromine is a new, reversible, and selective type-A monoamine oxidase inhibitor (MAOI) that also has serotonin reuptake inhibitory properties. Its dual pharmacologic effects offer promise in the treatment of a wide spectrum of depressed patients while producing less severe anticholinergic side effects in comparison with standard drugs. A multicenter, double-blind, placebo-controlled study including 220 patients was undertaken to evaluate the efficacy and safety of brofaromine in major depression. This study of a fixed-dose design and 6 weeks' duration found that brofaromine was significantly better than placebo on the Overall Evaluation of Efficacy, Beck self-rating scale, HAM-D Bech subscale, HAM-D total 14 items (minus the three sleep items), HAM-D depressed mood item and retardation factor, and worse than placebo on the insomnia items of HAM-D. Significantly more patients on placebo than on brofaromine did not complete the trial due to lack of efficacy. In comparative controlled studies (n = 899), brofaromine was found to be at least as efficacious as tricyclic antidepressants (imipramine) and standard MAOIs (tranylcypromine and phenelzine). Reductions of at least 50% in the HAM-D total score were seen in 58-66% of patients treated with either brofaromine or imipramine (n = 609). Brofaromine also was found to be of comparable efficacy to tranylcypromine in two clinical trials (n = 132), one of which included patients considered to have a treatment-resistant depression (n = 39). In another double-blind study that compared brofaromine (150 mg/day) to phenelzine (45 mg/day) (n = 158), there was no difference between brofaromine and phenelzine.

Modelling the cost effectiveness of antidepressant treatment in primary care.

The aim of this study was to estimate the cost effectiveness of nefazodone compared with imipramine or fluoxetine in treating women with major depressive disorder. Clinical decision analysis and a Markov state-transition model were used to estimate the lifetime health outcomes and medical costs of 3 antidepressant treatments. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine. The economic analysis was based on the healthcare system of the Canadian province of Ontario, and considered only direct medical costs. Health outcomes were expressed as quality-adjusted life years (QALYs) and costs were in 1993 Canadian dollars ($Can; $Can1 = $US0.75, September 1995). Incremental cost-utility ratios were calculated comparing the relative lifetime discounted medical costs and QALYs associated with nefazodone with those of imipramine or fluoxetine. Data for constructing the model and estimating necessary parameters were derived from the medical literature, clinical trial data, and physician judgement. Data included information on: Ontario primary care physicians' clinical management of major depression; medical resource use and costs; probabilities of recurrence of depression; suicide rates; compliance rates; and health utilities. Estimates of utilities for depression-related hypothetical health states were obtained from patients with major depression (n = 70). Medical costs and QALYs were discounted to present value using a 5% rate. Sensitivity analyses tested the assumptions of the model by varying the discount rate, depression recurrence rates, compliance rates, and the duration of the model. The base case analysis found that nefazodone treatment costs $Can1447 less per patient than imipramine treatment (discounted lifetime medical costs were $Can50,664 vs $Can52,111) and increases the number of QALYs by 0.72 (13.90 vs 13.18). Nefazodone treatment costs $Can14 less than fluoxetine treatment (estimated discounted lifetime medical costs were $Can50,664 vs $Can50,678) and produces slightly more QALYs (13.90 vs 13.79). In the sensitivity analyses, the cost-effectiveness ratios comparing nefazodone with imipramine ranged from cost saving to $Can17,326 per QALY gained. The cost-effectiveness ratios comparing nefazodone with fluoxetine ranged from cost saving to $Can7327 per QALY gained. The model was most sensitive to assumptions about treatment compliance rates and recurrence rates. The findings suggest that nefazodone may be a cost-effective treatment for major depression compared with imipramine or fluoxetine. The basic findings and conclusions do not change even after modifying model parameters within reasonable ranges.

Antidepressant plasma levels and clinical response in depressed patients treated with oxaprotiline and doxepin.

Relationship between plasma levels of a new tetracyclic antidepressant oxaprotiline and a tricyclic antidepressant doxepin, the clinical response and side-effects was studied in 30 patients with primary endogenous depression. Patients were treated following a placebo wash-out period with gradually increasing doses (75, 150, 225 mg/day) of either drug for 4 weeks. The clinical outcome (percentage of responders and of decrease in HAMD scores) was similar in groups of patients treated with the two drugs. No significant relationship was found between the plasma levels of the parent drugs (oxaprotiline or doxepin) and a measure of clinical response (HAMD scores). However, in patients treated with doxepin, there was a significant relationship between the therapeutic response and plasma levels of the drug's metabolite, desmethyldoxepin. In addition, side-effects were more frequently observed in patients with higher plasma levels of both drugs. Incidences of anticholinergic side-effects was significantly higher in patients treated with doxepin.