Prediction of response to nortriptyline and phenelzine by platelet MAO activity

Thirty-seven depressed patients over the age of 55 were treated for 5-7 weeks with either nortriptyline, a tricyclic antidepressant, or phenelzine, a monoamine oxidase (MAO) inhibitor. Patients' platelet MAO activity was measured following a drug washout period before treatment. Patients with higher MAO activity had a better response to treatment, regardless of which drug was used.     

Platelet MAO deamination of serotonin in depressed patients. Changes after imipramine treatment and clinical correlations

Monoamine oxidase (MAO) in blood platelets has been used as a model to study MAO in the central nervous system, where disorders in serotonergic systems are thought to occur in depression. Inconsistent changes in platelet MAO of depressed patients have been reported when several substrates other than serotonin (5-HT) have been used. To correlate changes in platelet MAO activity with the enzyme activity in central serotonergic systems, the platelet MAO activity of depressed patients (first unmedicated and then after 3 weeks and 2 months of imipramine treatment) and normal controls was measured using 5-HT as substrate. The results showed that there is a steady, measurable platelet MAO activity with that substrate. This activity was significantly higher in unmedicated depressed patients than in controls, and it decreased progressively with imipramine treatment, reaching a normal level when the patients were clinically recovered from depression after 2 months of therapy.     

Effect of neuroleptic drugs on platelet monoamine oxidase in psychiatric patients

The authors determined the platelet MAO activity of 57 psychotic patients after a placebo period and after 3-65 days of neuroleptic treatment. Platelet MAO activity significantly decreased in both men and women after neuroleptic treatment. The platelet MAO activity of neuroleptic-treated schizophrenic women was significantly less than that of drug-free schizophrenic women, who did not differ from normal women. There were trends in the same direction for the schizophrenic men. Previous studies that reported lower platelet MAO activity in neuroleptic-treated schizophrenic patients than in normal controls may have been influenced by this neuroleptic effect.     

MAO inhibition and control of anxiety following amitriptyline therapy

In a pilot study, 32 patients with mixed states of anxiety, depression, somatization and panic received amitriptyline for 4 weeks, the dose ranging from 50 to 300 mg/day. Steady-state plasma levels of the drug and activity of platelet monoamine oxidase were measured after 4 weeks. Clinical change was rated, using the SCL-90. Amitriptyline produced a small but significant inhibition of platelet monoamine oxidase activity (range 1.4–82%). A significant positive correlation was noted between MAO inhibition and improvement on somatization, and psychological and panic-phobic components of anxiety, but not for depression. No significant correlations were observed between improvement and combined or separate ami- + nortriptyline plasma levels.     

Response of psychotic and nonpsychotic depression to phenelzine

The authors studied 52 depressed inpatients to examine treatment response to phenelzine, a monoamine oxidase (MAO) inhibitor. All patients were classified into one of three RDC categories (definitely psychotic, probably psychotic, and nonpsychotic). For the entire sample, the mean platelet MAO inhibition level achieved with phenelzine was greater than 80%. Response to treatment was determined by independent clinical assessment and by the change in rating scores from baseline; 68% of the nonpsychotic, 43% of the probably psychotic, and 21% of the definitely psychotic patients were classified as responders. This differential response rate is similar to that reported in the literature for tricyclic antidepressants.     

Platelet and fibroblast monoamine oxidase in alcoholism

Monoamine oxidase (MAO) activity has been reported to be low in platelets (MAO B) and brain (MAO A and B) of some patients with alcoholism compared to control subjects. Whether the decreased platelet MAO activity found in alcoholism is secondary to the effect of alcohol or exists before alcohol abuse is not clear. The hypothesis that altered MAO A activity is determined by an abnormality in the genetic regulation of the enzyme can be tested by measuring MAO A activity in human fibroblasts cultured under controlled conditions. We first studied the kinetic parameters of platelet MAO B activity in patients hospitalized for treatment of alcoholism. Vmax was 38% lower in the patients (n = 14) than in normal controls (n = 22), but the enzyme affinity (Km) for the substrate tyramine was unchanged. Patients with the five lowest levels of platelet MAO activity had MAO activity measured from fibroblasts cultured from skin punch biopsies. Their fibroblast MAO activity was within the normal range, showing a dissociation between platelet MAO B and fibroblast MAO A activities and suggesting that MAO A activity is not low for genetic reasons in alcoholic subjects who do have low platelet MAO B activity.     

Mania induced by tricyclic-MAOI combination therapy in bipolar treatment-resistant disorder: case reports

Three patients with bipolar disorder developed manic symptoms while receiving a combination of isocarboxazid and amitriptyline during an episode of major depression refractory to previous treatments. It is suggested that mania be considered a possible complication of combined treatment with an MAO inhibitor and a tricyclic antidepressant.     

Long-term sertraline treatment and peripheral biochemical markers in female depressed patients

Serotonergic system is implicated in the pathogenesis of depression. Peripheral biochemical markers, platelet serotonin (5-HT) and platelet monoamine oxidase (MAO) activity were determined spectrofluorimetrically at baseline and after 4 and 24 weeks of sertraline (a selective serotonin reuptake inhibitor (SSRI)) treatment in 15 female nonsuicidal, nonpsychotic patients with major depression and compared with 15 drug-free healthy women. The aim of the study was to determine the effects of 4 and 24 weeks of sertraline treatment on platelet 5-HT concentration and platelet MAO activity in depressed patients subdivided according to the treatment response into remitters, responders and nonresponders after 4 and 24 weeks of sertraline treatment based on the 70%, 50-69% and <49% reductions in baseline Montgomery-Asperg Depression Rating Scale (MADRS) scores, respectively. Platelet 5-HT concentration was significantly lower in all depressed patients at baseline than in healthy subjects. Among patients, platelet 5-HT concentration or platelet MAO activity did not differ before treatment. There was no significant correlation between MADRS scores and peripheral biochemical markers. The limitation of the study was in a small number of patients, but its advantage was in a long-term (24 weeks) follow-up of both patients and healthy controls. Our results show that long-term sertraline treatment induced remission and response in 87% patients, decreased platelet 5-HT concentration after 4 and 24 weeks of treatment and decreased platelet MAO activity after 24 weeks and suggest that pretreatment values of platelet 5-HT and platelet MAO might not predict therapeutic outcome to sertraline treatment in female depressed patients.     

A probable neuroleptic effect on platelet monoamine oxidase in chronic schizophrenic patients

Platelet monoamine oxidase activity (MAO) was studied serially over time in 16 chronic schizophrenic patients when medication free and then when medicated. Thirteen of the 16 patients had significant decreases in platelet MAO activity following neuroleptic drug treatment. The change in MAO activity was found to be correlated with response to treatment and to dose of medication.     

Reduction of blood platelet monoamine oxidase activity in schizophrenic patients on phenothiazines.

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets (serotonin used as substrate) was applied for the measurement of the enzyme activity in 76 schizophrenic patients. No significant reduction was found in the blood platelet MAO activity in a group of 33 untreated schizophrenic patients, as compared to that in the normal controls. Male patients revealed to have lower enzyme activity than females in the schizophrenic group, as we described previously in the normal subjects. Treatment with phenothiazines caused significant reduction of blood platelet MAO activity, while platelet serotonin content and platelet count appeared to be not affected by the drug treatment. The authors suggest that blood platelet MAO activity may be related to hormonal factors but not to psychiatric diagnosis of schizophrenia or constitution liable to schizophrenic illnesses.     

Platelet monoamine oxidase and sex hormones in a population of depressed patients

The association between changes in platelet MAO activity and Major Depressive Episode have been demonstrated. Cyclical changes in sex hormones serum levels had never been related with changes of MAO activity in depressed patients. Platelet MAO activity, oestrogen serum levels, progesterone serum levels and testosterone serum levels, have been measured in drug free depressed patients: 22 men and 42 women. This study demonstrates no relationship between serum levels hormons and platelet MAO activity, measured in men and in women. If young women are separated from menopaused women, platelet MAO activity is negatively correlated with oestrogen serum levels, in non menopaused women. Significance of this variation in studies about the use of MAO as a biochemical marker in depression is discussed.     

Platelet MAO activity during treatment with pegylated interferon-alfa in melanoma patients

Depression and cognitive disturbance are well-known neuropsychiatric side effects of therapy with interferon-alfa (IFN-alfa). Aggression and irritability are also reported as side effects. Probably, central nervous system (CNS) serotonergic dysfunction is one of the underlying pathophysiological mechanisms of IFN-alfa-induced neuropsychiatric toxicity. Platelet activity of monoamine oxidase-B (MAO; EC1.4.3.4) is a possible indicator of central serotonergic function. Moreover, low platelet MAO activity is linked to impulsiveness, addiction and personality disorder. In this exploratory study in 17 high-risk melanoma patients, platelet counts, whole blood MAO, and platelet MAO activity were measured before and during therapy with IFN-alfa. Patients were randomized to treatment either with pegylated IFN-alfa (PEG-IFN-alfa) once a week at a dose of 6 microg/kg/week subcuteanously (s.c.) during 8 weeks, followed by a maintenance treatment of 3 microg/kg/week s.c. for a total of 5 years, or to observation only. Blood samples were taken at baseline, 4 and 8 weeks and 3 months. During treatment with IFN-alfa, platelet counts decreased at 4 and 8 weeks and 3 months, while platelet MAO activity increased, both compared to baseline and compared to non-treated controls. Compared to non-treated controls, platelet MAO activity increased with 86.4% (95 CI: 52.9-127.2). No significant changes in platelet MAO activity were observed in the control group. This indicates that platelet MAO activity is influenced by IFN-alfa. Since platelet MAO activity is a model for CNS MAO-B activity, it may be speculated that CNS MAO-B activity will also be increased. This could influence serotonin (5-HT) metabolism and thereby contribute to the development of psychiatric disturbance. However, a preferential inhibition of platelet production cannot be ruled out. Hypothetically, the antiproliferative effects of IFN-alfa could interfere more strongly with the synthesis of platelets than with the synthesis of mitochondria. In that case, increased platelet MAO activity reflects an increased number of mitochondria per platelet.     

Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder

Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 +/- 33 mg/d) (mean +/- SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.     

Platelet monoamine oxidase activity in obsessive-compulsive disorder

Response to SSRIs suggests the implication of the serotonergic system in obsessive-compulsive disorder (OCD). However, biological studies on serotonergic function in OCD have yielded contradictory results. Platelet monoamine oxidase (MAO) activity has been proposed as an index of cerebral serotonin activity. The aim of this study was to examine platelet MAO activity in 29 OCD patients and 29 healthy controls matched by age, sex and tobacco use. We also explored the relationship between platelet MAO activity and aggressive obsessions in OCD patients. There were no differences in platelet MAO activity between OCD patients and healthy controls. We found a significant correlation between platelet MAO activity and Y-BOCS scores in the group of patients with Y-BOCS scores >15. OCD patients with aggressive obsessions had significantly lower levels of platelet MAO activity than patients without aggressive obsessions. Our results suggest that platelet MAO activity may be a marker of OCD severity, and that low platelet MAO activity may be associated with aggressive obsessions in OCD patients.     

Measurement of basal plasma levels of 3 anterior pituitary hormones during acute or chronic treatment with tricyclic antidepressants

Prolactin, growth hormone and thyrotropin plasma levels have been evaluated in depressive in-patients, either during the first day of clomipramine or amitriptyline treatment, or after their chronic administration. Prolactin levels temporary rise during the first day of clomipramine or amitriptyline treatment in 6 patients out of 11, with a lag in relation to the drug plasma peak. A significant increase is observed after a 28 days treatment with clomipramine and a non significant decrease, after a 28 days treatment with amitriptyline. As for human growth hormone, a rise is found in 5 out of 8 clomipramine treated subjects but neither any variation with amitriptyline nor any significant variation with chronic administration of both drugs occur. Finally, thyrotropin plasma levels display no variation after acute or prolonged treatment with clomipramine or amitriptyline. These results are compared with those of literature, then discussed in the light of present theories on pituitary hormones secretion aminergic control and of tricyclic antidepressants effect on these hormones.     

Platelet MAO activity in anorexia nervosa patients with and without a major depressive disorder

Platelet MAO activity was determined in 33 anorexia nervosa patients. A subgroup of 15 patients who met Research Diagnostic Criteria for a concomitant major depressive disorder were found to have, both initially and after 5 weeks of treatment, significantly lower mean platelet monoamine oxidase (MAO) activity than 28 matched normal control subjects. In contrast, mean platelet MAO activity in the patients who did not meet criteria for major depressive disorder was similar to values in control subjects. The authors found that significantly more depressed patients had low MAO activity compared with nondepressed patients and controls. Platelet MAO activity may be useful in discriminating among subtypes of anorexia nervosa patients.     

A DOUBLE-BLIND TRIAL OF MAPROTILINE (LUDIOMIL®) AND AMITRIPTYLINE IN DEPRESSED OUTPATIENTS

The results of a double-blind trial of a tetracyclic antidepressant, maprotiline (Ludiomil®) and a conventional tricyclic, amitriptyline (Elavil®), in 67 ambulatory depressives are reported. hamilton's Rating Scale for Depression was the main outcome criterion. No statistically significant differences were found between the drugs in onset of action, efficacy, side effects or predictors of response. Patients on either drug showed a significant reduction in symptoms after 1 week of treatment and at the end of the trial. Both drugs were tolerated well. A review of double-blind comparisons of maprotiline and tricyclic antidepressants, spanning 13 countries, and including over 900 patients, both ambulatory and inpatient, shows essentially similar results. The main outcome criterion in all these studies was manifest psychopathology assessed on the Hamilton Rating Scale for Depression by the treating physician. The absence of additional types of outcome criteria or assessment techniques, which may have detected differences in motor activity or drive as originally postulated, may have obscured results which were expected to be subtle.     

Effects of neuroleptics on platelet monoamine oxidase activity

Platelet MAO activity in schizophrenics was significantly decreased, by about 15%, after 3 weeks of treatment with haloperidol. Treatment with thioridazine or butaperazine also tended to decrease platelet MAO activity. The neuroleptic-induced decrease began to appear within a few days of treatment and did not show tolerance over 1-2 months of treatment with haloperidol. Platelet MAO activity of schizophrenic patients measured during drug-free base-line was not significantly different from that of normal controls, but MAO activity of schizophrenics was significantly lower than normals after 3 weeks of treatment with neuroleptics. The extent of decrease in platelet MAO activity correlated negatively with base-line prolactin and its increase after 24 hr. With PEA as substrate, the decrease in activity correlated positively with steady state plasma haloperidol.     

The effect of lamotrigine on platelet monoamine oxidase type B activity in patients with bipolar depression

Lamotrigine is an anticonvulsant drug effective in the treatment of epilepsy and bipolar depression. Preclinical data showed that lamotrigine inhibited monoamine oxidase (MAO) activity in vitro. The aim of the study was to determine the effects of 6-weeks lamotrigine treatment on platelet MAO type B (MAO-B) activity in patient with bipolar depression. The study included 26 female patients with bipolar I disorder in depressive episode (DSM-IV criteria, Hamilton Depression Rating Scale (HAMD) and Young Mania Rating Scale). Platelet MAO-B activity was determined spectrofluorimetrically before and after 6 weeks of the treatment with a relatively low dose of lamotrigine (100 mg/day). Six weeks of treatment with lamotrigine significantly decreased platelet MAO-B activity in bipolar depressed patients. This inhibitory effect was not related to smoking status and was independent of the treatment combinations (lamotrigine alone or in combination with either lithium or antipsychotics). Lamotrigine treatment induced a decrease in total HAMD scores in bipolar depressed patients, which was not significantly correlated with reduction of platelet MAO-B activity. These findings provide in vivo insight of lamotrigine effect on platelet MAO-B activity in patients with bipolar depression. Its in vivo MAO-B inhibiting effect might have contributed in part to its antidepressant activity.     

Clinical correlates of tricyclic antidepressant-mediated inhibition of platelet monoamine oxidase

Previous reports suggest that tricyclic antidepressants inhibit platelet monoamine oxidase (MAO) activity in vitro and in vivo. This study was undertaken to examine the relationship between tricyclic-mediated inhibition of platelet MAO and resolution of clinical signs and symptoms which are commonly associated with the depressive syndrome. The results indicate that the sedative-hypnotic effects of the tricyclics closely correlate with the magnitude of platelet MAO inhibition. It appears that these effects may be mediated through alterations in the metabolism of serotonin and/or the phenylethylamines.