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Few studies have examined the relationship between the use of antidepressants and the onset of hyperglycemia and diabetes mellitus in Japan. We herein explored the possibility of this relationship using the Japanese Adverse Drug Event Report database (JADER). The present study included 20 individual antidepressants, consisting of 6 subclasses, which have been approved for use in Japan. We used Standardized MedDRA Queries 20000041 to extract patients who developed hyperglycemia/new onset diabetes mellitus (NODM) in JADER between April 2004 and September 2016. We calculated reporting odds ratios (RORs) with 95% confidence intervals (CI). We also calculated odds ratios defined as the ratio of odds of hyperglycemia/NODM to all other adverse drug events (ADEs) by the age cut-off group or sex in the cases of antidepressants. The lower limit of 95%CI of RORs for 13 antidepressants (imipramine, clomipramine, nortriptyline, amitriptyline, amoxapine, maprotiline, mianserin, sertraline, paroxetine, escitalopram, duloxetine, mirtazapine, and trazodone), which included all subclasses, exceeded 1. Younger age group was associated with hyperglycemia/NODM for 5 antidepressants (imipramine, amitriptyline, maprotiline, duloxetine, and trazodone), and female was associated with the ADEs for trazodone, although these results should be interpreted cautiously. Healthcare personnel need to be aware that the use of antidepressants may lead to hyperglycemia/NODM.

Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p

Vitreous humor has become in recent years an important alternative biological fluid in forensic toxicological analysis especially for the investigation of cases where alcohol and drugs of abuse are involved but there is limited scientific information regarding the distribution of antidepressant drugs in this material. This work aimed to study the distribution of antidepressant drugs in vitreous humor and to estimate the blood/vitreous humor concentration ratios of these drugs. For this purpose, a GC/MS method for the simultaneous determination of 9 antidepressant drugs, namely amitriptyline, nortriptyline, citalopram, clomipramine, fluoxetine, maprotiline, mirtazapine, sertraline and venlafaxine, and 4 of their metabolites, namely desmethylmaprotiline, desmethylmirtazapine, desmethylsertraline, O-desmethylvenlafaxine, was developed and validated. The developed method includes solid-phase extraction followed by derivatization with Heptafluorobutyric Anhydride. For all analytes, LOD and LOQ were 1.50 and 5.00ng/mL, respectively, and the calibration curves were linear within the dynamic range of 5.00-500.0ng/mL (R2≥0.990). The absolute recovery was found to be ≥86.3 % for all analytes. The accuracy (%Er) was found to range between -6.58 and 6.18 %, whereas the precision (%RSD) was less than 10.9 % for all analytes. The developed method was successfully applied to vitreous humor samples from 43 blood positive cases for antidepressant drugs. Whenever antidepressant drugs were detected in blood, they were also detected in the respective vitreous humor samples. The vitreous humor/blood concentration ratios were also calculated and were found to range from 0.04-7.07. Citalopram, mirtazapine, and its metabolite desmethylmirtazapine as well as venlafaxine and its metabolite O-desmethylvenlafaxine were the most identified substances in these samples (n≥4) and their results were better statistically evaluated. Our results suggest that vitreous humor could be an appropriate matrix for the determination of antidepressants in postmortem toxicology.

Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

What is known and objectives: Multiple adverse drug reactions (ADRs) are expected, and thus should be prevented in the elderly comorbid patient on polypharmacy. Rosuvastatin is commonly prescribed for the treatment and prevention of atherosclerotic diseases, and in rare cases, is associated with rhabdomyolysis. Maprotiline is a tetracyclic antidepressant, infrequently used in the United States, but seemingly more broadly in European countries. Acute colonic pseudo-obstruction (Ogilvie's syndrome) caused by maprotiline has thus far, to our knowledge, not yet been described in the literature. Case summary We present a unique case of synchronous rhabdomyolysis and Ogilvie's syndrome in an 80-year-old lung cancer survivor following a recent ischemic stroke for which she was prescribed clopidogrel and rosuvastatin for secondary prevention, and maprotiline for post-stroke, new-onset insomnia and anxiety. The ADRs resolved on removal of the offending agents and initiation of conservative treatment. Retrospective pharmacogenetic testing of the patient's drug-metabolizing enzymes and transporters was performed to guide further management and prevent future potential drug interactions and ADRs. What is novel and conclusions: This is an interesting, albeit unfortunate, complex case that depicts the risk of rare adverse effects to medications and their potential relationship to pharmacogenetics. The impact of anticholinergic side effects of antidepressants on gastrointestinal motility, risk of myopathies with statins, increased susceptibility to ADRs caused by drug-drug interactions, and the utility of pharmacogenomic testing are discussed. The question whether commercially available pharmacogenomic tools are relevant for everyday use to direct patient care and reduce harmful drug-drug interactions is addressed and warrants further research. .

The effects of intraperitoneal DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a noradrenergic neurotoxin) and maprotiline (an inhibitor of norepinephrine reuptake in synapses) on spectral components of heart rhythm variability were examined in outbred male and female rats treated with these agents in daily doses of 10 mg/kg for 3 days. At rest, DSP-4 elevated LF and VLF spectral components in male and female rats. Maprotiline elevated LF and VLF components in males at rest, increased HR and reduced all spectral components in resting females. Stress against the background of DSP-4 treatment sharply increased heart rate and reduced the powers of all spectral components (especially LF and VLF components). In maprotiline-treated rats, stress increased the powers of LF and VLF components. Thus, the central noradrenergic system participates in the formation of LF and VLF spectral components of heart rate variability at rest and especially during stressful stimulation, which can determine the phasic character of changes in the heart rate variability observed in stressed organism.

The acute effects of single oral doses of antidepressants, maprotiline and amoxapine on serum levels of prolactin (PRL), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were studied in six normally cycling women. After oral administration of 25 mg maprotiline, no significant increase was observed in serum PRL levels, but PRL levels increased significantly (p

BackgroundMany patients discontinue antidepressant therapy long before the six-month minimum duration recommended for the treatment of major depression and many other diagnoses.PurposeTo estimate the duration of antidepressant treatment and to analyse the following factors in relation to treatment adherence: age, sex, polypharmacy and type of drug.MethodsRetrospective cohort followed up for five years (2003–2007) based on prescription database. Selection criteria: Users who had received at least one antidepressant prescription in 2003 and who had not received antidepressants during the previous 12 months.Variables studiedAge, sex, drug, polypharmacy, period of treatment, packs dispensed. Adequate adherence was defined as dispensation of medication during at least 80% of the treatment period, and compliance was defined as good when, in addition, the treatment lasted more than four months.ResultsOf the 7525 patients selected, 56% abandoned medication during the first four months. Men were more likely to give up medication before time than women. Good compliance was recorded in 22% of patients and was twice as frequent in patients with high levels of polypharmacy than in those with low levels (31% vs. 15.3%). Patients receiving maprotiline, venlafaxine, mirtazapine, citalopram, clomipramine and fluoxetine presented the highest percentages of good compliance.ConclusionsOnly one out of five patients complied with treatment for over four months. Treatment periods were shorter in men. In chronic processes, patients receiving polypharmacy presented the best compliance.

Slices of rat lung were incubated with tritiated 5-hydroxytryptamine and the tissue uptake of tritium was studied after separating the free and bound radioactivity by filtration on glass fiber filters. At 37 degrees a rapid uptake occurred during the first 10 min. After that time the uptake was less marked but it was still present after 60 min. The uptake was moderately potentiated by the MAO inhibitor iproniazid (3 micrometers) after 30-60 min. incubation. The 5-hydroxytryptamine uptake was inhibited by some uptake inhibitors, their order of potency beeing: clomipramine greater than imipramine greater than or equal to nortriptyline greater than or equal to cocaine greater than or equal to desipramine greater than maprotiline. At 0 degrees the uptake of 5-hydroxytryptamine was negligible. Non-linear regression analysis of uptake data indicated that 5-hydroxytryptamine was taken up by two different mechanisms. One of the uptake processes was saturated by high concentrations of 5-hydroxytryptamine and showed an apparent Km of 8 X 10(-7) M. The other uptake was linearly related to the 5-hydroxytryptamine concentration and could not be saturated even by concentration up to 5 X 10(-5) M of the amine.

Development of new therapeutics against Select Agents such as Francisella is critical preparation in the event of bioterrorism. Testing FDA-approved drugs for this purpose may yield new activities unrelated to their intended purpose and may hasten the discovery of new therapeutics. A library of 420 FDA-approved drugs was screened for antibiofilm activity against a model organism for human tularemia, Francisella (F.) novicida, excluding drugs that significantly inhibited growth. The initial screen was based on the 2-component system (TCS) dependent biofilm effect, thus, the QseC dependence of maprotiline anti-biofilm action was demonstrated. By comparing their FDA-approved uses, chemical structures, and other properties of active drugs, toremifene and polycyclic antidepressants maprotiline and chlorpromazine were identified as being highly active against F. novicida biofilm formation. Further down-selection excluded toremifene for its membrane active activity and chlorpromazine for its high antimicrobial activity. The mode of action of maprotiline against F. novicida was sought. It was demonstrated that maprotiline was able to significantly down-regulate the expression of the virulence factor IglC, encoded on the Francisella Pathogenicity Island (FPI), suggesting that maprotiline is exerting an effect on bacterial virulence. Further studies showed that maprotiline significantly rescued F. novicida infected wax worm larvae. In vivo studies demonstrated that maprotiline treatment could prolong time to disease onset and survival in F. novicida infected mice. These results suggest that an FDA-approved drug such as maprotiline has the potential to combat Francisella infection as an antivirulence agent, and may have utility in combination with antibiotics.

Background Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method. Methods We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40 mg/d. Results We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40 mg/day was equivalent to paroxetine dosage of 34.0 mg/day, agomelatine 53.2 mg/day, amitriptyline, 122.3 mg/day, bupropion 348.5 mg/day, clomipramine 116.1 mg/day, desipramine 196.3 mg/day, dothiepin 154.8 mg/day, doxepin 140.1 mg/day, escitalopram 18.0 mg/day, fluvoxamine 143.3 mg/day, imipramine 137.2 mg/day, lofepramine 250.2 mg/day, maprotiline 118.0 mg/day, mianserin, 101.1 mg/day, mirtazapine 50.9 mg/day, moclobemide 575.2 mg/day, nefazodone 535.2 mg/day, nortriptyline 100.9 mg/day, reboxetine 11.5 mg/day, sertraline 98.5 mg/day, trazodone 401.4 mg/day, and venlafaxine 149.4 mg/day. Sensitivity analyses corroborated the results except for doxepin. Limitations The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants. Conclusions Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.

The importance of signal transduction processes beyond receptors involving receptor-G protein coupling, in both the pathophysiology and the treatment of mood disorders, is well documented. Thus, regulatory elements of G protein function may play a role in the molecular mechanisms underlying these alterations. Phosducin-like proteins, a family of regulators of G protein function expressed throughout brain and body, modulate G protein function by high affinity sequestration of G protein-betagamma subunits, thus impeding G protein-mediated signal transmission by both Galpha and Gbetagamma subunits. An important consequence of Gbetagamma neutralization is the prevention of G protein-coupled receptor kinase phosphorylation resulting in a temporary protection to agonist-bound receptor desensitization. Phosducin-like protein levels were measured in brain cortices of rats chronically treated with one of five classes of antidepressants: imipramine, venlafaxine, maprotiline, citalopram, and moclobemide. None of the antidepressant treatments had any significant effect on phosducin-like protein levels. Phosducin-like protein levels were evaluated in mononuclear leukocytes from a group of 15 patients diagnosed with major depressive episode, both before the initiation of antidepressant treatment and after 4 weeks of antidepressant medication. No protein changes were found in leukocytes of either untreated patients with major depressive disorder or after 4 weeks of the treatment in comparison with healthy volunteers.

Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 microM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.

State-dependent learning (SDL) is a phenomenon in which the retrieval of newly acquired information is possible if the subject is in the same physiological state as during the encoding phase. SDL makes it possible to separate the effects of drugs per se on learning from the effects due to changes in drug state during the task. The present work was designed to investigate whether the antidepressants amitriptyline (30 mg/kg), maprotiline (25 mg/kg), and fluoxetine (15 mg/kg) produce SDL of the inhibitory avoidance conditioning in male and female CD1 mice. In three separate experiments, independent groups were used for each pharmacological treatment and for each sex using a 2 × 2 experimental design. The results do not show SDL in any of the drugs. In the case of amitriptilyline, the data can be attributed to a memorization deficit, while the maprotiline results are interpreted as simultaneously influenced by memorization deficit and performance facilitation due to motor impairment. Fluoxetine treatment did not produce any deteriorating effect on the conditioning. Drugs had some different effects on the performance of males and females, males showing a slightly higher deterioration than females with administration of amitriptyline and maprotiline. This study shows that these antidepressants affect the acquisition/consolidation but not the retrieval process in the inhibitory avoidance learning.

The aim of this study was to explore the potential of a new selective serotonin transporter (5-HTT) inhibitor, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine (MADAM, K(i)=1.65 nM), as a PET radioligand for examination of 5-HTT in the nonhuman primate brain. MADAM was radiolabeled by an N-methylation reaction using [(11)C]methyl triflate and the binding was characterized by PET in four cynomolgus monkeys. Metabolite levels in plasma were measured by gradient high-performance liquid chromatography (HPLC). The radiochemical incorporation yield of [(11)C]MADAM was 75-80% and the specific radioactivity at the time of administration was 34-652 GBq/micromol (n=8). The highest uptake of radioactivity was observed in striatum, thalamus, mesencephalon, and the lower brainstem. Lower binding was detected in neocortex and the lowest radioactive uptake was found in the cerebellum. This distribution is in accordance with the known expression of 5-HTT in vitro. The fraction of the total radioactivity in monkey plasma representing unchanged [(11)C]MADAM was 20% at 45 min after injection, as measured by gradient HPLC. Pretreatment measurements, using unlabeled citalopram, GBR 12909, and maprotiline, as well as a displacement measurement, using unlabeled MADAM, confirmed that [(11)C]MADAM binds selectively and reversibly to 5-HTT, and support the use of the cerebellum as reference region. The present characterization of binding in the monkey brain suggests that [(11)C]MADAM is a potential PET radioligand for quantitative studies of 5-HTT binding in the human brain.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

The purpose of this study was to evaluate sensory nerve function using current perception thresholds (CPTs) in patients who were administrated maprotiline. Twelve patients with post-herpetic neuralgia and 20 control subjects were studied. The patients with post-herpetic neuralgia were given a daily dose of 60 mg of maprotiline and were maintained at the same dose for 6 months. Twenty control subjects were randomly selected from healthy volunteers. ACPT test was used for quantitative assessment of A beta, A sigma, and C fiber transmission, which are associated with pain, by three (2000, 250, and 5 Hz) different frequencies of electric stimulation. CPTs of 5, 250, and 2000 Hz in patients with post-herpetic neuralgia 2 months after administration of maprotiline were 141.7 +/- 17.3 for 5 Hz, 120.8 +/- 12.9 for 250 Hz, and 256.4 +/- 18.0 for 2000 Hz, which were significantly (P < 0.01) higher than those (67.0 +/- 9.1 for 5 Hz, 73.4 +/- 7.0 for 250 Hz, and 191.3 +/- 20.2 for 2000 Hz) before treatment and than those (35.3 +/- 15.8, 62.0 +/- 18.9, and 198.9 +/- 15.8) of control subjects. An increase in CPT for 5 Hz at 2 months after administration of maprotiline correlated (r = 0.71, p = 0.01) with a decrease in pain score. There were no correlations between an increase in CPT and changes in Hamilton Depression Scale (HAMD) values until 3 months after maprotiline treatment. However, we found that an increase in CPT for 5 Hz at 6 months after maprotiline treatment correlated (r = 0.68, p = 0.015) with a decrease in HAMD values. In conclusion, administration of 60 mg maprotiline significantly increased current perception thresholds at 2 months after the administration.

Background: Cloninger’s theory of personality, including 4 temperament dimensions and 3 character dimensions, is one of the most noteworthy theories in recent years. Several studies have explored temperament dimensions as a predictor of response to antidepressant treatments in major depression, but these have provided inconsistent results. The present study explored temperament as well as character dimensions, as measured by the Temperament and Character Inventory (TCI), as possible predictors of response to maprotiline, the most-widely prescribed antidepressant in Japan. Methods: 86 consecutive patients with major depression underwent a 16-week open trial of maprotiline. They filled out the TCI at baseline, and were followed up at weeks 8 and 16 by using the Hamilton Rating Scale for Depression. Results: Hierarchial logistic regression analyses demonstrated that response to maprotiline was significantly predicted by the cooperativeness score at the 8-week outcome assessment, and by the self-directedness score at the 16-week outcome assessment, after controlling the possible effects of clinical variables on the response. There was no evidence that either temperament dimensions or their 2-way interactions significantly predicted the response. Limitations: Large replication studies with other antidepressants are needed for generalizing the results in this study. Conclusions: The results in this study regarding temperament dimensions seem consistent with findings in previous studies, which are, as a whole, inconsistent with each other. It is suggested that character dimensions (particularly cooperativeness and self-directedness), rather than temperament dimensions, may be important predictors of response to antidepressants. Antidepressants may differ in the personality configurations that predict optimal responses.

There is considerable evidence that adding selective serotonin reuptake inhibitor (SSRI) antidepressants to antipsychotic treatment improves negative symptoms of schizophrenia. This augmentation effect may be due to "nonspecific" antidepressant action or be specifically related to action on the serotonergic system. This study examined the serotonergic specificity of SSRI augmentation by comparing an SSRI antidepressant with a comparably effective antidepressant acting via the noradrenergic system. Consenting patients having chronic schizophrenia with prominent negative symptoms were studied. Either fluvoxamine or maprotiline was added to their regular antipsychotic treatment in a double-blind manner for 6 weeks. Patients were assessed using the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, the Scale for the Assessment of Positive Symptoms, the Montgomery-Asberg Depression Rating Scale (MADRS), and the Neurological Rating Scale for Extrapyramidal Side Effects. Twenty-five patients completed the study. Negative symptoms improved significantly in the fluvoxamine group, but not in the maprotiline group. MADRS scores, which were low, did not change significantly in either group. Positive symptoms were not affected by either treatment. It is concluded that the mechanism by which fluvoxamine augmentation improves negative symptoms involves the serotonergic system and is distinct from its antidepressant action.

1. Repeated pinching at the scruff produces, in experimental test/retest sessions, prolonged cataleptic-like immobility in mice that may mimic immobilities seen in some natural situations. 2. In the first experiment, on male mice, imipramine and amitriptiline (20 and 30 mg/kg i.p.) augmented the number of pinches necessary to reach the criterion of induced catalepsy and reduced the total time of catalepsy. 3. In the second experiment, on female mice, compounds that modulate the central 5-HT transmission, like fluvoxamine, fluoxetine (20 mg/kg i.p.) and ondansetron (0.1 and 1 mg/kg i.p.), retarded the occurrence and shortened the duration of pinch induced catalepsy at doses that did not modify the open field performances. Maprotiline (a selective inhibitor of the NA reuptake) did not modify the mice's performances in respect to controls. 4. Female mice presented a more rapid occurrence and a prolonged duration of pinch-induced catalepsy in respect to male controls. The present behavioral test may become a simple experimental model to detect new antidepressant or anxiolytic compounds and the significant sex difference could make the test a more useful tool in investigating anxiety behaviour in rodents.

Objective: To compare amitriptyline and maprotiline in the treatment of painful polyneuropathy in diabetics and nondiabetics. Design: A double-blind, crossover trial of treatment with amitriptyline, maprotiline, and placebo. Treatment was given in randomized order for periods of 4 weeks. Each period was separated by a I -week washout. The final dose was 75 mg/day for both amitriptyline and maprotiline. Patients: Thirty-seven patients with diabetic and nondiabetic painful polyneuropathy. Outcome Measures: The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale (0 = no pain and 10) = worst thinkable pain) and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale (pain relief scale). For the assessment of depression, the Comprehensive Psychopathological Rating Scale (CPRS) was used. Results: Using the global assessment of pain relief at the end of each treatment period. 22 of 33 patients reported reduced pain on amitriptyline treatment compared with 14 of 33 patients on maprotiline treatment and 8 patients on placebo treatment (p

In view of the fact that controlled prospective studies on the benefits of dose escalation of the selective serotonin re-uptake inhibitor (SSRI) paroxetine are lacking, we conducted a double-blind, randomized, parallel-group multicentre study designed to compare the possible benefits of dose escalation of paroxetine and maprotiline in patients suffering from major or minor depression according to modified Research Diagnostic Criteria (RDC) with inadequate treatment response. The study sample consisted of 544 out-patients with different degrees of severity of depression. Patients received either 20 mg paroxetine (n = 271) or 100 mg maprotiline (n = 273) for the first 3 weeks in a double-blind manner. Response after 3 weeks was defined using explicit operationalized criteria. Patients with inadequate treatment response (paroxetine group, n = 86; maprotiline group, n = 88) were again randomized to either continuation of the previous dosage (paroxetine, n = 36; maprotiline, n = 48) or increased doses, i.e. 40 mg paroxetine (n = 50) or 150 mg maprotiline (n = 40), respectively. Intention-to-treat and completer analyses were performed. Defining response as a reduction in Hamilton Depression Rating Scale (17-item version) (HAMD-17) score of at least 50% from baseline, no significant benefits of dose escalation were found for either paroxetine or maprotiline. Stratification according to baseline severity of depression also revealed no significant benefits of dose escalation. After dose escalation, new adverse events that had not been present during treatment with lower doses rarely occurred. Our results support the view that a dose of 20 mg paroxetine is optimal for the acute treatment of depression in the majority of patients.

This study was designed to investigate the relationship between platelet serotonin (5-HT) and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG) measures in depressed outpatients obtained from the same patient with unipolar depression during the pretreatment period and subsequent response to 6 weeks of treatment with either fluoxetine or maprotiline. Compared to the nonresponder group, the fluoxetine responders showed significantly higher pretreatment levels of MHPG, but no difference in pretreatment 5-HT levels. There were no significant differences in either 5-HT or MHPG levels between maprotiline responders and nonresponders. As to posttreatment levels, there were no between-group differences in 5-HT or MHPG between responders and nonresponders to either fiuoxetine or maprotiline. When the relationships between changes in 5-HT or MHPG levels and treatment response were examined, 5-HT values showed a marked decrease in both fiuoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fiuoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatrnent levels of plasma free MHPG appear to predict response to fluoxetine.

The present study investigated the potential of therapeutic drug monitoring data to document pharmacokinetic drug interactions with psychotropic medication, both in terms of methodology and applicability. It focused on 105 patients exposed to one of five agents known for their capacity to induce (phenytoine, phenobarbital, and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. These patients were matched by gender, age, and monitored psychotropic medication to 105 patients randomly selected from a pool of subjects nonexposed to target comedication. Such a paired approach was shown to be effective in reducing variability for a majority of substances. Power analysis suggested that eight to 10 pairs of exposed and nonexposed patients would effectively allow the detection of twofold effects of interacting substances. In keeping with the literature, analysis of the ratios of dose-normalized exposed to nonexposed concentrations indicated that phenothiazine comedication led to significantly higher concentrations of desmethylated metabolites but not parent compounds, when clomipramine, imipramine, or amitriptyline were administered. A similar, as yet undocumented interaction was observed for the tetracyclic antidepressant mianserine. In contrast, the present study revealed that maprotiline concentrations were increased, but its metabolite was largely unaffected by phenothiazine comedication. Increased concentrations were also observed for moclobemide, but not citalopram or its metabolite. In addition to its long recognized capacity to decrease haloperidol concentrations, carbamazepine was shown to induce the metabolism of clopenthixol and possibly flupenthixol. The consistency of such a picture substantiates the need to consider therapeutic drug monitoring databases as cost-effective and reliable tools for postmarketing surveillance.

In 2 young adult women who experienced acute heterocyclic antidepressant intoxication, we found a quite unusual electrocardiographic pattern characterized by abnormal ST-tract elevation in the right precordial leads associated with a marked QRS widening (right bundle branch block and left anterior fascicular block type). Because serum electrolyte imbalance and acute myocardial ischemic events were excluded, the mechanism by which antidepressant overdose may produce such elevation of the ST tract remains unclear.

In the choice of an antidepressant drug the clinician must often consider the presence of a cardiovascular comorbidity in depressed patients. In the present study the cardiovascular effects of fluvoxamine and maprotiline were compared in a double-blind trial in which the quantitative changes in ECGs were assessed before and during a 3-week treatment. A total of 33 patients (mean age 44 years; range 20–65 years) with major depressive disorder (RDC) who were free from clinically relevant organic diseases were investigated. After a 7-day wash-out period, a 3 week treatment phase was started with 200 mg daily of either fluvoxamine (n=18) or maprotiline (n=15). On days 0, 7, 14 and 21 a 12-lead standard ECG was performed and the drug plasma levels were determined. All ECGs were analysed in a blind fashion by an internist. Maprotiline caused a significant prolongation of the PR interval (P

Recent studies indicate that antidepressant drugs with potent serotonin reuptake inhibiting properties are effective in reducing the symptoms of premenstrual syndrome (PMS). In order to elucidate whether all antidepressant drugs are equally effective in the treatment of PMS or whether potent serotonin reuptake inhibition is a prerequisite for reducing premenstrual complaints, women suffering from severe PMS were treated daily for three menstrual cycles with a selective serotonin reuptake inhibitor, paroxetine (n = 22), or with a selective noradrenaline reuptake inhibitor, maprotiline (n = 21); in addition, a placebo group was included (n = 22). Six symptoms (irritability, depressed mood, tension/anxiety, increased appetite/craving for carbohydrates, bloating, and breast tenderness) were rated by the participants daily throughout the study. With respect to all outcome measurements, the symptom reduction obtained with paroxetine was significantly superior to that obtained with placebo; with respect to irritability, increased appetite/carbohydrate craving, bloating, and breast tenderness, as well as global self-rating, paroxetine was significantly superior also to maprotiline. The clear-cut superiority of paroxetine over maprotiline indicates that not all antidepressant drugs are equally effective in the treatment of PMS; rather, like panic disorder and obsessive compulsive disorder, but in contrast to depression, PMS apparently responds better to serotonin reuptake inhibitors than to antidepressants with a noradrenergic profile.

Therapeutic drug monitoring (TDM) data of antidepressant drugs are often evaluated using homogeneous samples of selected individuals without psychiatric or somatic comorbidity. These data may have limitations in transferability to everyday clinical practice. Hence, studies under naturalistic conditions are important to clarify the full clinical relevance of TDM of antidepressants. TDM analyses were retrospectively evaluated for a 3-year period from 2008 to 2010. The influence of gender and age on dose-corrected serum concentrations of antidepressants was examined in a standard clinical setting. 693 TDM analyses of amitriptyline and nortriptyline (AMI + NOR), 160 of citalopram (CIT), 152 of clomipramine and N-clomipramine (CLO + N-CLO), 272 of doxepine and N-doxepine (DOX + N-DOX), 359 of escitalopram (ESC), 198 of fluoxetine and N-fluoxetine (FLU + N-FLU), 92 of maprotiline (MAP), 888 of mirtazapine (MIR), and 77 of sertraline (SER) remained in the sample. Females had significantly higher dose-corrected serum concentrations of AMI + NOR (32 %), CIT (29 %), DOX + N-DOX (29 %), and MIR (20 %), and patients older than 60 years had significantly higher dose-corrected serum concentrations of AMI + NOR (21 %), CIT (40 %), DOX + N-DOX (48 %), MAP (46 %), MIR (24 %), and SER (67 %). Comparing the two extreme groups, females >60 years showed a remarkably higher dose-corrected serum concentration of AMI + NOR (52 %), CIT (78 %), DOX + N-DOX (86 %), and MIR (41 %) in contrast to males ≤60 years. Gender and age have a significant influence on the serum concentrations of different antidepressant drugs, and additive effects must be considered. TDM is recommended to reduce the risk of adverse effects due to supratherapeutic serum levels, also in a naturalistic clinical setting.

The predictive value of eight domains or sets of variables including sociodemographic aspects, premorbid history, symptomatology, personality, social and diagnostic data are evaluated in depressed outpatients with a Hamilton Rating Scale for Depression (HRSD) score of at least 14. Patients were treated using a three-phase sequential treatment strategy. Of the 119 patients, 88 completed the trial. The HRSD-score at the end of phases I, II or III was used as an outcome measure. Patients with an initially high HRSD-score and an obsessive-compulsive personality had a greater chance of recovery, while patients with somatization and a passive-aggressive personality had less of a chance of recovery. Variables involving psychiatric history, premorbid history or symptomatology of the depression, were not significantly related to outcome. The endogenous/non-endogenous distinction was not a predictor of response.

The 24-hour motor activity pattern was evaluated in 26 inpatients with major depression at treatment onset and after 4 weeks of antidepressant therapy. Clinical state, depression, and psychomotor retardation, as well as motor activity level and circadian rhythm, were simultaneously assessed. Treatment responders and nonresponders were also considered. Diurnal hypoactivity and reduced 24-hour rhythm amplitude were found at treatment onset. Activity level increased significantly on discharge. The rest-activity cycle for each depressed patient fit a cosine function of 24-hour periodicity. Data tended to show no phase shift but a large intragroup phase variability. Preliminary findings of a negative correlation between basic activity level and clinical improvement, and a trend toward responders having a lower activity level than nonresponders, suggest that activity could be used to predict therapeutic response.

Depressed outpatients (n = 51) resistant to treatment with maprotiline were treated in a blind, randomized, single-centre study, for 6 weeks with either the reversible and selective monoamine oxidase A-inhibitor (MAO-A-I), brofaromine or lithium addition to maprotiline. The Hamilton Rating Scale for Depression was scored by an independent rater before and after the 6 week treatment period. No significant differences in efficacy were found between the two treatment regimes. In the patients who completed the trial, brofaromine was well tolerated with the exception of insomnia. Anticholinergic effects as well as thyroid dysfunctions (17 out of 20) were more frequent in the maprotiline/lithium group.

The combination of an antidepressant with a neuroleptic is standard pharmacotherapy for delusional depression today. The neuroleptics used are rarely specified: occasionally haloperidol or perphenazine are mentioned. In two different open-treatment studies, consecutively admitted delusional depressed inpatients received a butyrophenone [haloperidol, bromperidol, approximately 10 mg/day (n = 16)] or zotepine [150-200 mg/day (n = 15)] as a neuroleptic in combination with a tri- or tetracyclic antidepressant (amitriptyline, maprotiline, 150 mg/day). There was a significant improvement in both groups in the sum score of the Hamilton depression scale (24-item version), in a subscore of so-called delusional items (items 2, 17, 19, 20, 23, and 24 together), in the subscore of remaining items and also in most single items such as mood, inhibition, agitation, feelings of guilt or hopelessness.

A randomized double-blind, multicenter 6-week study was undertaken in 80 depressed patients to compare the effects of moclobemide, a selective and reversible monoamine oxidase-A inhibitor (300 mg daily), and maprotiline (75 mg daily). Efficacy was assessed by Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI). Tolerability was assessed by adverse events reports. After 6 weeks of therapy, both groups of patients showed significant improvement in HDRS and CGI. Speed of onset of action was faster with moclobemide (significant difference at week 3, p = 0.025). There was a significant reduction of depression ratings (HDRS) in both the moclobemide and maprotiline group in all types of depression according to ICD-9 criteria (major depressive disorder, neurotic depression and adjustment-prolonged depressive reaction). Significantly fewer patients in the moclobemide group reported adverse events (28.9% compared with 70.2%) including weight gain (2.6% compared to 21.6%). Anticholinergic side effects were less frequent with moclobemide. It is concluded that both drugs are at least equivalent in terms of therapeutic efficacy, but moclobemide is better tolerated.

Introduction Although several adverse effects of antidepressants on the gastrointestinal tract have been described (bleeding, constipation, dolichocolon), their influence on gallbladder motility was not investigated.The aim of our study was to investigate the effects of selected antidepressants on gallbladder emptying in patients with major depression. Methods The study was set up as an open clinical trial, with the same intervention (ingestion of test meal provoking gallbladder emptying) undertaken in 112 patients with major depression. There were 30 patients not taking antidepressants (the control group), 25 patients taking amitriptyline, 30 patients taking maprotiline, and 27 patients taking fluoxetine. The volume of gallbladder in the study patients was measured by ultrasonography before the test meal, and 15, 30, 45 and 60 min after the meal. Results 1 h after ingestion of the study meal, the amitriptyline group showed incomplete gallbladder emptying (F=10.829, df=3, p=0.000; mean residual volume 11.0±6.1 mL), while in the control, maprotiline and fluoxetine groups emptying of gallbladder was complete (mean residual volumes 5.0±3.3 mL, 5.6±3.7 mL and 5.7±2.3 mL, respectively). Discussion In patients with cholecystitis, it would be wise to use antidepressants which do not impair gallbladder emptying, like maprotiline or fluoxetine, and to avoid amitriptyline.

In patients with dementia and mild depression (DSM-III-R 290.21), the effect of low doses of the antidepressant maprotiline (up to 75 mg/d) was examined. The main parameter was a video rating of global impression. The Mini-Mental State Examination (MMS) and the Geriatric Depression Scale (GDS) were applied to evaluate the effect of maprotiline on cognitive and depressive symptoms. The double-blind, placebo-controlled trial was of eight weeks' duration and included 127 patients, randomized in two groups. The antidepressant effect of maprotiline was reflected in the GDS. There was, however, no indication of an effect of maprotiline on cognitive performance. The global impression, evaluated by video rating, gave no indication as to a beneficial effect of the treatment. - The video analysis showed a significant interrater reliability. The discrepancy between the results of the video rating and the GDS is discussed. - The results confirm similar findings of other authors; i.e., that a sedating antidepressant with some anticholinergic effects cannot be expected to improve cognitive functions despite its antidepressant effect. The main interest of this study, however, lies in its methodology (video analysis).

Ventricular fibrillation (VF) is a fatal event in humans unless electrical defribillation is applied within minutes. Recent publications describe spontaneous termination of VF in various animals and even in humans. Certain drugs can transfer a fatal, sustained VF (SVF) into a self-terminating, transient VF (TVF). Based on results obtained in animals of various species and ages, we have suggested that the occurrence of TVF requires a high cardiac catecholamine level at the time of VF. According to our hypothesis, drugs which decrease catecholamine reuptake by the sympathetic nerve terminals will increase the ability of the heart ventricles to defibrillate spontaneously. In the present study, we examined the effects of desipramine, maprotiline, mianserin, iprindole, cocaine and amphetamine on the type of VF in cats exhibiting SVF prior to the treatment. The results show that the ability of these compounds to transfer SVF to TVF is closely related to their potency to inhibit catecholamine reuptake. The establishment of the catecholamine related mechanisms of TVF may lead to the development of a new class of antiarrhythmic — defibrillatory drugs.

AIMS: To study whether listed putative corrected QT (QTc)-prolonging psychotropic drugs indeed prolong the QTc interval under everyday circumstances and to evaluate whether this is a class effect or an individual drug effect, we conducted a prospective population-based cohort study. METHODS: This study was conducted as part of the Rotterdam Study and included 3377 men and 4845 women (>or=55 years) who had triennial electrocardiograms (ECGs). The primary end points of the study were the length of the QTc interval at each ECG, the difference in QTc interval between consecutive ECGs within one person, and the risk of an abnormally prolonged QTc interval. Drug use at the index date was obtained from automated dispensing records. The associations were examined by means of a repeated measurement analysis, adjusted for age, sex, diabetes mellitus, hypertension, myocardial infarction, heart failure, and use of class 1 QTc-prolonging drugs. RESULTS: Of the 8222 participants, 813 participants (9.9%) developed QTc prolongation during follow-up and 492 participants (74.4% women) used psychotropic drugs at the time of an ECG. Starting tricyclic antidepressants increased the QTc interval significantly with 6.9 milliseconds (95% confidence interval [CI], 3.1-10.7 milliseconds) between consecutive ECGs in comparison with consecutive ECGs of participants not using tricyclic antidepressants, in particular starting amitriptyline (8.5 milliseconds; 95% CI, 2.8-14.2 milliseconds), maprotiline (13.9 milliseconds; 95% CI, 3.6-24.3 milliseconds), and nortriptyline (35.3 milliseconds; 95% CI, 8.0-62.6 milliseconds). Starting lithium also increased the QTc interval significantly (18.6 milliseconds; 95% CI, 4.8-32.4 milliseconds). CONCLUSIONS: In this population-based prospective cohort study, we confirmed the importance of antidepressants and antipsychotics as potential contributors to QTc prolongation. Especially, starting tricyclic antidepressant drugs (as a class) is associated with a significant intraindividual increase in the QTc interval in comparison to the change in nonusers. The tricyclic antidepressants seem to prolong the QTc interval as a class effect.

Platelet 5-HT levels and scores on the 17-item Hamilton Rating Scale for Depression (HRS) were studied in patients with unipolar depression before and after antidepressant treatment. Before treatment there were no differences in platelet 5-HT values or in HRS scores between patients who showed a good and a poor therapeutic response. Repeated administration of 5-HT uptake inhibitors (amitriptyline, clovoxamine, fluvoxamine) for 28 days markedly decreased platelet 5-HT levels. Chronic treatment with trazodone or maprotiline (weak inhibitors of platelet 5-HT uptake) produced no changes in platelet 5-HT levels. No significant correlation was observed between platelet 5-HT concentrations and the HRS scores before or during treatment. The findings suggest that the changes in platelet 5-HT levels after antidepressant treatment are mainly due to the effects of antidepressants on the 5-HT uptake system.

In a six-week double-blind randomized trial, preceded by a one-week period of single-blind placebo treatment, the efficacy and the side-effects of fluvoxamine (100-300 mg/d) (n = 24) and maprotiline (50-150 mg/d) (n = 24) were compared in moderately depressed outpatients with DSM-III Major Depression (n = 22) or Dysthymic Disorder (n = 26). Efficacy was measured by means of the Hamilton Depression Rating Scale, the Zung Depression Selfrating Scale, and a Clinical Global Impression of Severity Scale. Side-effects were evaluated by an Adverse Event Inventory and a Psychosomatic Symptom Scale. A statistically significant improvement was achieved in both treatment groups but success rates were modest: in both groups, 29% of the patients achieved a clinically significant improvement after six weeks of treatment. After six weeks of treatment, no difference in efficacy was found between fluvoxamine and maprotiline. Nausea was the most common complaint in the fluvoxamine group, while in the maprotiline group, it was dry mouth and constipation. One maprotiline-treated patient developed a convulsive attack.

Efficacy and safety of the following antidepressants: amitryptiline (tricyclic antidepressant), escitalopram (selective inhibitor of serotonin reuptake), milnacipran (selective inhibitor of serotonin and noradrenalin reuptake) and maprotiline (selective inhibitor of noradrenalin reuptake) have been compared during the treatment of 120 patients with chronic daily headache. A positive effect was found for all drugs, in particular in the presence of depressive and anxiety symptoms. Most effective proved to be milnacipran and amitryptiline. Escitalopram and milnacipran were more tolerable and had less side-effects. The authors suggested that the combination of noradrenergic and serotoninergic components appears to be most effective in treatment of chronic daily headache.

The aim of the study was to evaluate the long-term effects of antidepressive therapy on chronic pain and related disability, and masseter silent period in psychiatric depressive patients with temporomandibular disorders (TMD). The study included hospitalized psychiatric depressive patients on antidepressive therapy protocol (tetracyclic antidepressant-maprotiline and anxiolytic-diazepam) (n=30) and non-psychiatric patients seeking prosthodontic treatment (control group, n=38). TMD were diagnosed by Research Diagnostic Criteria for temporomandibular disorders proposed by Dworkin and LeResche. The surface electromyography was recorded from left and right masseter muscles and masseter inhibitory reflex (masseter silent period) was recorded after mechanical stimulation. The incidence of TMD appearance was very similar, of approximately 40% in both group of patients. The results of the study also indicated a higher prevalence of joint related TMD, a lower prevalence of muscular subtype of TMD and a lower grade of chronic pain and related disability in the psychiatric group of patients on antidepressive therapy in comparison with findings in the control group. In the patients on antidepressive therapy with TMD masseter silent period was not prolonged , while in the control group of patients with TMD the prolongation of the silent period was observed. The study provided evidence that long-term, combined therapy (maprotiline and diazepam) in psychiatric depressive patients significantly modulated signs and symptoms of TMD in comparison with the control group.

A gas chromatographic-mass spectrometric (GC-MS) method in positive ion chemical ionization mode in combination with a solid phase extraction was optimized for new-generation antidepressants and their metabolites in postmortem blood, brain tissue, and hair. Twelve antidepressants and their active metabolites (i.e., mirtazapine, viloxazine, venlafaxine, citalopram, mianserin, reboxetine, fluoxetine, fluvoxamine, sertraline, maprotiline, melitracen, paroxetine, desmethylfluoxetine, desmethylmianserin, desmethylmirtazapine, desmethylsertraline, desmethylmaprotiline, desmethylcitalopram, and didesmethylcitalopram) could be quantified. In this article, in addition to the validation of the GC-MS method, four postmortem cases are discussed to demonstrate the usefulness of the described method in forensic toxicology. In these cases, sertraline, fluoxetine, citalopram, and trazodone in combination with their active metabolites were quantified. Blood concentrations ranged from subtherapeutic to toxic concentrations, while brain to plasma ratios ranged from 0.8 to 17. Hair concentrations ranged from 0.4 to 2.5 ng/mg depending on the compound and hair segment.

Although repeated but not single administration of antidepressants exerts therapeutic effect on clinical depression, the mechanism of the clinical efficacy of antidepressants remains unknown. This report shows a novel action of antidepressants which can explain the delayed onset of clinical action of the drugs. Continuous infusion of the antidepressants maprotiline or desipramine into the rat cerebral cortex pretreated with the catecholamine neurotoxin 6-hydroxydopamine induced regeneration of noradrenergic axon terminals. This finding provides evidence that antidepressants possess the ability to cause axonal sprouting of central noradrenergic (and possibly dopaminergic) neurons in the mature brain.

The thyrotropin-releasing hormone (TRH) test was performed in 100 depressed patients, including 73 patients with a major depressive episode (MDE) according to DSM-III. Thirty-one patients subsequently received an antidepressant with a predominant serotoninergic action (indalpine or citalopram), and 27 patients received a noradrenergic antidepressant (maprotiline). The diagnostic value of the TRH test was not conclusive for any of the subgroups of depressed patients: MDE, MDE with melancholia or MDE in bipolar patients. Similarly, the value of the TRH test in the choice of antidepressant treatment according to the monoaminergic action was not convincing. These results are discussed in the light of the data of the international literature.

To observe the effect and side effect of Danzhi Xiaoyao powder (DXP) in treating depression.A randomized controlled and double-blinded study was conducted in 63 cases of depression by divided them into the western medicine group (WMG, 31 cases) treated with maprotiline, and the Chinese medicine group (CMG, 32 cases) treated with DXP. The effect of therapy was evaluated before and at the 2nd, 4th and 6th week of the treatment with Hamilton's depressive scale (HAMD), self-rating depression scale (SDS), self-rating anxiety scale (SAS) and the scale for TCM syndrome and symptom differentiation (TCM-SSD), and the side-effect of therapy was assessed with Asberg side-effect scale as well.There was no significant difference between the two groups in scores of HAMD, SDS, SAS, and TCM-SSD. The markedly effective rate in CMG was 84% and in WMG 87%, showed no significance between them (P0.05). The scores of HAMD, SDS and SAS of both groups were remarkably lowered after therapy (P0.05). However, the score of Asberg in CMG was lower than that in WMG (P0.05).DXP shows the effect equivalent to that of maprotiline, but with obviously less side-effect.

In an open pilot study of 21 therapy-resistant depressive inpatients, plasma levels of antidepressants were determined during treatment with a combination of moclobemide/ trimipramine (n = 15) and moclobemide/maprotiline (n = 6). After combined administration of trimipramine and moclobemide (MCB), a significant increase in the plasma level of trimipramine (39%) was observed. After combination of maprotiline with moclobemide, maprotiline levels were increased (25%, n.s.). The results show that moclobemide, as an inhibitor of isoenzymes of the cytochrome P 450 oxidase, can cause increases in the plasma levels of tricyclic and tetracyclic antidepressants. No correlation between the serum level of the antidepressants and treatment outcome was found in this open study.

An analysis of EEG spectral characteristics of placebo effect and antidepressant (fluoxetine, maprotiline) monotherapy in patients with mild or moderate depressive episodes (ICD-10) has been conducted. Depending on clinical effects of placebo and antidepressants, the groups of placebo- and medication-responders/non-responders were compared. Placebo caused both particular and similar with the action of a single antidepressant dose changes in spectral power of EEG bands, which reduced during the pharmacotherapy course. The EEG changes achieved a significant level mostly in placebo-responders. Differences in EEG reactions between medication responders and non-responders were rare and emerged at the stage of the placebo therapy and single antidepressant dose intake. The change of between-hemisphere asymmetry of alpha-rhythm low band power in the frontal brain regions corresponding to the increase of activation of these regions in the left hemisphere, was found to be characteristic of thymoleptic effect of pharmacotherapy.

The authors postulate mechanisms linking tricyclic antidepressants, QT interval prolongation, torsade de pointes, and sudden cardiac death. Case reports identify amitriptyline and maprotiline as the tricyclic antidepressants most likely to provoke torsade de pointes. Risk factors of family history of congenital long QT syndrome, age, female sex, metabolic and cardiovascular disease, metabolic inhibitors, hypokalemia, drug overdose, and co-prescription of drugs associated with QT interval prolongation were found in cases of torsade de pointes associated with tricyclic antidepressants. Clinicians should be cautious when prescribing tricyclic antidepressants with other drugs, such as thioridazine, that are capable of prolonging the QT interval.