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Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is upregulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI), reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression. We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BDNF by testing for region-specific changes in areas CA1, CA3, and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP. Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and Western blotting. LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected. LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium influx.

Objective: Despite the recognized anti-inflammatory potential of heterocyclic antidepressants, the mechanisms concerning their modulating effects are not completely known. Thus, we evaluated the anti-inflammatory effect of amitriptyline, clomipramine, and maprotiline and the possible modulating properties of these drugs on neutrophil migration and mast cell degranulation. Methods: The hind paw edema and air-pouch models of inflammation were used. Male Wistar rats were treated with saline, amitriptyline, clomipramine or maprotiline (10, 30, or 90 mg/kg, per os [p.o.]) 1 h before the injection of carrageenan (300 μg/0.1 mL/paw) or dextran (500 μg/0.1 mL/paw). Then, edema formation was measured hourly. Neutrophil migration to carrageenan (500 μg/pouch) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (10-6 M/mL/pouch) was also investigated in 6-day-old air-pouch cavities. Compound 48/80-induced mast cell degranulation was assessed in the mesenteric tissues of antidepressant-treated rats. Results: All tested antidepressants prevented both carrageenan- and dextran-induced edema. The anti-inflammatory effect of these drugs partially depends on the modulation of neutrophil migration, since they significantly counteracted the chemotactic response of both carrageenan and fMLP (p < 0.01). Furthermore, amitriptyline, clomipramine and maprotiline inhibited compound 48/80-induced mast cell degranulation (p < 0.001). Conclusions: These results suggest an important anti-inflammatory role of heterocyclic antidepressants, which is dependent on the modulation of neutrophil migration and mast cell stabilization.

The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain. We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However, evidence from basic science is needed to improve our understanding of the mechanisms of action and their possible pharmacodynamic interactions.

Influences of psychotropic drugs, six antipsychotics and three antidepressants, on acetylcholine receptor-operated potassium current (IK.ACh) were examined by a whole-cell patch clamp method in freshly isolated guinea-pig atrial myocyte. IK.ACh was induced by a superfusion of carbachol (CCh) or by an intracellular application of guanosine 5'-[thio] triphosphate (GTPγS). To elucidate mechanism for anticholinergic action, IC50 ratio, the ratio of IC50 for GTPγS-activated IK.ACh to CCh-induced IK.ACh, was calculated. Antipsychotics and antidepressants inhibited CCh-induced IK.ACh in a concentration-dependent manner. The IC50 values were as follows; chlorpromazine 0.53 μM, clozapine 0.06 μM, fluphenazine 2.69 μM, haloperidol 2.66 μM, sulpiride 42.3 μM, thioridazine 0.07 μM, amitriptyline 0.03 μM, imipramine 0.22 μM and maprotiline 1.81 μM. The drugs, except for sulpiride, inhibited GTPγS-activated IK.ACh with following IC50 values; chlorpromazine 1.71 μM, clozapine 14.9 μM, fluphenazine 3.55 μM, haloperidol 2.73 μM, thioridazine 1.90 μM, amitriptyline 7.55 μM, imipramine 7.09 μM and maprotiline 5.93 μM. The IC50 ratio for fluphenazine and haloperidol was close to unity. The IC50 ratio for chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine and maprotiline was much higher than unity. The present findings suggest that the psychotropics studied suppress IK.ACh. Chlorpromazine, clozapine, thioridazine, amitriptyline, imipramine, maprotiline and sulpiride are preferentially acting on muscarinic receptor. Fluphenazine and haloperidol may act on G protein and/or potassium channel.

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.

EDITOR, - N Freemantle and colleagues propose that, compared with selective serotonin reuptake inhibitors, “newer tricyclic and related antidepresants … will have similar impact on rates of suicide but at considerably less cost.”1 The drugs that are listed as newer tricyclic and related antidepressants, however, have important differences in pharmacology, clinical profile, toxicity, and cost. Maprotiline is indeed related to tricyclic antidepressants both structurally and pharmacologically. It is also equally toxic,2 as table 1 of the authors' article clearly shows. To class it among compounds that are of “similar toxicity” to selective serotonin reuptake inhibitors is misleading and a serious error. Trazodone and mianserin are relatively safe in overdose but differ from selective serotonin reuptake inhibitors in being highly sedating.2 For some patients a sedating drug will be preferred,3 but this will be a clinical decision rather than an economic one. Economic factors may, of course, favour the use of one “safe” sedating antidepressant over another. Trazodone is as expensive as selective serotonin reuptake inhibitors, and, although mianserin is cheaper, the expense and inconvenience of the blood count monitoring required by the British National Formulary have not been taken into account in the costs shown by the authors. Viloxazine is used little in Britain. It was released on to the market before licensing authorities required new antidepressant drugs to undergo rigorous placebo controlled testing of efficacy. Its efficacy compared with that of placebo has not been satisfactorily shown,4 and calls for its more widespread prescription require careful examination. Lofepramine is non-sedating and relatively safe in overdose. It is indeed a viable alternative to the selective serotonin reuptake inhibitors in the treatment of major depression.3 Evidence suggests that it is more effective than placebo,5 but not at the dose that Freemantle and colleagues used …

We studied heart rate variability and β-adrenergic responsiveness of erythrocytes and changes in these parameters in response to single administration of β-adrenoblocker propranolol (2 mg/kg) in outbred male rats against the background of activation of the noradrenergic, serotonergic, and dopaminergic neurotransmitter systems achieved by 4-fold injections maprotiline (10 mg/kg), 5-hydroxytryptophan (50 mg/kg) combined with fluoxetine (3 mg/kg), and L-DOPA (20 mg/kg) with amantadine (20 mg/kg), respectively. Stimulation of the noradrenergic system moderately enhanced the heart rhythm rigidity and β-adrenergic responsiveness of erythrocytes. In addition, it markedly augmented the moderating effect of subsequently administered propranolol on LF and VLF components in the heart rate variability and reversed the effect of propranolol on β-adrenergic responsiveness of erythrocytes. Stimulation of the serotonergic system dramatically decreased all components in the heart rate variability and pronouncedly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol slightly restored all components in the heart rate variability and decreased β-adrenergic responsiveness of erythrocytes to the control level. Stimulation of the dopaminergic system made the heart rate more rigid due to decrease of all components in the heart rate variability; in addition, it slightly but significantly enhanced β-adrenergic responsiveness of erythrocytes. Subsequent injection of propranolol produced no significant effects on all components in the heart rate variability and on β-adrenergic responsiveness of erythrocytes. Stimulation of noradrenergic, serotonergic, and dopaminergic neurotransmitter systems produced unidirectional and consorted effects on heart rate variability and β-adrenergic responsiveness of erythrocytes, although the magnitudes of these effects were different. Probably, the changes in the heart rate variability in rats with stimulated neurotransmitter systems results from modification of the cellular sensitivity in peripheral organs to adrenergic influences. However, the differences in the reactions to β-adrenoblocker attest to specificity of the mechanisms underlying the changes in membrane reception and adrenergic pathways in every experimental model employed in this study.

The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A

The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (5) and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl)-N-methylmethanamine (6) as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3) and (4) were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5), (6) and (3) showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively.

Around 20 % of people with intellectual disability (ID) develop epileptic seizures. ID is a risk factor for the development of epileptic seizures also in patients with autism (21.5 % vs 8 % in the general population). In both these conditions generalized seizures are more common than partial seizures. The incidence of epilepsy is four to seven times higher in patients with depression than in the general population. Epilepsy and depression share an unusually high co-occurrence leading to a common etiology. A lifetime history of depression is also associated with a worse seizure outcome even after anterior temporal lobectomy. Patients treated with an antidepressant have a 50 % reduction in the occurrence of seizures. Epilepsy and bipolar disorder also could share a number of biochemical and pathophysiological underpinnings, even though the current literature is scarce. Patients with schizophrenia have an 11-fold increase in the prevalence of comorbid epilepsy. At therapeutic doses, drugs with high epileptogenic potential include clozapine and phenothiazines; drugs with intermediate epileptogenic potential include maprotiline and tricyclic antidepressants, while drugs with low epileptogenic potential include bupropion. The antidepressants with higher seizure potential after overdose are imipramine, desipramine, nortriptyline, maprotiline, and bupropion.

Alterations in cardiac function were observed in antidepressants treated patients and published in several clinical reports. These detected changes could be either a consequence of the treatment or of depression itself, which has already been proved to be a risk factor in heart diseases. In order to determine a possible influence of chronic treatment with norepinephrinergic reuptake inhibitor, maprotiline, on the heart, we investigated gene expression of cardiac β-adrenoceptors both in controls and in animals with signs of depression. The rats were divided into two groups, unstressed controls and those exposed to chronic unpredictable mild stress (CUMS). The groups were further divided into two subgroups, one receiving daily intraperitoneal injections of vehicle (sterile water) and another one maprotiline (10 mg/kg) for four weeks. Tissue samples were collected after the last application. Gene expression of cardiac β1- and β2-adrenoceptor was determined using Real-time RT-PCR analysis. Our results show that in control animals expression of both adrenoreceptors was decreased in the right atria after 4 weeks of maprotiline application. Contrary, the same treatment led to a significant increase in expression of cardiac β1-adrenoceptor in the stressed rats, with no change in the characteristics of β2-adrenoceptor. Our findings might reflect the that molecular mechanisms are underlying factors involved in the development of cardiovascular diseases linked with antidepressant treatment. Vários relatórios clínicos observaram alterações de funcionamento cardíaco de pacientes depressivos que foram tratados com os antidepressivos. As alterações detectadas podem ser consequência do tratamento ou, por outro lado, da depressão que, como se tem provado, é um fator de risco no caso de doenças cardíacas. De modo a determinar a possível influência de tratamento crônico com o inibidor da recaptação de norepinefrina, maprotilina, no coração, foi investigada a expressão do gene aos receptores β-adrenérgicos cardíacos dos animais em grupos de controle e em grupos com sinais de depressão. Os ratos foram divididos em grupos de controle não estressados e os grupos de ratos submetidos ao estresse crônico moderado imprevisível (CUMS). Os grupos foram, ainda, divididos em dois subgrupos, que, durante quatro semanas, diariamente receberam injeções intraperitoneais de placebo (água estéril) ou de maprotilina (10 mg/kg). As amostras de tecido foram coletadas após a última aplicação. A expressão do gene aos receptores adrenérgicos β1 e β2 foi determinada utilizando a análise PCR quantitativa em tempo real (RT-PCR). Os nossos resultados demonstram a diminuição de expressão dos ambos os receptores adrenérgicos no átrio direito dos animais do grupo de controle depois de quatro semanas de aplicação de maprotilina. Em contraste, o mesmo tratamento conduziu ao aumento significativo na expressão do receptor β1-adrenérgico no coração dos ratos estressados, sem qualquer alteração nas características do receptor β2-adrenérgico. Estes resultados podem refletir os mecanismos moleculares envolvidos no desenvolvimento de doenças cardiovasculares associadas ao tratamento com os antidepressivos.

The chromatographic behavior of seven tricyclic antidepressants (amitryptiline, clomipramine, doxepin, imipramine, maprotiline, nortryptiline, and trimipramine) was examined with micellar mobile phases containing the nonionic surfactant Brij-35. Acetonitrile-water mixtures were also used for comparison purposes. Tricyclic antidepressants are moderately polar basic drugs, which are positively charged in the usual working pH. This gives rise to a strong association with the alkyl chains and residual ionized silanols in silica-based stationary phases, which is translated in a high consumption of organic solvent to get appropriate retention times. Brij-35 modifies the surface of the stationary phases creating a neutral bilayer that masks silanols and reduces the polarity. Consequently, the retention times are decreased. A simple chromatographic procedure for the control of tricyclic antidepressants in pharmaceutical formulations was developed, using 0.02 M Brij-35 at pH 3 and UV detection. Satisfactory recoveries were achieved, with intra- and inter-day relative standard deviations usually below 1 and 2%, respectively. The preparation of the samples was simple and only required solubilization and filtration steps previous to injection. The proposed procedure has the advantage of not using an organic solvent in the mobile phase, and the biodegradable character of Brij-35. This makes an example of "green" liquid chromatographic analysis.

This study investigated the antidepressant activity of ethanolic extract ofU. lanosaWallich var.appendiculataRidsd (ULEtOH) for two-weeks administrations by using FST and TST on mice. In order to understand the probable mechanism of antidepressant-like activity of ULEtOHin FST and TST, the researchers measured the levels of monoamines and monoamine oxidase activities in mice brain, and combined the antidepressant drugs (fluoxetine, imipramine, maprotiline, clorgyline, bupropion and ketanserin). Lastly, the researchers analyzed the content of RHY in the ULEtOH. The results showed that ULEtOHexhibited antidepressant-like activity in FST and TST in mice. ULEtOHincreased the levels of 5-HT and 5-HIAA in cortex, striatum, hippocampus, and hypothalamus, the levels of NE and MHPG in cortex and hippocampus, the level of NE in striatum, and the level of DOPAC in striatum. Two-week injection of IMI, CLO, FLU and KET enhanced the antidepressant-like activity of ULEtOH. ULEtOHinhibited the activity of MAO-A. The amount of RHY in ULEtOHwas 17.12 mg/g extract. Our findings support the view that ULEtOHexerts antidepressant-like activity. The antidepressant-like mechanism of ULEtOHmay be related to the increase in monoamines levels in the hippocampus, cortex, striatum, and hypothalamus of mice.

Background/Aim. Antidepressants are a widely used class of drugs. The aim of this study was to investigate different aspects of antidepressant prescribing practice at University Psychiatric Clinic in Belgrade. Methods. This cross-sectional study was carried out by retrospective analysis of the patient's medical charts. The study included all patients with antidepressant prescribed at discharge during 2009 (n = 296). The evaluation was focused on patient- related factors (socio-demographic and illness related), psychiatrist-related factors (sex and duration of working experience) and drug related factors (type of antidepressant, dose, polypharmacy and reimbursement by national health insurance). Results. Antidepressants were prescribed for unipolar depression (F32-34, ICD X) either without comorbidity (46.2%) or with comorbidity (24.7%), mostly as a monotherapy (91% had one antidepressant), to the patients who were 65% female, aged 50.1 ± 8.9, most of them with 12 years of education (52.6%), married (69.3%) and employed (55.9%). The majority of patients had a history of two hospitalizations (Med 2; 25th-75th perc. 1-4) during nine years (Med 9; 25th-75th perc. 2-15) after the first episode of depression. Among them, 19% were found to be suicidal in a lifetime. The single most prescribed antidepressant was sertraline (20.4%), followed by fluoxetine (13.3%) and maprotiline (11.7%). Utilization of antidepressants was positively correlated with the rate of reimbursement (p < 0.01). The most prescribed antidepressant group was selective serotonin reuptake inhibitors (SSRI) (47.8%), followed by tricyclic antidepresants (TCA) (25.3%) and new antidepressants - venlafaxine, tianeptine, mirtazapine, bupropion, trazodone (15.1%). Most of the drugs were prescribed in doses which are at the lower end of the recommended dose-range. Regarding severity of the actual depressive episode, TCA were prescribed for severe depression with psychotic features, while SSRI were choice for episodes with moderate symptom severity (p = 0.01). Psychiatrists with longer working age (20-30 years) hesitated to prescribe new antidepressants in comparison to younger colleagues (p = 0.01). Conclusion. Economic issues in Serbia as developing country influence the choice of antidepressants, as well as a psychiatrist’s working age and severity of depression. However, SSRI are the drugs of the first choice, as it was shown in most of the developed countries nowadays.

Background Cholinergic urticaria is uncommon and accounts for 10% of all young adults. To date, there is no effective therapy for cholinergic urticaria.Objective To determine the therapeutic efficacy of different drug combinations in the treatment of cholinergic urticaria.Patients and Methods The participants included in the study are in the age range of 16 to 29 years, with cholinergic urticaria of any duration as diagnosed by physicians. Patients were recruited from Asthma and Allergy Centers in Baghdad and Tikrit. The selected patients were divided randomly into 3 groups according to the treatment protocol. All patients completed screening before treatment.Results The study indicated that cholinergic urticaria was completely controlled in 30.4% of patients (group A) receiving 4 mg of chlorpheniramine maleate, half hour before the exercise, plus chlordiazopoxide (5 mg) and clindium bromide (2.5 mg) tablets, 3 times daily. However, cure rate was higher (83.1%) in patients (group B) receiving 4 mg of chlorpheniramine maleate (histadine), 3 times daily, plus 25 mg of maprotiline HCl (ludiomil), once daily at night. Furthermore, the complete cure rate was 85.4% in patients (group C) receiving 4 mg of chlorpheniramine maleate (histadine)3 times daily, plus 200 mg of cimetidine (tagadine), 3 times daily. The frequency of relapse was higher in group A (89%) as compared with group B (68.4%) and group C (23.5%) (P

We evaluated the anti-depressive activity of ethanolic extracts of Gardenia jasminoides Ellis. (GJ EtOH), Gardenia jasminoides Ellis. var. grandiflora Nakai. (GJG EtOH) and geniposide with mouse forced swimming test (FST) and tail suspension test (TST). In addition, we investigated the possible mechanisms of action of anti-depressive effect of geniposide (GPO). The results showed that GJEtOH (0.1, 1.0 g/kg, p.o.) and GJG EtOH (0.1, 1.0 g/kg, p.o.) significantly reduced the immobility time of mice in both FST and TST, but they did not affect the locomotor activity of mice. Geniposide (10 mg/kg, i.p.) augmented the anti-depressive effect of desipramine (5 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) in the FST, but it did not affect the anti-depressive effect of clorgyline and maprotiline. Geniposide (10 mg/kg, i.p.) increased the levels of serotonin and 5-HIAA in striatum and serotonin in hippocampus. These results suggested that anti-depressive mechanism of GPO may be related to the increasing serotonin level in striatum and hippocampus in mice. Key words: Gardenia jasminoides Ellis., Gardenia jasminoides Ellis. var. grandiflora Nakai., geniposide, forced swimming test, anti-depressive effect, monoamines.

There is increasing interest in the pathophysiology and neurochemistry of the prefrontal cortex (PFC) in depression. Blood flow and metabolism are decreased in the PFC of patients with depression compared to controls. Changes in long-chain polyunsaturated fatty acids (PUFAs) are also associated with depression. This study was conducted to elucidate a possible role of PFC activity of an enzyme involved in the release of docosahexaenoic acid (DHA), i.e. calcium-independent phospholipase A2 (iPLA₂), in the effects of the norepinephrine reuptake inhibitor (NRI) antidepressant, maprotiline, in mice. Treatment of Balb/C mice with maprotiline for 4 wk resulted in reduction in the level of behavioural despair, as determined by decreased immobility and increased climbing during the forced swim test. In contrast, mice treated with maprotiline plus bilateral prefrontal cortical injections of antisense oligonucleotide to iPLA₂, showed significantly increased immobility and decreased climbing, to levels comparable to saline-treated controls, indicating abolishment of the antidepressant-like effect of maprotiline. Lipidomic analyses showed significant decreases in phosphatidylcholine species containing long-chain PUFAs and increases in lysophosphatidylcholine after maprotiline treatment, indicating increased PLA₂ activity and endogenous release of eicosapentaenoic acid (EPA) or DHA after maprotiline treatment. These changes in lipid profiles were absent in mice that received maprotiline and PFC injections of antisense oligonucleotide to iPLA₂. Together, the results indicate that PFC iPLA₂ activity plays an important role in the antidepressant-like effect of maprotiline, possibly through endogenous release of long-chain PUFAs.

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Aim of the review Although there are several case reports in literature linking use of antidepressants and disturbances in glucose control, it is difficult to identify risk factors for serious adverse drug events from individual case reports. The aim of this review is to provide a descriptive analysis of the demographic and clinical characteristics of published glucose dysregulation case reports following initiation of antidepressant agents. Methods Published case reports of glucose dysregulation associated with antidepressants were accessed through PubMed (Medline), PsycINFO, and Web of Science (WOS) between January 1, 1970 and April 30, 2010. The following key words were used: antidepressant agents, glucose dysregulation, hypoglycemia, hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Case reports were excluded if glucose dysregulation occurred after a drug overdose/improper dosing or after the patient was prescribed drugs known to cause glucose disturbances in addition to antidepressant agents. Results Out of the 17 cases reports reviewed, nine (53%) were of hyperglycemia while eight (47%) were of hypoglycemia. Hyperglycemia was reported following treatment with clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline. Hypoglycemia was reported following treatment with doxepine, fluoxetine, imipramine, nefazodone, nortriptyline, maprotiline, and sertraline. Fourteen out of the seventeen patients were female (82%) while ten had a history of diabetes mellitus (59%). The average age of the patients was 53.9 (SD = 17.5) years (range: 24–84 years). The time to onset of glucose dysregulation ranged from 4 days to 5 months after initiation of antidepressant therapy. More than two-thirds (68%) of the cases (n = 11) reported glucose control disturbances within 1 month of therapy. Conclusions It is not clear from published case reports whether changes in glucose regulation, following antidepressant therapy initiation are due to antidepressants or changes in mood and lifestyle. Nonetheless, healthcare providers should be aware of the potential changes in glucose regulation especially in the first month of antidepressant therapy, and use appropriate clinical and laboratory monitoring to prevent serious adverse events in patients at risk.

Noradrenaline exerts inhibitory effects on seizure susceptibility. Subtype selective agonists and antagonists were used to identify the anticonvulsant hippocampal adrenoreceptors. Intrahippocampal dialysis was used for administration of all compounds, including pilocarpine for limbic seizure induction, and as the neurotransmitter sampling tool. The noradrenaline reuptake inhibitor maprotiline mediated anticonvulsant effects, associated with dose-dependent increases in extracellular hippocampal noradrenaline, dopamine and GABA levels. At high concentrations, maprotiline produced proconvulsant effects associated with high levels of noradrenaline, dopamine and glutamate. Maprotiline's anticonvulsant effect was blocked by administration of either a selective α(2) - and β(2) -antagonist. α(2) -Antagonist administration with maprotiline was associated with a further increase in noradrenaline and dopamine from maprotiline alone; whereas β(2) -antagonist administered with maprotiline inhibited the dopamine increases produced by maprotiline. α(1A) -Antagonism blocked the GABA-ergic but not the anticonvulsive effect of maprotiline. These results were confirmed as combined but not separate α(2) - and β(2) -adrenoreceptor stimulation, using selective agonists, inhibited limbic seizures. Interestingly, α(1A) -receptor stimulation and α(1D) -antagonism alone also inhibited seizures associated with respectively significant hippocampal GABA increases and glutamate decreases. The main findings of this study are that (i) increased hippocampal noradrenergic neurotransmission inhibits limbic seizures via combined α(2) - and β(2) -receptor activation and (ii) α(1A) - and α(1D) -adrenoreceptors mediate opposite effects on hippocampal excitability.

1 Repeated maprotiline (a noradrenaline reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor) treatment on gene expression of catecholamine biosynthetic enzymes were examined in adrenal medulla of unstressed control and chronic unpredictable mild stressed rats. 2 Maprotiline did not change gene expression of catecholamine biosynthetic enzymes in control and stressed rats. 3 Fluoxetine increased gene expression of tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH), but did not phenylethanolamine N-methyltransferase in both unstressed and chronic unpredictable mild stressed animals. 4 In conclusion, we have demonstrated that repeated administration of fluoxetine enhanced gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in adrenal medulla of control and stressed rats.

To explore the site of action of maprotiline, as an atypical antidepressant, on carrageenan-induced paw edema.Male Wistar rats were used.Firstly, the anti-inflammatory effect of systemic maprotiline (12.5, 25 and 50 mg kg(-1)) was assessed using a paw edema model. Secondly, different doses of maprotiline were administrated intracerebroventricularly, intrathecally and locally before carrageenan challenge. Finally, we tried to reverse the anti-inflammatory effect of maprotiline by propranolol (10 mg kg(-1)), prazosin (4 mg kg(-1)), yohimbine (10 mg kg(-1)), naloxone (4 mg kg(-1)) and mifepristone (5 mg kg(-1)).Systemic, intracerebroventricular and subplantar application of maprotiline significantly inhibited peripheral edema, but intrathecal maprotiline did not alter the degree of paw swelling. The applied antagonists failed to change the anti-inflammatory activity of maprotiline.These results demonstrate that maprotiline has a potent anti-inflammatory effect and this effect is linked to the peripheral and supraspinal actions of the drug.

Resistance to chemotherapy is a major obstacle for the success of cancer therapy and is most commonly attributed to the inability of cancer cells to die by apoptosis, the archetypal programed cell death (PCD) response. The development of anticancer drugs that can overcome this resistance to apoptosis and induce other forms of cell death is therefore paramount for efficient cancer therapy. We report that the antidepressants maprotiline and fluoxetine induce autophagic PCD in the chemoresistant Burkitt's lymphoma (BL) cell line DG-75, which does not involve caspases, DNA fragmentation or PARP cleavage, but is associated with the development of cytoplasmic vacuoles, all consistent with an autophagic mode of PCD. Autophagic PCD was confirmed by transmission electron microscopy, upregulation of Beclin-I and the extent of PCD being reduced by the autophagic inhibitor 3-MA. In contrast, these compounds induced apoptotic PCD in the biopsy-like chemosensitive BL MUTU-I cell line. We provide evidence that the chemoresistant DG-75 cells do not express the proapoptotic Bcl-2 proteins Bax and Bak, show diminished levels of stored intracellular calcium and display shortened rod-like mitochondria, all of which are known to be associated with a defective "apoptotic" response in cancer cells. PCD in the two cell lines has different Ca(2+) responses to maprotiline and fluoxetine, which may also account for their differential PCD responses. Our study, therefore, supports a new mechanistic role for maprotiline and fluoxetine as novel proautophagic agents in the treatment of resistant BL, and thus an alternative therapeutic application for these compounds.

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

The effect of maprotiline on cytosolic free Ca2+ concentrations ([Ca2+]i) and cell viability was explored in human osteosarcoma cells (MG63), using the fluorescent dyes fura-2 and WST-1, respectively. Maprotiline at concentrations of ≥20 µM increased [Ca2+]i in a concentration-dependent manner. The Ca2+ signal was reduced partly by removing extracellular Ca2+. The maprotiline-induced Ca2+ influx was sensitive to inhibition by aristolochic acid (a phospholipase A2 inhibitor). In Ca2+-free medium, after treatment with 1 µM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor), 200 µM maprotiline failed to induce a [Ca2+]i rise. At concentrations of 50–100 µM maprotiline killed cells in a concentration-dependent manner. The cytotoxic effect of 60 µM maprotiline was slightly enhanced by prechelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Propidium iodide staining data suggested that maprotiline induced apoptosis between concentrations of 60–70 µM, which was enhanced by BAPTA. Collectively, in MG63 cells, maprotiline induced [Ca2+]i rises by causing Ca2+ release from the endoplasmic reticulum and Ca2+ influx from phospholipase A2-regulated Ca2+ channels. Furthermore, maprotiline caused apoptosis that was regulated by Ca2+. Drug Dev Res 71: 268–274, 2010. © 2010 Wiley-Liss, Inc.

Objective: To construct a model for classification of antidepressants on the basis of their binding properties to six common transporter and receptor sites. Design and methods: Receptor binding was quantified by calculating receptor/ transporter occupancy (hereafter: receptor occupancy) for the serotonin (5HT) transporter, norepinephrine (NE) transporter, 5HT2Creceptor, M3receptor, H1receptor and a, receptor. Receptor occupancy has been proven to be an appropriate measure to estimate the pharmacological effects among drugs with the same mechanism of action. To identify groups of antidepressants showing similar patterns of receptor occupancy for different receptors, hierarchical cluster analysis (HCA) and principal component analysis (PCA) were performed. To visualize (a)symmetry between binding profiles of antidepressants, radar plots were used. Results: On the basis of HCA, PCA and the radar plots, four clusters of antidepressants with similar pharmacological properties were identified. The first cluster (sertraline, fluvoxamine, escitalopram, paroxetine, venlafaxine, fluoxetine, Citalopram, duloxetine and clomipramine) included antidepressants with specific affinity for the 5HT transporter. The second cluster (amitriptyline, doxepin and Imipramine) included antidepressants with high affinity for all receptors Investigated. The third cluster (maprotiline, nortriptyline, mianserin and mirtazapine) included antidepressants with high affinity for the NE transporter, H1receptor and 5HT2Creceptor. The fourth cluster (trazodone, nefazodone, reboxetine and bupropion) was identified as group with no specific similarities. Conclusions: The use of the receptor occupancy theory combined with HCA, PCA and radar plots is a useful method to visualize (a)symmetry in binding profiles of antidepressants. It could be a helpful tool in evidence-based practice, selecting the right antidepressant for the right patient, and may be used in pharmacovigilance as a prediction model for adverse effects of novel drugs entering the market.

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.

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Maprotiline (N-methyl-9,10-ethanoanthracene-9(10H)-propanamine) is a tetra cyclic antidepressant. It is a highly selective inhibitor of norepinephrine reuptake. The solid and solution in CCl4 and methanol infrared spectra of maprotiline were recorded. The fully optimized equilibrium structure of maprotiline was obtained from DFT calculations by using the B3LYP functional in combination with 6-31G and 6-311G(d,p) basis sets. The results of harmonic and anharmonic frequency calculations on maprotiline were presented. The vibrational spectra were interpreted, with the aid of normal coordinate analysis based on a scaled quantum mechanical (SQM) force field. Vibrational assignment of all the fundamentals was made using the total energy distribution (TED). The possible interaction between maprotiline and neurotransmitter serotonin (5-HT) were investigated.

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.

A universal gas chromatographic method for the determination of the most commonly used antidepressant drugs in I ml of serum is described. Prior to extraction the samples were washed with hexane at acid pH. After the hexane wash the drugs were extracted into hexane at pH approximately 10, and subsequently reextracted from the hexane into a 1% solution of formic acid in methanol. The methanolic phase was evaporated, the residue dissolved in isopropanol and analysed by gas chromatography with nitrogen detection on a 3% OV-225 column. Recoveries for amitriptyline, nortriptyline, clomipramine, desmethylclomipramine, doxepin, desmethyldoxepin, imipramine, desipramine, maprotiline, protriptyline, trimipramine and desmethyl-trimipramine were found to be 80% or higher. Limits of detection were found to be 5–10 ng/ml for tertiary amines and 10–20 ng/ml for secondary amines. Interferences from some common basic drugs were investigated as well as interferences between different antidepressant drugs. Gas chromatographic data are given for 28 drugs and metabolites.

Influence of previous stress exposure on the effects of serotonergic and noradrenergic antidepressants on subsequent newly induced stress is still far from being completely understood. The aim of the present study was to investigate changes in the activity of the sympatho-adrenomedullary system in unstressed and chronic unpredictable mild stressed (CUMS) rats treated with either maprotiline or fluxilan, both under basal conditions and subsequent immobilization stress. Maprotiline and fluxilan elevated plasma norepinephrine in unstressed control and CUMS rats. Immobilization increased norepinephrine less in unstressed maprotiline- or fluxilan controls than in vehicle group. Subsequent immobilization elevated norepinephrine in CUMS rats the differences between the groups being insignificant. Maprotiline didnt affect epinephrine in unstressed and CUMS rats and fluxilan increased it. Subsequent immobilization elevated epinephrine in unstressed maprotiline controls less than in vehicle animals. Epinephrine increase was similar in maprotiline CUMS and vehicle CUMS rats. Immobilization of fluxilan unstressed and CUMS rats significantly increased epinephrine but without differences compared to vehicle group. Novel stressor activated sympatho-adrenomedullary system of CUMS rats upon antidepressants. (c) 2008 Elsevier B.V. All rights reserved.

A method for the simultaneous determination of six commonly prescribed cyclic antidepressants and their major metabolites in urine is presented. This method can be used for quantitation of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, desmethyldoxepin, and maprotiline in human urine, in addition to the qualitative determination of their hydroxylated metabolites. This method is suitable for confirmation of drug abuse in health care professionals and overdose cases where the identity of the abused cyclic antidepressant may not be known. Samples are spiked with internal standard and hydrolyzed with beta-glucuronidase from Escherichia coli. Hydrolysis is found to be essential to the extraction procedure as the tertiary cyclic antidepressants are found to be extensively conjugated in urine. The secondary cyclic antidepressants, on the contrary, are found to be minimally conjugated. Drugs are extracted from alkalinized urine into solvent and derivatized with MSTFA/ammonium iodide/ethanethiol reagent. This reagent produces more stable derivatives compared to reagents previously employed. Gas chromatographic (GC)-mass spectrometric analysis is performed in electron ionization mode by selective ion monitoring, using hydrogen as a carrier gas, a short narrow bore GC capillary column, and fast temperature program, allowing for a rapid analytical cycle. While maintaining specificity for these drugs, concentrations in human urine ranging from 50 to 20,000 ng/mL can be measured with intraday and interday precisions, expressed as variation coefficient, of less than 2.8% for all analytes.

Maprotiline, an atypical antidepressant, can induce prolonged QT andtorsades de pointes. We studied the effects of maprotiline on humanether- a- go- go-related gene(HERG) channels expressed inXenopus oocytes and HEK293 cells. Maprotiline induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and tail currents of HERG. The V1/2 values in the absence and presence of 1–20 μM maprotiline were not significantly different, while the values decreased according to the concentrations of the drug at 50–300 μM. The IC50 for a maprotiline block of HERG current inXenopus oocytes did not change according to depolarization; 39.5 ± 3.2 (μM at -40 mV and 43.6 ± 2.8 μM at +40 mV. The block of HERG by maprotiline was examined after treatment of trinitrobenzene sulfonic acid (TNBS), an amino-group reagent that neutralizes the positively charged amino-groups of peptide N-terminal and lysine residues. TNBS inhibited the change of V1/2 values induced by 50–300 mM maprotiline, and aggravated the drug-induced gmax decrease. The IC50 for the maprotiline-induced blockade of HERG currents in HEK293 cells at 36°C was 0.13 nM at +20 mV. Our findings suggest that the arrhythmogenic side effects of maprotiline are caused by a blockade of HERG and possibly by a blockade of delayed rectifier K+ channel.

Serotonin and noradrenaline are involved in the mechanisms of action of most antidepressant drugs. We examined the effects of chronic treatment with maprotiline, a selective inhibitor of noradrenaline reuptake, and fluxilan, a selective inhibitor of serotonin reuptake, on the behavior of unstressed controls and chronic unpredictable mild stress (CUMS) model rats in the forced swim test (FST) and elevated plus maze test. Both selective reuptake inhibitors resulted in a significant reduction of time spent in immobility. Climbing was significantly increased in maprotiline- and swimming was exclusively elicited in the fluxilan-treated unstressed control and CUMS rats. Maprotiline-treated ani?mals displayed decreased anxiety and fluxilan-treated rats enhanced anxiety. The obtained results suggest that central noradrenergic and serotonergic systems might be affected differently during FST. The results also demonstrate that the anxiogenic effects of chronic fluxilan treatment are similar to those reported by many other studies. These differences observed for the effects of fluxilan in relation to those reported for maprotiline and probably due to the different phar?macological profiles of these drugs.

To investigate the effects of antidepressants on glucose-insulin homeostasis, we provided homogenous situation and performed standard procedures to assess the interactions of antidepressants and glucose regulation during hospitalization.Twenty-three non-diabetic depressed males were recruited and assigned to two groups based on the antidepressants received (maprotiline n=11, fluoxetine n=12). The severity of depression was evaluated using a 21-item Hamilton depression rating scale (HAM-D). Before and after the 4-week treatment, participants underwent 75-g oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response (AIR), and disposition index (DI) were estimated using minimal model method.The HAM-D scores were reduced significantly (P0.005) after antidepressant treatment. Following maprotiline treatment, the body weight and BMI were significantly increased (P=0.02). Individuals treated with maprotiline displayed a significantly increased AIR (3239+/-682 vs. 4698+/-597 pmol; P=0.04) during the FSIGT.The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course.The results suggest that the beta-cell function is hyperbolic in order to offset the insulin resistance following maprotiline treatment. Our findings imply that norepinephrine reuptake inhibitor (NRI) antidepressants might attenuate insulin sensitivity.

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 μmol/L) flattened the concentration–response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 μmol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration–response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 ± 0.1) > clomipramine (pA2, 7.0 ± 0.1) > fluoxetine (pKB, 6.5 ± 0.1) = mibefradil (pKB, 6.6 ± 0.1) > amitriptyline (pKB, 6.3 ± 0.1) = maprotiline (pKB, 6.2 ± 0.1) > fluvoxamine (pKB, 5.9 ± 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.

The present study was undertaken to investigate the spontaneous epileptiformic activity induced by antidepressants using amygdala-kindled rats. The intraperitoneal injection of imipramine and amitriptyline resulted in potent behavioral and electroencephalogram (EEG)-detected seizures in amygdala-kindled rats compared with those seen in sham rats (non-kindled rats). Almost the same findings were observed with clomipramine and maprotiline. On the other hand, paroxetine caused no or little behavioral or EEG seizures in either amygdala-kindled or sham rats, even at a dose of 50 mg/kg. In conclusion, our results indicate that epileptiformic activity induced by kindling increases the susceptibility to cyclic antidepressant-induced seizures.

D- and L-amphetamine sulphate isomers, methylphenidate and atomoxetine, are effective treatments for attention-deficit hyperactivity disorder (ADHD). This study provides a detailed comparison of their effects on the synaptosomal and vesicular accumulation of dopamine (DA) and noradrenaline (NA) and release in vitro in rat prefrontal cortex and striatum. D-amphetamine was more potent than L-amphetamine at inhibiting accumulation of DA or NA in synaptosomes and vesicles. All drugs were weaker at inhibiting the accumulation of vesicular DA and NA compared to synaptosomal accumulation and more potently inhibited NA accumulation than DA. Methylphenidate was weak at inhibiting vesicular accumulation of DA and NA compared to its potent synaptosomal effects. The D-isomer had greater potency than the L-isomer on basal and electrically stimulated striatal DA release; however the L-isomer was 2-fold more potent than the D-isomer on basal fronto-cortical NA release. The selective DA reuptake inhibitor, GBR-12909 and NA reuptake inhibitors, maprotiline and atomoxetine, had different release profiles both on the potency and magnitude of basal and stimulated DA and NA release compared to the amphetamine isomers. These results identify distinct pharmacological action by the amphetamine isomers on dopaminergic and noradrenergic neurotransmission, which may impact on their therapeutic effects in the treatment of ADHD.

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.

Introduction: Treatment effect of maprotiline at different doses (50-150 mg/d) as a tetracyclic antidepressant, with major effects on NEP and less anticholinergic side effects compared to some other tricyclic medications, has been compared with other medications. Given ethical and cultural differences as well as pharmacokinetic characteristics between Iranian populations, the current study was carried out to determine the effect of different doses of maprotiline in treatment of moderate MDD, its therapeutic ratio and related side effects in each dose, and also to define the effective dose of maprotiline. Materials and Methods: This quasi-experimental study was performed on the patients with moderate MDD who referred to psychiatry clinics. Thirty cases were selected from the patient with age between 25-50 years, with 20≤ BMI≤30, and without any systemic diseases. Firstly, HAMD-17 test was performed for all subjects and then they took 50mg/d of maprptiline. After two weeks, the subjects were visited again, in case of HAMD-17 < 50%, they received 25mg/d of maprotiline for another two more weeks until their depression was completely treated. Side effects were also checked at two-week intervals. Finally, the number of cured subjects, side effects and effective dose were defined. Results: 27 out of 30 patients were followed up to the end of the study. They included 15 women (55.5%) and 12 men (44.4%) with mean age of 36.2±2.3 years. In dose of 50mg/d , 5 out of 27, in dose of 75 mg/d, 11 out of 22,in dose of 100mg/d, 6 out of 11 ,in dose of 125 mg/d ,3 out of 5 and finally in dose of 150mg/d the remaining 2 patients were cured. With respect to side effects, dry mouth was seen in 8 out of 22 patients received a dose of 75 mg/d and 7 out of 11 patients given a dose of 100mg/d. A significant difference was observed between the mean effective doses in the patients with past history of depression (105 mg/d) in comparison with patients without previous history of Depression (76.5mg/d) (P-value=0.01). The mean effective dose was calculated as 78.03 mg/d. Conclusion: The highest frequency of cure was seen in doses of 75 mg/d and 100mg/d with mean of 78.03 mg/d. Furthermore, the mean effective dose in the patients with a previous history of depression was higher than those without a previous history of depression. In addition, side effects were increased with higher doses of maprotiline. Regarding the restrictions of this study such as the lower number of samples in higher doses, further studies are essential to be conducted in this field.

A simultaneous determination of 20 antidepressant drugs (imipramine, amitriptyline, desipramine, trimipramine, nortriptyline, clomipramine, amoxapine, lofepramine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipran, sulpiride, tandspirone, methylphenidate and melitracen) in human plasma was developed using LC/MS with sonic spray ionization (SSI) method. These drugs showed good separation and sensitivity by LC–MS using an Inertsil C-8 column with methanol:10 mM ammonium acetate (pH 5.0):acetonitrile (70:20:10) as mobile phase at 0.10 mL/min at 35 °C. Solid-phase extraction of these drugs added to the human plasma was performed with an Oasis ® HLB cartridge column. Recovery and limit of detection of these drugs were between 69 and 102% and between 0.03 and 0.63 μg/mL, respectively. The present procedure offers an easier and more convenient screening method for antidepressants, and will be useful for forensic toxicology investigations.