Central and peripheral anti-inflammatory effects of maprotiline on carrageenan-induced paw edema in rats.

OBJECTIVE: To explore the site of action of maprotiline, as an atypical antidepressant, on carrageenan-induced paw edema. SUBJECTS: Male Wistar rats were used. METHODS: 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)). RESULTS: 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. CONCLUSION: 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.

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

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.

TMD chronic pain and masseter silent period in psychiatric patients on antidepressive therapy.

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.

Comparisons of glucose-insulin homeostasis following maprotiline and fluoxetine treatment in depressed males.

BACKGROUND: 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. METHODS: 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. RESULTS: The HAM-D scores were reduced significantly (P<0.005) 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. LIMITATIONS: The sample size was limited. Furthermore, the study was conducted in the early phase of depression-treated course. CONCLUSIONS: 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.

Primidone inhibits TRPM3 and attenuates thermal nociception in vivo.

The melastatin-related transient receptor potential (TRP) channel TRPM3 is a nonselective cation channel expressed in nociceptive neurons and activated by heat. Because TRPM3-deficient mice show inflammatory thermal hyperalgesia, pharmacological inhibition of TRPM3 may exert antinociceptive properties. Fluorometric Ca influx assays and a compound library containing approved or clinically tested drugs were used to identify TRPM3 inhibitors. Biophysical properties of channel inhibition were assessed using electrophysiological methods. The nonsteroidal anti-inflammatory drug diclofenac, the tetracyclic antidepressant maprotiline, and the anticonvulsant primidone were identified as highly efficient TRPM3 blockers with half-maximal inhibition at 0.6 to 6 µM and marked specificity for TRPM3. Most prominently, primidone was biologically active to suppress TRPM3 activation by pregnenolone sulfate (PregS) and heat at concentrations markedly lower than plasma concentrations commonly used in antiepileptic therapy. Primidone blocked PregS-induced Cai influx through TRPM3 by allosteric modulation and reversibly inhibited atypical inwardly rectifying TRPM3 currents induced by coapplication of PregS and clotrimazole. In vivo, analgesic effects of low doses of primidone were demonstrated in mice, applying PregS- and heat-induced pain models, including inflammatory hyperalgesia. Thus, applying the approved drug at concentrations that are lower than those needed to induce anticonvulsive effects offers a shortcut for studying physiological and pathophysiological roles of TRPM3 in vivo.

[Clinical observation on effect of danzhi xiaoyao powder in treating depression].

OBJECTIVE: To observe the effect and side effect of Danzhi Xiaoyao powder (DXP) in treating depression. METHODS: 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. RESULTS: 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 (P > 0.05). The scores of HAMD, SDS and SAS of both groups were remarkably lowered after therapy (P < 0.05). However, the score of Asberg in CMG was lower than that in WMG (P < 0.05). CONCLUSION: DXP shows the effect equivalent to that of maprotiline, but with obviously less side-effect.

Analysis of the anti-allodynic effects of combination of a synthetic cannabinoid and a selective noradrenaline re-uptake inhibitor in nerve injury-induced neuropathic mice.

BACKGROUND: Combining drugs not only reduces specific adverse effects of each of the drug at a higher dose but also may lead to enhanced efficacy. Tapentadol is a recently discovered analgesic possessing µ-opioid receptor agonism and noradrenaline re-uptake inhibition in a single molecule. Taking into consideration, the pharmacological similarities between opioids and cannabinoids, we assumed that combination of cannabinoids with noradrenaline re-uptake inhibitors might also be effective. We therefore aimed to determine whether combining 1:1, 1:3 and 3:1 fixed ratios of the synthetic cannabinoid WIN 55,212-2 and the selective noradrenaline re-uptake inhibitor maprotiline exert anti-allodynic synergy on nerve-injured neuropathic mice. METHODS: Partial tight ligation of the sciatic nerve was made in mice; on pre-operative and post-operative 15 days basal mechanical allodynia, cold allodynia and motor function were assessed using von Frey filaments, hot/cold plate and rota rod apparatus. RESULTS: Mechanical and cold allodynia developed in all groups on post-operative 15 days. Development of cold allodynia was statistically significant in all groups (p < 0.05); therefore, cold allodynia was used in combination studies. As shown by isobolographic analysis, interactions of 1:1 and 3:1 ratios of WIN 55,212-2:maprotiline combinations were supra-additive, whereas 1:3 ratio was sub-additive. CONCLUSIONS: Overall, our data suggest that combination of a cannabinoid with a selective noradrenaline re-uptake inhibitor may offer a beneficial treatment option for neuropathic pain.

Screen of FDA-approved drug library identifies maprotiline, an antibiofilm and antivirulence compound with QseC sensor-kinase dependent activity in Francisella novicida.

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.

Concurrent use of antidepressants and propranolol: case report and theoretical considerations.

The therapeutic indications for propranolol have been steadily increasing in recent years. Propranolol and other beta-adrenergic blocking agents are now generally acknowledged to be helpful in the management of hypertension, certain cardiac arrhythmias, migraine, essential tremor, angina pectoris, and most recently, immediately after myocardial infarction (Frishman, 1981; Norwegian Multicenter Study Group, 1982). Because of the myriad clinical settings in which propranolol has been found to be of benefit, the interactions of these drugs with other commonly utilized pharmacological agents is of great pragmatic interest. In this report we describe the successful concomitant clinical use of propranolol and an antidepressant drug. This finding is also of interest because of recent theories concerning the mechanism of action of antidepressant drugs. Because propranolol readily penetrates into the CNS, it blocks beta-adrenergic receptors in both the periphery and the CNS (Weiner, 1980). Much attention has been focused recently on the effects of long-term antidepressant therapy on central beta-adrenergic receptors in the brain as a possible mechanism of action of these drugs. The concurrent use of propranolol and an antidepressant drug in the patient described in this report did not attenuate the therapeutic effects of the antidepressant.

A clinical test of noradrenergic involvement in the therapeutic mode of action of an experimental antidepressant.

The noradrenaline (NA) hypothesis of depression is founded primarily on preclinical and clinically indirect evidence. In two three-compartment randomized parallel clinical trials conducted serially, we examined the significance of NA uptake for antidepressant activity. The racemic compound oxaprotiline (hydroxymaprotiline) is a highly specific inhibitor of NA uptake, whereas its R-(-) enantiomer levoprotiline is totally devoid of this property. Oxaprotiline significantly resembled amitriptyline in its antidepressant potential. Conversely, levoprotiline significantly resembled placebo in antidepressant potential. Therefore, NA uptake was necessary for the observed therapeutic effect of this experimental antidepressant.

Prolactin in patients with major depressive disorder and in healthy subjects. II. Longitudinal study of basal prolactin and post-TRH-stimulated prolactin levels.

Longitudinal investigations of basal prolactin (PRL) and prolactin concentrations following thyrotopin-releasing hormone (TRH) stimulation (delta PRL) were conducted in 17 patients with major depressive disorder and healthy subjects. The patients were being treated with either clomipramine or maprotiline. Both basal and delta PRL increased significantly after clinical response during treatment with both drugs. However, these increases in basal and delta PRL were independent of each other. Surprisingly, elevations of basal PRL were significantly greater in responders than in nonresponders, whereas those in delta PRL showed no corresponding significant difference. These results suggest that the two drugs stimulate basal and delta PRL by different mechanisms. The increases in basal prolactin levels found in responders may possibly be due to weaker inhibition of prolactin due to "down-regulated" beta adrenergic receptors and/or enhanced activity of supersensitive serotonergic receptors. Neither basal PRL nor delta PRL proved to be a predictor of therapy response. The intraindividual retest reliabilities of both basal and delta PRL in healthy subjects was so good that a single blood sample would seem to be sufficient for investigating most issues involving PRL in psychiatric patients.

Plasma free 3-methoxy-4-hydroxyphenylglycol predicts response to fluoxetine.

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 fluoxetine 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 fluoxetine responders and nonresponders, but no significant changes were found in the maprotiline treatment groups. On the other hand, MHPG levels in the fluoxetine nonresponders tended to increase (borderline significance), whereas the MHPG levels for fluoxetine responders and maprotiline responders and nonresponders were unaffected from pre- to posttreatment. Pretreatment levels of plasma free MHPG appear to predict response to fluoxetine.

Does platelet serotonin receptor supersensitivity accompany endogenous depression?

In a population of drug-free bipolar and unipolar depressed women, it was found that the concentration of serotonin sufficient to induce half-maximal shape change velocity in platelets is significantly (p less than 0.001) lower (0.13 +/- 0.0.04 microM) than that of closely matched controls (0.532 +/- 0.1 microM). This platelet concentration becomes higher after 1-3 months of antidepressant treatment (0.47 +/- 0.16 microM). Possible mechanisms for this up- or down-regulation of platelet serotonin receptor responsiveness are discussed.

MHPG as a predictor of antidepressant response to imipramine and maprotiline.

To explore the hypothesis that depressed patients with low pretreatment levels of urinary 3-methoxy-4-hydroxyphenylglycol (MHPG) respond more favorably to antidepressant drugs which act on noradrenergic neuronal systems than do patients with high MHPG levels, the authors administered 150--200 mg/day of imipramine or maprotiline to 13 depressed patients. All of the 5 patients with low pretreatment MHPG levels responded to treatment compared with 1 of the 14 patients with high MHPG levels; 4 patients dropped out of the study.

Incidence of seizures with tricyclic and tetracyclic antidepressants.

One hundred eighty-six depressed psychiatric inpatients were seen at our institution during 1982. Forty-five of these patients were treated with tricyclic antidepressants, 32 received maprotiline hydrochloride, a tetracyclic compound, 20 received other medications, and 82 received no drug treatment. One patient in the tricyclic group (2.2%) and five patients in the maprotiline group (15.6%) developed seizures. In four patients the seizure followed the institution of maprotiline therapy by less than three weeks. These data indicate that depressed patients taking the tetracyclic drug maprotiline are at risk for developing epileptic seizures.

Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, crossover trial.

Amitriptyline (AT) relieves some patients with postherpetic neuralgia (PHN). Many patients suffer side effects and better therapies are necessary. The aim of this study was to evaluate the efficacy of maprotiline (MT) (noradrenergic) compared to AT (mixed noradrenergic and serotonergic) in this disorder. Thirty-five patients entered a randomized, double-blind, crossover trial of these two agents. We found that MT relieved PHN in many patients but was not as effective as AT. Side effects were troublesome with both agents. Relief of steady pain, brief pain and pain on tactile stimulation occurred. Four groups of responses were identified. Some patients reported relief with both agents, some with neither agent and others with only one of the drugs. Most patients were not depressed and analgesia was observed to occur without change in depression ratings in most patients who responded. This result provides evidence that in some patients AT may act via a selective noradrenergic mechanism in relieving PHN and that individuals may differ in the balance and type of neurotransmitters inhibiting pain. Selective noradrenergic agents may be effective if AT fails.

Effects of noradrenergic and serotonergic antidepressants on chronic low back pain intensity.

To understand the relative efficacy of noradrenergic and serotonergic antidepressants as analgesics in chronic back pain without depression, we conducted a randomized, double-blind, placebo-control head-to-head comparison of maprotiline (a norepinephrine reuptake blocker) and paroxetine (a serotonin reuptake blocker) in 103 patients with chronic low back pain. Of these 74 completed the trial; of the 29 who did not complete, 19 were withdrawn because of adverse effects. The intervention consisted of an 8-week course of maprotiline (up to 150 mg daily) or paroxetine (up to 30 mg daily) or an active placebo, diphenhydramine hydrochloride (up to 37.5 mg daily). Patients were excluded for current major depression. Reduction in pain intensity (Descriptor Differential Scale scores) was significantly greater for study completers randomized to maprotiline compared to placebo (P=0.023), and to paroxetine (P=0.013), with a reduction of pain by 45% compared to 27% on placebo and 26% on paroxetine. These results suggest that at standard dosages noradrenergic agents may provide more effective analgesia in back pain than do selective serotonergic reuptake inhibitors.

The serotonin reuptake inhibitor paroxetin is superior to the noradrenaline reuptake inhibitor maprotiline in the treatment of premenstrual syndrome.

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.

Effects of antidepressant drugs on a quickly-learned conditioned-suppression response in mice.

Mice experienced to electric shock, exhibited a marked suppression of motor activity when placed in the same cage 24 hr after administration of shocks. Acute administration of imipramine-HCl (10 mg/kg, i.p.), desipramine-HCl (5 and 10 mg/kg, i.p.) and amitriptyline-HCl (5 and 10 mg/kg, i.p.) caused marked reduction of the conditioned suppression of shocked mice, but reduced the motor activity of the non-shocked mice. Maprotiline, mianserin and dimetacrine did not cause reduction of the conditioned suppression. Nialamide (100 mg/kg, i.p.) and pargyline-HCl (100 and 200 mg/kg, i.p.) caused marked reduction of the conditioned suppression but did not increase the motor activity of the non-shocked mice, and tranylcypromine-HCl (10 and 20 mg/kg, i.p.) did not cause reduction of the conditioned suppression. Diphenhydramine-HCl (10 and 20 mg/kg, i.p.) reduced the conditioned suppression of shocked mice in a dose-related manner. Chronic administration of imipramine-HCl (1 and 5 mg/kg, i.p.) for 14 days significantly reduced the conditioned suppression but did not influence the motility rate of the non-shocked mice. Also, chronic administration of amitriptyline (1 mg/kg, i.p.), desipramine (5 mg/kg, i.p.) and dimetacrine (10 mg/kg, i.p.), for 10 days, significantly reduced the conditioned suppression, but did not influence the motility rate of the non-shocked mice. Chronic administration of maprotiline reduced the conditioned suppression. On the other hand, chronic administration of mianserin (5 mg/kg, i.p.) and diphenhydramine (10 mg/kg, i.p.) did not cause a reduction of the conditioned suppression.