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Concept: Imipramine

27

Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca2+, which interacts with calmodulin to subsequently activate nitric oxide (NO) synthase. We hypothesised that uncoupling nNOS from the NMDA-R through the scaffolding protein PSD-95 would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the FST and TST following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg) the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.Neuropsychopharmacology accepted article preview online, 27 February 2013; doi:10.1038/npp.2013.57.

Concepts: Hypothesis, Nitric oxide, Antidepressant, Selective serotonin reuptake inhibitor, Tricyclic antidepressant, Imipramine, Tricyclic

25

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8min. The assay was linear in the range 20-500µg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and<15% at other concentrations. The initial LLOQ was 20µg/L however for CMP and DMCP it was increased to 40µg/L. The blood volume per spot did not influence the results, but a low hematocrit (≤ 30%) was associated with a>15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method.

Concepts: Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Tricyclic antidepressant, Norepinephrine reuptake inhibitor, Imipramine, Monoamine oxidase inhibitor, Tricyclic antidepressants

24

Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: -0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant.

Concepts: Effect size, Antidepressant, Selective serotonin reuptake inhibitor, Sertraline, Tricyclic antidepressant, Imipramine

14

BACKGROUND: This systematic review describes a comparison between several standard treatments for major depressive disorder (MDD) in adult outpatients, with a focus on interpersonal psychotherapy (IPT). METHODS: Systematic searches of PubMed and PsycINFO studies between January 1970 and August 2012 were performed to identify (C-)RCTs, in which MDD was a primary diagnosis in adult outpatients receiving individual IPT as a monotherapy compared to other forms of psychotherapy and/or pharmacotherapy. RESULTS: 1233 patients were included in six eligible studies, out of which 854 completed treatment in outpatient facilities. IPT combined with nefazodone improved depressive symptoms significantly better than sole nefazodone, while undefined pharmacotherapy combined with clinical management improved symptoms better than sole IPT. IPT or imipramine hydrochloride with clinical management showed a better outcome than placebo with clinical management. Depressive symptoms were reduced more in CBASP (cognitive behavioral analysis system of psychotherapy) patients in comparison with IPT patients, while IPT reduced symptoms better than usual care and wait list condition. CONCLUSIONS: The differences between treatment effects are very small and often they are not significant. Psychotherapeutic treatments such as IPT and CBT, and/or pharmacotherapy are recommended as first-line treatments for depressed adult outpatients, without favoring one of them, although the individual preferences of patients should be taken into consideration in choosing a treatment.

Concepts: Psychology, Cognitive behavioral therapy, Major depressive disorder, Seasonal affective disorder, Types of psychological depression, Family therapy, Imipramine, Interpersonal psychotherapy

7

Alzheimer’s disease (AD) is a major and devastating neurodegenerative disease, and the amyloid-β (Aβ) hypothesis is still the central theory for AD pathogenesis. Meanwhile, another major mental illness, depression, is one of the risk factors for AD. From a high-throughput screening (HTS), amoxapine, a typical secondary amine tricyclic antidepressant (TCA), was identified to reduce Aβ production. A follow-up investigation on antidepressants showed that most of the TCAs harbour similar activity. Previous studies have indicated that TCAs improve cognitive function in AD mouse models as well as in preliminary clinical data; however, the underlying mechanism is controversial, and the effect on Aβ is elusive. Thus, we developed a secondary screening to determine the molecular target of amoxapine, and serotonin receptor 6 (HTR6) was identified. Knockdown of HTR6 reduced the amoxapine’s effect, while the HTR6 antagonist SB258585 mimicked the activity of amoxapine. Further mechanistic study showed that amoxapine and SB258585 reduced Aβ generation through multiple HTR6-mediated targets, including β-arrestin2 and CDK5. Taken together, our study suggests that amoxapine, though no longer a first-line drug for the treatment of depression, may be beneficial for AD and further structural modification of TCAs may lead to desirable therapeutic agents to treat both AD and depression.

Concepts: Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Norepinephrine, Tricyclic antidepressant, Norepinephrine reuptake inhibitor, Imipramine, Tetracyclic antidepressant

7

The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y12, potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y12 inhibitors may have applicability for treating glioma.

Concepts: Protein, Gene, Glioma, Antidepressant, Selective serotonin reuptake inhibitor, Tricyclic antidepressant, Imipramine, Tricyclic

7

A critical issue in drug development is developing effective, non-invasive delivery routes to the central nervous system (CNS). Major depressive disorder (MDD) is an illness associated with significant morbidity. Even with multiple antidepressant trials, 10-15% of patients continue to experience persistent depressive symptoms. We previously developed an interfering peptide that has antidepressant-like effects in rats when injected directly into brain. To be clinically viable, it must demonstrate efficacy via a non-invasive administration route. We report here that the interfering peptide designed to disrupt the interaction between the D1 and D2 dopamine receptors can be delivered to relevant brain areas using the Pressurized Olfactory Device (POD), a novel intra-nasal delivery system developed by Impel NeuroPharma. We validate this delivery method by demonstrating that, at doses greater than or equal to 1.67 nmol/g, the D1-D2 interfering peptide, has a significant antidepressant-like effect comparable to that of imipramine in the forced swimming test (FST), a common test for antidepressant efficacy. The antidepressant-like effect of the interfering peptide can be detected for 2 h after intranasal administration. Furthermore, we show that the interfering peptide disrupts the D1-D2 interaction and it can be detected in the prefrontal cortex after intranasal administration. This study provides strong preclinical support for intranasal administration of the D1-D2 interfering peptide as a new treatment option for patients suffering from MDD.Neuropsychopharmacology accepted article preview online, 17 March 2014; doi:10.1038/npp.2014.61.

Concepts: Central nervous system, Nervous system, Brain, Human brain, Serotonin, Bipolar disorder, Major depressive disorder, Imipramine

6

The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2-3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.Molecular Psychiatry advance online publication, 17 December 2013; doi:10.1038/mp.2013.155.

Concepts: Human brain, Hippocampus, Neurogenesis, Serotonin, Antidepressant, Selective serotonin reuptake inhibitor, Major depressive disorder, Imipramine

6

High rates of early relapse following electroconvulsive therapy (ECT) are typically reported in the literature. Current treatment guidelines offer little information to clinicians on the optimal nature of maintenance therapy following ECT. The aim of this study was to provide a systematic overview of the existing evidence regarding post ECT relapse. A keyword search of electronic databases was performed for studies appearing in the peer-reviewed literature before January 2013 reporting on relapse rates in responders to an acute course of ECT administered for a major depressive episode. Meta-analyses were performed where appropriate. Thirty-two studies with up to two years' duration of follow-up were included. In modern-era studies of continuation pharmacotherapy, 51.1% (95% CI=44.7-57.4%) of patients relapsed by 12 months following successful initial treatment with ECT, with the majority (37.7%, 95% CI=30.7-45.2%) relapsing within the first six months. The six-month relapse rate was similar in patients treated with continuation ECT (37.2%, 95% CI=23.4-53.5%). In randomised controlled trials, antidepressant medication halved the risk of relapse compared to placebo in the first six months (risk ratio=0.49, 95% CI=0.39-0.62, p<0.0001, number needed to treat=3.3). Despite continuation therapy, the risk of relapse within the first year following ECT is substantial, with the period of greatest risk being the first six months. The largest evidence base for efficacy in post ECT relapse prevention exists for tricyclic antidepressants. Published evidence is limited or non-existent for commonly used newer antidepressants or popular augmentation strategies. Maintenance of well-being following successful ECT needs to be improved.Neuropsychopharmacology accepted article preview online, 18 June 2013; doi:10.1038/npp.2013.149.

Concepts: Randomized controlled trial, Antidepressant, Selective serotonin reuptake inhibitor, Bipolar disorder, Major depressive disorder, Tricyclic antidepressant, Electroconvulsive therapy, Imipramine

4

Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in part in the pharmacokinetic phase.

Concepts: Nervous system, Brain, Antidepressant, Selective serotonin reuptake inhibitor, Sertraline, Tricyclic antidepressant, Fluoxetine, Imipramine