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Chronic treatment with clomipramine, a tricyclic antidepressant drug, reduces symptoms of obsessive-compulsive disorder (OCD) and can influence the activity of the hypothalamic-pituitary-adrenal axis. However, little is known regarding the effects of acute clomipramine on the immediate expression of stress responses. Serotonergic drugs can elicit surfacing, a behavioral profile potentially related to toxicity in fish, although surfacing has not yet been observed after clomipramine exposure. The present study investigated the impact of acute exposure to clomipramine on basal and stress-induced behaviors in the novel tank test and cortisol levels in mixed-sex, wild-type, adult zebrafish ( Danio rerio ). The findings show clomipramine-exposed groups (regardless of stress exposure) spent much more time in the top of the novel tank and had significantly less overall motor activity in the behavioral task compared to the fish not exposed to the drug. Then, the dose-dependent effects of acute clomipramine on activity in the surface of the novel tank (top third of the top half) were investigated further. Clomipramine dose-dependently increased surface-dwelling and elicited a dose-dependent hypoactivity in overall motor behavior. There were no statistically significant differences in whole-body cortisol levels in either experiment. Like other serotonin-acting drugs, clomipramine strongly elicited surface-dwelling and depressed motor behavior in adult zebrafish. Additional testing is needed to elucidate whether surfacing represents a toxic state and how serotonin regulates surfacing., Competing Interests: The authors declare there are no competing interests., (©2024 Shafiq et al.)

Background: Molecular mechanisms of depression remain unclear. The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Rats were exposed to chronic ultrasound stress and treated with intranasal and intraperitoneal clomipramine. We then analyzed 28 metabolites in the frontal cortex and hippocampus., Methods: Rats' behavior was identified in such tests: social interaction, sucrose preference, forced swim, and Morris water maze. Metabolic analysis was performed with liquid chromatography., Results: After ultrasound stress pronounced depressive-like behavior, clomipramine had an equally antidepressant effect after intranasal and intraperitoneal administration on behavior. Ultrasound stress contributed to changes of the metabolomic pathways associated with pathophysiology of depression. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should also be evaluated from this point of view.

In recent years, the use of skeletal tissue as an alternative matrix in forensic toxicology has received new interest. In cases where extreme decomposition has taken place, analysis of skeletal tissue is often the only option left. In this article, a fully validated method is presented and the distribution of clomipramine, citalopram, midazolam, and metabolites after chronically administration is examined within skeletal tissue. Rats were chronically dosed with respectively clomipramine, citalopram, or midazolam. Extracts were quantitatively analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Clomipramine, citalopram, and metabolites, respectively desmethylclomipramine and desmethylcitalopram are shown to be detectable in all bone types sampled. Midazolam and its metabolite α-OH-midazolam could not be detected. The absence of midazolam in extracts gives an indication that drugs with pKa values under physiological pH are badly or not incorporated in bone tissue. Bone and post-mortem blood concentrations were compared. A range of different bone types was compared and showed that the concentration is strongly dependent on the bone type. In concordance with previous publications, the humerus shows the highest drug levels. Skeletal tissue concentrations found ranged from 1.1 to 587.8 ng/g. Comparison of the same bone type between the different rats showed high variances. However, the drugs-metabolite ratio proved to have lower variances (<20%). Moreover, the drugs-metabolite ratio in the sampled bones is in close concordance to the ratios seen in blood within a rat. From this, we can assume that the drugs-metabolite ratio in skeletal tissue may prove to be more useful than absolute found concentration., (© 2019 John Wiley & Sons, Ltd.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) possess as primary action mechanism the inhibition of cyclooxygenases (COX-1, COX-2, and COX-3), thus producing a decreasing prostaglandin synthesis. This study was designed to evaluate whether the antinociception induced by NSAIDs could be modulated by clomipramine or risperidone using a chemical model of inflammatory acute visceral pain, the abdominal acetic acid induced a writhing test in mice. Dose-response curves, intraperitoneal, or intrathecal for the antinociceptive activity displayed by ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol were analyzed in order to obtain the ED 50 of each drug. Pretreatment of mice with either clomipramine or risperidone, increased antinociceptive potency of ketoprofen, piroxicam, nimesulide, parecoxib, and paracetamol, expressed by a decrease in the values of antinociceptive ED 50. The results that were obtained are in line with those where the inhibition of COXs provides a justification for most of the pharmacological actions. Nevertheless, several findings suggest other molecular mechanisms, among which may be mentioned, L-selecting shedding; inhibition of i-NOS; inhibition of NF-Kappa B; suppression metaloproteinasas; inhibition of ß2 integrin activation; activation of α 2 -adrenoceptor; increase of IL-1ß; upregulation IL-6. In conclusion, the data generated in this study demonstrated that risperidone and clomipramine, separately, increase antinociceptive potency of NSAIDs in a chemical model of inflammatory acute visceral tonic pain., (© 2019 Wiley Periodicals, Inc.)

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and d-AMP on monoamine neurotransmission in mice by assessing sensitivity to acute d-AMP, desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of d-AMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, d-AMP, MeHg, and d-AMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of d-AMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of d-AMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent d-AMP increased sensitivity to acute d-AMP, desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent d-AMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Administering clomipramine during the early days of life induced several behavioral and neurochemical alterations in adult male rats, which resemble major depression disorder. The alterations included poor sexual performance, which is considered a reward-seeking behavior regulated by dopaminergic system. Given that estrogen receptors are expressed in different areas of the brain involved in regulating reproductive behavior, motivation and mood. The objective of this study was to analyze the effect of a non-selective dopamine agonist (apomorphine) on sexual incentive motivation in rats exposed to clomipramine (CMI) in the neonatal period. In addition, we evaluated the expression of mRNA ERα and ERβ in nucleus accumbens (NAcc) and septum of CMI rats. We found that only a few rats subjected to neonatal CMI treatment performed mounts, intromissions and ejaculations. Also, those rats spent less time exploring the sexual incentive zone and had lower preference scores; this effect was reverted by administering 0.1 mg/kg of apomorphine. Finally, the CMI rats presented higher levels of mRNA ERα and ERβ, only in septum area. These data indicate that neonatal treatment with CMI altered the expression of mRNA ERα and ERβ in the septum, which participates in regulating the motivational component of sexual behavior., (Copyright © 2019. Published by Elsevier Inc.)

Introduction: Although the treatment of obsessive-compulsive disorder (OCD), a common, chronic, and disabling psychiatric condition, has significantly improved in the last decades, with the demonstration of the specific effectiveness of serotonin reuptake inhibitors (SRIs), a large proportion of patients still show high relapse rates. In addition, pharmacological treatments should be maintained for years, so that the clinicians should take into account the pharmacokinetic changes in the long-term, which may be responsible for dangerous side effects or interactions. Areas covered: The aim of this paper was to review the literature on the pharmacokinetics of SSRIs and clomipramine, and on their pharmacokinetic parameters in OCD patients. Expert opinion: Although the literature on the pharmacokinetics of both clomipramine and SSRIs is consistent, data on pharmacokinetic parameters in OCD patients are very few. Given the impact of OCD, its chronicity requiring long-term treatments, together with the need to increase the clinical response rate, more studies in this field are urgently required.

Purpose: The aim of the current trial was to assess the efficacy of on demand clomipramine 15 mg administered before sexual intercourse for the treatment of premature ejaculation., Materials and Methods: A total of 159 patients at 5 centers in Korea were randomly assigned to 2 groups. The first group of 53 men received placebo and the second group of 106 received clomipramine 15 mg for 12 weeks. All patients were evaluated at the beginning of the study and every 4 weeks thereafter. Patients were instructed to ingest a tablet approximately 2 to 6 hours before sexual intercourse. Efficacy was assessed by scores on the IELT (Intravaginal Ejaculation Latency Time) and the PEDT (Premature Ejaculation Diagnostic Tool)., Results: Analyses of the IELT fold change in each group in the intent to treat population revealed that the IELT of the clomipramine 15 mg group was significantly increased 12 weeks after administration compared with the placebo group (mean ± SD 4.40 ± 5.29 vs 2.68 ± 2.03, p <0.05). The IELT fold change in the per protocol population also significantly differed between the clomipramine 15 mg group and the placebo group (mean 4.66 ± 5.64 vs 2.80 ± 2.19, p <0.05). There was a significant difference in the PEDT scores between the 2 groups (p <0.001). The most commonly reported adverse events were nausea in 15.7% of men and dizziness in 4.9%. Adverse events were mild to moderate in severity., Conclusions: The results of this multicenter, randomized, double-blind, placebo controlled, fixed dose clinical phase III study suggest that administering clomipramine 15 mg on demand to treat premature ejaculation is effective and safe.

Aim: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release., Methods: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated., Results: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities., Conclusion: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.

Hatching is an important phase of the development of pulmonate gastropods followed by the adult-like extracapsular foraging life. Right before hatching the juveniles start to display a rhythmic radula movement, executed by the buccal complex, consisting of the buccal musculature (mass) and a pair of the buccal ganglia. In order to have a detailed insight into this process, we investigated the serotonergic regulation of the buccal (feeding) rhythm in 100% stage embryos of the pond snail, Lymnaea stagnalis, applying quantitative immunohistochemistry combined with the pharmacological manipulation of the serotonin (5-HT) synthesis, by either stimulating (by the 5-HT precursor 5-hydroxytryptophan, 5-HTP) or inhibiting (by the 5-HT synthesis blocker para-chlorophenylalanine, pCPA) it. Corresponding to the direction of the drug effect, significant changes of the fluorescence intensity could be detected both in the cerebral ganglia and the buccal complex. HPLC-MS assay demonstrated that 5-HTP increased meanwhile pCPA decreased the 5-HT content both of the central ganglia and the buccal complex. As to the feeding activity, 5-HTP induced only a slight (20%) increase, whereas the pCPA resulted in a 20% decrease of the radula protrusion frequency. Inhibition of 5-HT re-uptake by clomipramine reduced the frequency by 75%. The results prove the role of both central and peripheral 5-HTergic processes in the regulation of feeding activity. Application of specific receptor agonists and antagonists revealed that activation of a 5-HT1-like receptor depressed the feeding activity, meanwhile activation of a 5-HT6,7-like receptor enhanced it. Saturation binding plot of [3H]-5-HT to receptor and binding experiments performed on membrane pellets prepared from the buccal mass indicated the presence of a 5-HT6-like receptor positively coupled to cAMP. The results suggest that 5-HT influences the buccal (feeding) rhythmic activity in two ways: an inhibitory action is probably exerted via 5-HT1-like receptors, while an excitatory action is realized through 5-HT 6,7 -like receptors.

Anxiety is the most prevalent mental disorder among adults in the United States and females tend to have significantly higher rates of anxiety compared with men. Common treatments for anxiety include usage of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants, however, sex differences in the efficacy of these drugs exist. In this study, we were interested in determining if acutely manipulating serotonin mechanisms at the whole-animal level affects cellular metabolism and oxidative stress in primary fibroblast cells from clomipramine-treated Sprague-Dawley rats. Our groups included a female and male control group that was injected with a saline solution, a female and male group that was injected with a low dosage of clomipramine, and a female and male group of rats that were injected with a high dosage of clomipramine. We then compared cellular oxygen consumption rates, rates of glycolysis and oxidative stress parameters in primary fibroblasts grown from each of the groups described above. We found that clomipramine-treated rats had significantly lower rates of glycolysis and glycolytic capacity, regardless of sex. Coupling efficiency was significantly higher in male rats compared with female rats across treatment groups. Our data suggest that in female rats reduced glutathione (GSH) is nonsignificantly reduced, yet lipid peroxidation (LPO) damage still accumulates, meaning that enzymatic antioxidants may be acting to reduce any continual increases in LPO damage. This is a metabolically costly process that may be happening because of our drug treatments. Our results provide further evidence of sex differences in the behavioral and metabolic responses to short-term clomipramine treatment. Continued investigation into these sex differences may reveal their potential for improving our understanding of how different therapeutic interventions may be better suited for treating males and females., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

To evaluate the adequate therapeutic dosage of clomipramine 15 mg/day and clomipramine 30 mg/day in male patients with premature ejaculation (PE), this study enrolled men aged 20-65 years who met diagnostic criteria for PE including Intravaginal Ejaculation Latency Time (IELT) less than 2 min for at least 75% of their sexual intercourses. Subjects received placebo, clomipramine 15 mg, or clomipramine 30 mg prn (2~6 h before intercourse) for 4 weeks. Efficacy was assessed using fold change, percentile change, and mean change of IELT, as well as Drug Coitus Interval Time (DCIT). A total of 101 patients were randomized into the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group. Analyses of fold changes of IELT in each group revealed that the IELT of both the clomipramine 15 mg group and clomipramine 30 mg group was significantly increased 4 weeks after administration than the placebo group. Adverse events were reported by 11.76, 32.35, and 57.57% of patients in the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group, respectively. Most common adverse events in the clomipramine treatment groups were gastrointestinal disorders and psychiatric disorders of mild to moderate severity. On-demand regimen of clomipramine 15 mg resulted in a significant improvement in IELT and was superior to a regimen of clomipramine 30 mg in terms of risk-to-benefit ratio.

Administration of clomipramine (CMI), a tricyclic antidepressant, in early stages of development in rats, is considered an animal model for the study of depression. This pharmacological manipulation has induced behavioral and physiological alterations, i.e., less pleasure-seeking behaviors, despair, hyperactivity, cognitive dysfunction, alterations in neurotransmitter systems and in HPA axis. These abnormalities in adult male rats are similar to the symptoms observed in major depressive disorders. One of the main pleasure-seeking behaviors affected in male rats treated with CMI is sexual behavior. However, to date, no effects of early postnatal CMI treatment have been reported on female reproductive cyclicity and sexual behavior. Therefore, we explored CMI administration in early life (8-21 PN) on the estrous cycle and sexual behavior of adult female rats. Compared to the rats in the early postnatal saline treatment (CTRL group), the CMI rats had fewer estrous cycles, fewer days in the estrous stage, and longer cycles during a 20-day period of vaginal cytology analysis. On the behavioral test, the CMI rats displayed fewer proceptive behaviors (hopping, darting) and had lower lordosis quotients. Also, they usually failed to display lordosis and only rarely manifested marginal or normal lordosis. In contrast, the CTRL rats tended to display normal lordosis. These results suggest that early postnatal CMI treatment caused long-term disruptions of the estrous cycle and female sexual behavior, perhaps by alteration in the hypothalamic-pituitary-gonadal (HPG) axes and in neuronal circuits involved in the regulation of the performance and motivational of sexual behavior as the noradrenergic and serotonergic systems., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Second generation antipsychotics (SGA) are used in children for the treatment of various psychiatric diseases, including pervasive developmental disorders. These drugs can cause metabolic effects as hyperglycemia and diabetes. A 16-year-old young-boy, diagnosed with autism, developed diabetes mellitus type 1 whilst he was on treatment with olanzapine (started 4 months before), clomipramine, valproic acid and lithium. The hypothesis of druginduced diabetes imposed olanzapine interruption and clozapine initiation. Insulin therapy was practiced, with progressive dosage reduction, until complete cessation of treatment after 13 months. Blood sugar and HbA1c levels remained stable for about a year and then increased again, requiring the introduction of metformin that improved glycemia. In children and adolescents assuming SGA serum glucose and lipid profile should always be assessed before therapy and then frequently monitored. Drug selection must consider family history and the individual risk. Molecule final choice remains equilibrium between efficacy and safety.

Neonatal administration of clomipramine (CMI) induces diverse behavioral and neurochemical alterations in adult male rats that resemble major depression disorder. However, the possible behavioral alterations in adult female rats subjected to neonatal treatment with clomipramine are unknown. Therefore, the aim of this study was to explore the effect of neonatal treatment with CMI on adult female rats in relation to locomotion and behavioral despair during the estrus cycle. Also evaluated was the effect of chronic treatment with E2 on these female CMI rats. We found no effects on spontaneous locomotor activity due to neonatal treatment with CMI, or after 21days of E2 administration. In the FST, neonatal treatment with CMI increased immobility and decreased active swimming and climbing behaviors. Influence of the ovarian cycle was detected only in relation to climbing behavior, as the rats in the MD phase displayed less climbing activity. Chronic E2 administration decreased immobility but increased only swimming in CMI rats. These results suggest that neonatal treatment with CMI induces despair-like behavior in female rats, but that chronic E2 administration generates antidepressant-like behavior by decreasing immobility and increasing swimming, perhaps through interaction with the serotonergic system., (Copyright © 2017. Published by Elsevier Inc.)

Trichotillomania is a relatively understudied psychiatric disorder. Even less is known about this disorder in the elderly. We describe an unusual case of an elderly woman presenting for the first time with trichotillomania at age 70 and highlight the treatment complexities we encountered.

Neonatal rodents chronically treated with the tricyclic antidepressant clomipramine show depression-like behavior, which persists throughout adulthood. Therefore, this animal model is suitable to investigate the pathomechanism of depression, which is still largely unknown at the molecular level beyond monoaminergic dysfunctions. Here, we describe protein level changes in the prefrontal cortex of neonatally clomipramine-treated adult rats correlating with behavioral abnormalities. Clomipramine was administered to rat pups twice daily between postnatal days 8-21, while controls received saline injections. Behavioral tests were performed on 3months old rats. The proteomic study was conducted using two-dimensional differential gel electrophoresis. We have identified 32 proteins by mass spectrometry analysis of the significantly altered protein spots. The changed proteins are related to several biological functions, such as inflammation, transcription, cell metabolism and cytoskeleton organization. Among the altered proteins, the level of macrophage migration inhibitory factor showed the largest alteration, which was confirmed with Western blot. Macrophage migration inhibitory factor showed widespread distribution and was predominantly expressed in astrocytes in the forebrain of rats which were described using immunohistochemistry. We conclude that neonatal clomipramine exposure induces sustained modification in the proteome, which may form the molecular basis of the observed depression-like behavior in adult rats., Biological Significance: It is known that some of the psychiatric disorders, such as autism, depression or schizophrenia may be at least in part, developmental disorders. We hypothesized that clomipramine treatment in early stage of brain development, which is known to induce depression-like behavior in adult rats, results in pathological distortion in neuronal and glial network development, which can be reflected by the cellular proteome in adulthood. Thus, we performed an unbiased proteomics experiment in adult rats, which were neonatally administered with clomipramine to reveal protein level changes three months after treatment. Many of the identified changed proteins are previously associated with depressive symptoms, e.g., the macrophage migration inhibitory factor (MIF), the level of which showed the largest alteration among the identified proteins. Based on our data, we suggest that neonatal clomipramine treatment is a reliable model to study the developmental effect of psychoactive drugs applied in the sensitive early phase of brain development. Furthermore, our findings support the idea that the alteration of early development of the brain induced by antidepressant treatment could result in sustained pathological changes in the cellular phenotype in the prefrontal cortex leading to depression-like behavioral symptoms., (Copyright © 2016. Published by Elsevier B.V.)

Background: Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people., Methods: We did a network meta-analysis to identify both direct and indirect evidence from relevant trials. We searched PubMed, the Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, LiLACS, regulatory agencies' websites, and international registers for published and unpublished, double-blind randomised controlled trials up to May 31, 2015, for the acute treatment of major depressive disorder in children and adolescents. We included trials of amitriptyline, citalopram, clomipramine, desipramine, duloxetine, escitalopram, fluoxetine, imipramine, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, and venlafaxine. Trials recruiting participants with treatment-resistant depression, treatment duration of less than 4 weeks, or an overall sample size of less than ten patients were excluded. We extracted the relevant information from the published reports with a predefined data extraction sheet, and assessed the risk of bias with the Cochrane risk of bias tool. The primary outcomes were efficacy (change in depressive symptoms) and tolerability (discontinuations due to adverse events). We did pair-wise meta-analyses using the random-effects model and then did a random-effects network meta-analysis within a Bayesian framework. We assessed the quality of evidence contributing to each network estimate using the GRADE framework. This study is registered with PROSPERO, number CRD42015016023., Findings: We deemed 34 trials eligible, including 5260 participants and 14 antidepressant treatments. The quality of evidence was rated as very low in most comparisons. For efficacy, only fluoxetine was statistically significantly more effective than placebo (standardised mean difference -0·51, 95% credible interval [CrI] -0·99 to -0·03). In terms of tolerability, fluoxetine was also better than duloxetine (odds ratio [OR] 0·31, 95% CrI 0·13 to 0·95) and imipramine (0·23, 0·04 to 0·78). Patients given imipramine, venlafaxine, and duloxetine had more discontinuations due to adverse events than did those given placebo (5·49, 1·96 to 20·86; 3·19, 1·01 to 18·70; and 2·80, 1·20 to 9·42, respectively). In terms of heterogeneity, the global I(2) values were 33·21% for efficacy and 0% for tolerability., Interpretation: When considering the risk-benefit profile of antidepressants in the acute treatment of major depressive disorder, these drugs do not seem to offer a clear advantage for children and adolescents. Fluoxetine is probably the best option to consider when a pharmacological treatment is indicated., Funding: National Basic Research Program of China (973 Program)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Melasma is a hyperpigmented dermatological condition common in females. Drugs such as steroids, cosmetics, and photosensitizing agents are known to cause melasma. We report here a case of an adult male with obsessive-compulsive disorder, receiving clomipramine, who developed melasma.

Diurnal animals are a better model for seasonal affective disorder (SAD) than nocturnal ones. Previous work with diurnal rodents demonstrated that short photoperiod conditions brought about depression-like behavior. However, rodents are at a large phylogenetic distance from humans. In contrast, nonhuman primates are closely similar to humans, making them an excellent candidate for SAD model. This study made the first attempt to develop SAD in rhesus macaque (Macaca mulatta) and it was found that short photoperiod conditions could lead monkeys to display depressive-like huddling behavior, less spontaneous locomotion, as well as less reactive locomotion. In addition to these depression-related behavioral changes, the physiological abnormalities that occur in patients with SAD, such as weight loss, anhedonia and hypercortisolism, were also observed in those SAD monkeys. Moreover, antidepressant treatment could reverse all of the depression-related symptoms, including depressive-like huddling behavior, less spontaneous locomotion, less reactive locomotion, weight loss, anhedonia and hypercortisolism. For the first time, this study observed the SAD symptoms in rhesus macaque, which would provide an important platform for the understanding of the etiology of SAD as well as developing novel therapeutic interventions in the future., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: This open trial was conducted to evaluate the effectiveness of intravenous clomipramine (CMI) in refractory obsessive-compulsive disorder (OCD)., Methods: Thirty OCD poor responders to previous multiple trials of anti-obsessive medications were selected and admitted to the hospital. Severity of the illness and response to treatment were primarily assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). CMI was gradually administered intravenously for one week. All patients were thereafter switched to oral CMI with a maximum dose of 225 mg/day., Results: The Y-BOCS total score mean at admission was in the severe range (24-31), and dropped on discharge and follow-ups to the moderate range (16-23). At discharge, 23 patients (76.7%) had a decrease in Y-BOCS ≥ 25% and were considered responders, while only 18 (60%) were still responders at 24 weeks. No relevant persistent side effects were reported., Conclusion: Intravenous clomipramine could be of benefit for severe OCD cases that have not adequately responded to several therapies, including oral clomipramine., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

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 4.8 min. The assay was linear in the range 20-500 µg/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 20 µg/L however for CMP and DMCP it was increased to 40 µg/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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Various functional magnetic resonance imaging studies addressed the effects of antidepressant drugs on brain functioning in healthy subjects; however, none specifically investigated positive mood changes to antidepressant drug. Sixteen subjects with no personal or family history of psychiatric disorders were selected from an ongoing 4-week open trial of small doses of clomipramine. Follow-up interviews documented clear positive treatment effects in six subjects, with reduced irritability and tension in social interactions, improved decision making, higher self-confidence and brighter mood. These subjects were then included in a placebo-controlled confirmatory trial and were scanned immediately after 4 weeks of clomipramine use and again 4 weeks after the last dose of clomipramine. The functional magnetic resonance imaging (fMRI) scans were run during emotion-eliciting stimuli. Repeated-measures analysis of variance of brain activity patterns showed significant interactions between group and treatment status during induced irritability (P<0.005 cluster-based) but not during happiness. Individuals displaying a positive subjective response do clomipramine had higher frontoparietal cortex activity during irritability than during happiness and neutral emotion, and higher temporo-parieto-occipital cortex activity during irritability than during happiness. We conclude that antidepressants not only induce positive mood responses but also act upon autobiographical recall of negative emotions.

Painful diabetic neuropathy is a common, difficult-to-manage complication of diabetes. We report two case of intractable painful diabetic neuropathy which occurred after the rapid lowering of blood sugar level. Although pregabalin, antidepressants, opioid analgetics and various nerve block did not improve their pain, clomipramine dramatically reduced their pain.

A small body of literature suggests that clomipramine may usefully augment selective serotonin reuptake inhibitor (SSRI) treatment in obsessive-compulsive disorder (OCD) patients who do not respond to SSRI monotherapy. The combination, however, is associated with the risk of clinically significant drug interactions. Clomipramine can raise the blood levels and hence the adverse effects of most SSRIs, and many SSRIs can raise the blood levels and hence the adverse effects of clomipramine. The latter situation is more important because certain dose-dependent adverse effects of clomipramine, such as seizures, can be life-threatening. This article presents an evidence-based discussion of the pharmacodynamic and pharmacokinetic adverse effects of the SSRI-clomipramine combination along with suggestions for dosing and monitoring when the combination is used in OCD., (© Copyright 2013 Physicians Postgraduate Press, Inc.)

Since little is known about the teratogenic effects of clomipramine used concurrently with caffeine during the organogenesis period, the aim of this study was to test the teratogenic effects of a coadministration of caffeine and clomipramine on rat fetuses. We divided 42 pregnant rats into seven groups, randomly. The first group (control) received 0.5 mL of normal saline. Clomipramine was injected at 40 mg/kg and 80 mg/kg to the second and third groups, respectively. The fourth and fifth groups received caffeine in doses of 60 mg/kg and 120 mg/kg, respectively. The sixth group received a combination of 40 mg/kg clomipramine and 60 mg/kg caffeine, and the seventh group was given clomipramine and caffeine at 80 mg/kg and 120 mg/kg, respectively. The fetuses were removed on the 17th day of pregnancy and studied in terms of microscopic and macroscopic morphological features. Fetuses of rats receiving high doses of caffeine or combinations of caffeine and clomipramine showed a significant rate of cleft palate development, open eyelids, mortality, torsion anomalies, shrinkage of skin, and subcutaneous haemorrhage (P ≤ 0.001). This study concludes that caffeine in high doses or the simultaneous administration of caffeine and clomipramine leads to teratogenicity.

The interactions of tricyclic antidepressant drug, clomipramine (CLO), with pig ear stratum corneum (SC) and model membranes were investigated by electron paramagnetic resonance (EPR) spin labeling to get some insight into the possible application of this drug in transdermal delivery. The changes in membrane characteristics caused by CLO in the regions that are close to the water-lipid interfaces and the central parts of the membranes were searched. The experimental results were supported by computer simulation of EPR spectra, which showed heterogeneity of the membranes composed of regions with different fluidity characteristics. CLO was effective in both parts of the layers, indicating intercalation of the drug into model membranes as well as into the pig ear SC. Introduction of various molar ratios of CLO caused a decrease in the order parameter and an increase in the rotational diffusion of nitroxide moiety in different membrane regions as well as an increase in the polarity of spin probe environment. It also changed the number of resolved spectral components, which reflects the heterogeneity of the membrane. The fluidizing effect of CLO on pig ear SC throughout the whole membrane layers indicates that CLO penetrates into the SC, which is important for its transdermal delivery., (© 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Background: There is growing evidence that memantine, a noncompetitive N-methyl-D-aspartate receptor antagonist, may be applied as an add-on in treating patients suffering from obsessive-compulsive disorders (OCD). The aim of the present study was therefore to assess the effect of adjuvant memantine in a double-blind, randomized, and placebo-controlled study of the treatment of patients suffering from OCD., Method: A total of 40 inpatients (32 females (80 %); mean age = 31.25 years) suffering from OCD were randomly assigned to a treatment (administration of memantine) or a control group (placebo). Treatment lasted for 12 consecutive weeks. All patients were treated with selective serotonin re-uptake inhibitors or clomipramine. Patients completed the Yale-Brown Obsessive Compulsive Scale four times. Experts' ratings consisted in clinical global impression (clinical global impressions (CGI), illness severity and illness improvement; two to three times). Liver enzymes SGOT and SGPT were also assessed (twice)., Results: Of the 40 inpatients approached, 29 completed the 12 consecutive weeks of the study. Of the 11 dropouts, 6 were in the target group and five in the control group. Symptoms significantly decreased across the period of the study, but particularly in the treatment compared with the control group (significant time × group interaction). Illness severity (CGI severity) also significantly decreased over time but more so in the treatment than in the control group (significant time × group interaction). Illness improvements (CGI improvements) were not significant., Conclusions: The pattern of results from the present double-blind, randomized, and placebo-controlled study for the treatment of patients suffering from OCD suggests that adjuvant memantine does significantly and favorably impact on OCD.

The aim of this study was to explore the possible relationship between plasma clomipramine and its major metabolite (N-desmethylclomipramine) levels and related parameters, and clinical features in patients with obsessive-compulsive disorder (OCD). Twenty-six outpatients (13 men, 13 women), suffering from OCD were consecutively enrolled in this study. The severity of OCD was assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). The measurements were taken after 4 weeks and 6 months from the beginning of the treatment. The drug levels were measured by a high-performance liquid chromatography method developed by us. The correlations between biological and clinical parameters were analyzed by means of Spearman's correlation coefficient. The Mann-Whitney test was used for comparing biological and clinical variables between men and women. The results showed that clomipramine levels were related to the doses at the two assessment times. A significant and positive correlation was detected at the beginning between the N-desmethylclomipramine ratio and the Y-BOCS total score; however, this was true only for men, where the similar correlations were measured also with the Y-BOCS subscale. After 6 months of clomipramine, men showed a significant improvement of the compulsions. These findings would highlight the potential impact of assessing clomipramine plasma levels and their relationships with specific symptoms, as well as the influence of the sex on the drug response.

Anxiety disorders represent the most prevalent psychiatric disorders. In addition, a considerable burden is associated with them, not only for individual sufferers, but also for the health care system. However, many patients who might benefit from treatment are not diagnosed or treated. This may partly be due to lack of awareness of the anxiety disorders by primary care practitioners and by the sufferers themselves. In addition, the stigma still associated with psychiatric disorders and lack of confidence in psychiatric treatments are factors leading to no/under recognition and treatment, or the use of unnecessary or inappropriate treatments. This paper aims to provide a comprehensive review of recommendations for the pharmacological treatment of two common anxiety disorders, in particular obsessive-compulsive disorder (OCD) and panic disorder (PD). The first-line treatments of OCD include medium-high doses of selective serotonin reuptake inhibitors (SSRIs) and clomipramine, a tricyclic (TCA) antidepressant with prevalent serotonergic activity. The recommended drugs for PD include SSRIs, TCAs and serotonin-norepinephrine reuptake inhibitors (SNRIs); in treatment-resistant cases, benzodiazepines like alprazolam may be used in patients with no history of addiction and tolerance. Other treatment options include irreversible and reversible monoamine-oxidase inhibitors, hydroxyzine, and others. Besides pharmacological treatments, some psychological strategies have been shown to be effective, in particular, cognitive behavior therapy (CBT) and other variants of behavior therapy that have been sufficiently investigated in controlled studies, and, therefore, will be reviewed herein.

Obsessive-compulsive disorder patients who do not improve sufficiently after treatment with a selective serotonin reuptake inhibitor might improve further if other drugs were added to the treatment regimen. The authors present a double-blind, placebo-controlled trial comparing the efficacy of adding quetiapine or clomipramine to a treatment regimen consisting of fluoxetine. Between May 2007 and March 2010, a total of 54 patients with a primary diagnosis of obsessive-compulsive disorder, as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and a current Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score of at least 16, the score having dropped by less than 35% after fluoxetine monotherapy, were allocated to 1 of 3 arms (n = 18 per arm): quetiapine + fluoxetine (≤200 and ≤40 mg/d, respectively), clomipramine + fluoxetine (≤75 and ≤40 mg/d, respectively), or placebo + fluoxetine (≤80 mg/d of fluoxetine). Follow-up was 12 weeks. The Y-BOCS scores were the main outcome measure. No severe adverse events occurred during the trial, and 40 patients (74%) completed the 12-week protocol. The Y-BOCS scores (mean [SD]) were significantly better in the placebo + fluoxetine and clomipramine + fluoxetine groups than in the quetiapine + fluoxetine group (final: 18 [7] and 18 [7], respectively, vs 25 [6], P < 0.001) (reduction from baseline: -6.7 [confidence interval {CI}, -9.6 to -3.8; and -6.5 [CI, -9.0 to -3.9], respectively, vs -0.1 [CI, -2.9 to 2.7], P < 0.001; number needed to treat = 2.4). The clomipramine-fluoxetine combination is a safe and effective treatment for fluoxetine nonresponders, especially those who cannot tolerate high doses of fluoxetine. However, the period of monotherapy with the maximum dose of fluoxetine should be extended before a combination treatment strategy is applied.

Rationale: Repeated administrations of the D2/D3 agonist quinpirole (QNP) to rats elicit an antieconomical pattern of drinking called "contrafreeloading" (CFL), a putative model of compulsive-like behavior., Objectives: We tested the sensitivity of QNP-induced CFL to haloperidol (HAL), aripiprazole (ARI), and clomipramine (CIM), the latter proven effective in the treatment of obsessive-compulsive disorder (OCD)., Methods: Rats were trained under a schedule of reinforcement (FR3) for water. On days 1-6, water was only available through lever pressing. On days 7-15, a choice between operant and free access was provided. QNP 0.5 mg/kg was administered alone or in combination with HAL (0.1 or 0.2 mg/kg), ARI (0.3 or 1 mg/kg), or CIM (5 or 10 mg/kg)., Results: Acutely QNP suppressed operant behavior and, therefore, water intake; upon repeated administrations, tolerance developed to this suppressant effect on responding but only to a lesser extent to the antidipsic effect. In choice conditions, QNP induced a progressive preference for the operant access (CFL). HAL per se, but not CIM and ARI, significantly reduced both responding and drinking (operant phase). In the choice phase, HAL and CIM inhibited CFL, but only the latter reinstated total water intake. ARI, in combination with QNP, increased responding., Conclusions: CIM reinstates control patterns of drinking, while HAL and ARI where partially or not effective at all, respectively. As far as CIM is considered a first line treatment in OCD, these results further strengthen the notion that QNP-induced CFL belongs to the realm of dopaminergic drug-induced compulsive behaviors.

Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.

The effect of oxidative stress (OS) on the pharmacokinetics of clomipramine (CPM), particularly addressing the change of CPM distribution to plasma components, was studied in ferric-nitrilotriacetate-induced oxidative-stress model rats (OS rats). First, CPM pharmacokinetic studies in OS rats were performed using CPM continuous infusion (17.5 μg/min/kg). Plasma concentration of CPM at a steady state in OS rats (0.20 ± 0.02 μg/mL) was significantly lower than that in control rats (0.30 ± 0.02 μg/mL). However, no difference was found in the amounts of CPM in the brains of control rats (1.67 ± 0.13 μg/g) and OS rats (1.63 ± 0.09 μg/g). Both of plasma unbound fraction and distribution to erythrocytes in OS rats were significantly higher than those of control rats. These results suggest that the lower CPM concentration in plasma in OS condition does not induce an inferior pharmacological effect.

The aim of this article was to analyze systematically literature information published in English (between 1966 and January 2011) on the efficacy of antidepressants in pediatric obsessive-compulsive disorder. Data were identified through different databases by using variously combined patterns of search terms. Searches provided 85 articles, excluding duplicates, but only articles reporting primary data on use of antidepressants in this specific disorder were reviewed. Fifty-nine articles were excluded because they did not report primary efficacy data or investigated patients with different psychiatric diagnosis. Twenty-five electronically recognized articles met the inclusion criteria. Two additional studies, available as congress communication, were identified by manually checking the references' list of electronically identified articles. Reviewed studies show several methodological biases (the lack/limited number of long-term trials and head-to-head comparisons and the inclusion of patients who continued different forms of psychotherapy), which make it difficult to individuate the best pharmacological strategy. Despite these limitations, evidence-based information suggests that clomipramine and sertraline, especially for long-term treatments, should be considered as first-choice agents for treating obsessive-compulsive disorder at onset during childhood or adolescence.

The lateral septum (LS) is a limbic brain region that receives serotonergic projections from raphe neurons and participates in the modulation of stress responses and affective states. The present study determined whether mineralocorticoid receptors (MRs) and/or glucocorticoid receptors (GRs) located in the LS interact with the serotonergic system in the regulation of depressive-like behavior of rats subjected to the forced swimming test (FST). We also studied the effect of corticosterone release induced by the FST on MR- and GR-mRNA expression in the LS. Specifically, we studied the antidepressant-like effects of spironolactone (a MR antagonist), mifepristone (a GR antagonist), and the antidepressant clomipramine (CMI) administered directly into the LS. In addition, spironolactone and CMI actions were studied in animals with serotonergic depletion induced by dl-p-chlorophenylalanine (pCPA). Finally, adrenalectomized and Sham-operated rats were subjected to the FST to determine MR- and GR-mRNA expression in the LS at different post-FST intervals. The results showed that intraseptal injection of spironolactone, but not mifepristone induced antidepressant-like actions in the FST; this effect was blocked by pCPA treatment. CMI and spironolactone increased 5-HT concentrations in the LS of rats subjected to the FST. Increases in corticosterone release, induced by the FST, correlated with a decrease in MR-mRNA expression in the LS; no correlation was found with GR-mRNA expression. In conclusion, MRs in the lateral septum, but not GRs, participate in the regulation of depressive-like behavior of animals subjected to the FST. Both serotonin and corticosterone play an important role in MR actions in the LS., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Women experience major depression at roughly twice the rate of men. Inconclusive clinical evidences assist the notion that responsiveness to antidepressant pharmacotherapy is sexually dimorphic with the two sexes presenting differential responses when treated with tricyclic antidepressants (TCAs). Notably, responsiveness to antidepressive agents presents marked inter-individual variability, the biological basis of which remains elusive. Herein, we sought to investigate putative sex differences to chronic antidepressant treatment with the TCA clomipramine in rats selected on the basis of their reactions to novelty. Our data revealed that high novelty-seeker (HR) male rats were more responsive to clomipramine treatment as far as the alleviation of anxiety and nociception are concerned, compared to low novelty-seeker (LR) males and HR/LR female rats. Surprisingly, chronic clomipramine treatment attenuated depressive-like symptomatology in the forced swim test (FST) of behavioral despair in both sexes albeit in the opposite novelty-seeking phenotypes (i.e. in male HR and female LR). Interestingly in male HR rats, clomipramine treatment diminished serotonergic neurochemical responses post-FST exposure in all limbic brain regions examined, while these were boosted in their LR counterparts. Dopaminergic and glutamatergic neurochemistry also presented phenotype-related alterations. On the contrary, in females the neurochemical substrate was only modestly affected. Notably, corticosteroid responses were augmented in female but attenuated in male drug-treated rats. Overall, the current dataset lends further support that the male sex may benefit to a greater extent when treated with TCAs and reveals that individual differences are associated with qualitative and quantitative sex-related behavioral and neurochemical manifestations in response to chronic antidepressant treatment., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Rationale: Norepinephrine transporter (NET) is one of the key targets for antidepressants such as combined serotonin and norepinephrine reuptake inhibitors as well as some of the tricyclic antidepressants. Clomipramine, a tricyclic antidepressant, has been reported to have an active metabolite, desmethylclomipramine, which has high affinity for NET in vitro. However, the NET occupancy of clomipramine and desmethylclomipramine has not fully been evaluated in vivo., Objectives: In this positron emission tomography (PET) study, we investigate NET occupancy by clomipramine and desmethylclomipramine, respectively, in non-human primates with a selective radioligand for NET, (S,S)-[(18)F]FMeNER-D(2)., Methods: PET measurements were performed with (S,S)-[(18)F]FMeNER-D(2) at baseline and after the intravenous administration of clomipramine and desmethylclomipramine, respectively. NET binding was calculated with the simplified reference tissue model using the caudate as reference region. NET occupancy was calculated as the difference in NET binding between the baseline and pretreatment condition. The relationship between NET occupancy and dose/plasma concentration was evaluated using hyperbolic functions., Results: NET occupancy by both clomipramine and desmethylclomipramine increased in a dose and plasma concentration-dependent manner. The mean Kd values, expressed as the dose or plasma concentration at which 50% of NET was occupied, were 0.44 mg/kg and 24.5 ng/ml for clomipramine and 0.11 mg/kg and 4.4 ng/ml for desmethylclomipramine., Conclusions: Not only desmethylclomipramine but also clomipramine was demonstrated to occupy NET in the non-human primate in vivo. It can thus be assumed that NET occupancy during clinical treatment with clomipramine is a combined effect of unchanged clomipramine and its main metabolite desmethylclomipramine.

Based on the evidence that aripiprazole added to serotonin reuptake inhibitors (SRIs) or clomipramine in treatment-resistant obsessive-compulsive disorder (OCD) has reported promising results, the present 16-week, double-blind, randomized, placebo-controlled trial had the aim to explore the efficacy of aripiprazole add-on pharmacotherapy on clinical symptoms and cognitive functioning in a sample of treatment-resistant OCD patients receiving SRIs. After clinical and neurocognitive assessments, patients were randomly allocated to receive, in a double-blind design, 15 mg/d of aripiprazole or a placebo. A final sample of 30 patients completed the study. The results obtained indicate that aripiprazole added to stable SRI treatment substantially improved obsessive-compulsive symptoms as measured by changes on the Yale-Brown Obsessive Compulsive Scale total score and subscores (obsessions, P = 0.007; compulsions, P = 0.001; total score, P < 0.0001). Regarding cognitive functions, improvement was observed in some explored areas, such as attentional resistance to interference (Stroop score, P = 0.001) and executive functioning (perseverative errors, P = 0.015). The findings provide evidence that aripiprazole augmentation of SRIs/clomipramine treatment is well tolerated and may be proposed as an effective therapeutic strategy to improve outcome in treatment-resistant OCD.

The main aim of this study was to evaluate the anxiolytic-like effects of the serotonergic antidepressant, clomipramine (0.6-5.0 mg/kg), and the 5-HT1A agonist, (±)8-hydroxy-2-(di-n)-propil-aminotetraline hydrobromide (8-OH-DPAT; 0.01-0.5 mg/kg), in two strains of rat with different anxiety vulnerability: Wistar-Kyoto (WKY; with trait anxiety) and Wistar rats (control strain). The anxiety model used was the burying behavior test; decreases in burying, grooming of the snout, and freezing were interpreted as a reduction of anxiety-like levels. A second objective was to explore the participation of 5-HT1A receptors in the effects of clomipramine and 8-OH-DPAT. Behavior in the burying behavior test was strain dependent. In addition to the burying behavior, WKY rats showed high levels of freezing and grooming of the snout. Clomipramine and 8-OH-DPAT decreased the burying behavior in both strains of rats through a direct interaction with the 5-HT1A receptor. 8-OH-DPAT decreased freezing behavior in both strains through a mechanism that was not related to 5-HT1A receptors. Finally, clomipramine was able to block freezing and grooming behaviors only in WKY rats. In conclusion, strains with different anxiety vulnerability express different behavioral responses toward the same aversive stimulus, and the anxiolytic-like effects of clomipramine and 8-OH-DPAT are both behavior and strain dependent.

Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.