The harmful acute effects of clomipramine in the rat liver: Impairments in mitochondrial bioenergetics.

Clomipramine, a tricyclic antidepressant used to treat depression and obsessive-compulsive disorder, has been linked to a few cases of acute hepatotoxicity. It is also recognized as a compound that hinders the functioning of mitochondria. Hence, the effects of clomipramine on mitochondria should endanger processes that are somewhat connected to energy metabolism in the liver. For this reason, the primary aim of this study was to examine how the effects of clomipramine on mitochondrial functions manifest in the intact liver. For this purpose, we used the isolated perfused rat liver, but also isolated hepatocytes and isolated mitochondria as experimental systems. According to the findings, clomipramine harmed metabolic processes and the cellular structure of the liver, especially the membrane structure. The considerable decrease in oxygen consumption in perfused livers strongly suggested that the mechanism of clomipramine toxicity involves the disruption of mitochondrial functions. Coherently, it could be observed that clomipramine inhibited both gluconeogenesis and ureagenesis, two processes that rely on ATP production within the mitochondria. Half-maximal inhibitory concentrations for gluconeogenesis and ureagenesis ranged from 36.87 µM to 59.64 µM. The levels of ATP as well as the ATP/ADP and ATP/AMP ratios were reduced, but distinctly, between the livers of fasted and fed rats. The results obtained from experiments conducted on isolated hepatocytes and isolated mitochondria unambiguously confirmed previous propositions about the effects of clomipramine on mitochondrial functions. These findings revealed at least three distinct mechanisms of action, including uncoupling of oxidative phosphorylation, inhibition of the FoF1-ATP synthase complex, and inhibition of mitochondrial electron flow. The elevation in activity of cytosolic and mitochondrial enzymes detected in the effluent perfusate from perfused livers, coupled with the increase in aminotransferase release and trypan blue uptake observed in isolated hepatocytes, provided further evidence of the hepatotoxicity of clomipramine. It can be concluded that impaired mitochondrial bioenergetics and cellular damage are important factors underlying the hepatotoxicity of clomipramine and that taking excessive amounts of clomipramine can lead to several risks including decreased ATP production, severe hypoglycemia, and potentially fatal outcomes.

Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders guidelines for the treatment of adult obsessive-compulsive disorder. Part I: pharmacological treatment.

OBJECTIVES: To summarize evidence-based pharmacological treatments and provide guidance on clinical interventions for adult patients with obsessive-compulsive disorder (OCD). METHODS: The American Psychiatric Association (APA) guidelines for the treatment of OCD (2013) were updated with a systematic review assessing the efficacy of pharmacological treatments for adult OCD, comprising monotherapy with selective serotonin reuptake inhibitors (SSRIs), clomipramine, serotonin and norepinephrine reuptake inhibitors (SNRIs), and augmentation strategies with clomipramine, antipsychotics, and glutamate-modulating agents. We searched for the literature published from 2013-2020 in five databases, considering the design of the study, primary outcome measures, types of publication, and language. Selected articles had their quality assessed with validated tools. Treatment recommendations were classified according to levels of evidence developed by the American College of Cardiology and the American Heart Association (ACC/AHA). RESULTS: We examined 57 new studies to update the 2013 APA guidelines. High-quality evidence supports SSRIs for first-line pharmacological treatment of OCD. Moreover, augmentation of SSRIs with antipsychotics (risperidone, aripiprazole) is the most evidence-based pharmacological intervention for SSRI-resistant OCD. CONCLUSION: SSRIs, in the highest recommended or tolerable doses for 8-12 weeks, remain the first-line treatment for adult OCD. Optimal augmentation strategies for SSRI-resistant OCD include low doses of risperidone or aripiprazole. Pharmacological treatments considered ineffective or potentially harmful, such as monotherapy with antipsychotics or augmentation with ketamine, lamotrigine, or N-acetylcysteine, have also been detailed.

Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity.

FKBP51 is an important inhibitor of the glucocorticoid receptor (GR) signaling. High FKBP51 levels are associated to stress-related disorders, which are linked to GR resistance. SUMO conjugation to FKBP51 is necessary for FKBP51's inhibitory action on GR. The GR/FKBP51 pathway is target of antidepressant action. Thus we investigated if these drugs could inhibit FKBP51 SUMOylation and therefore restore GR activity. Screening cells using Ni2+ affinity and in vitro SUMOylation assays revealed that tricyclic antidepressants- particularly clomipramine- inhibited FKBP51 SUMOylation. Our data show that clomipramine binds to FKBP51 inhibiting its interaction with PIAS4 and therefore hindering its SUMOylation. The inhibition of FKBP51 SUMOylation decreased its binding to Hsp90 and GR facilitating FKBP52 recruitment, and enhancing GR activity. Reduction of PIAS4 expression in rat primary astrocytes impaired FKBP51 interaction with GR, while clomipramine could no longer exert its inhibitory action. This mechanism was verified in vivo in mice treated with clomipramine. These results describe the action of antidepressants as repressors of FKBP51 SUMOylation as a molecular switch for restoring GR sensitivity, thereby providing new potential routes of antidepressant intervention.

Eficácia e segurança de Duloxetina comparado a outros antidepressivos disponíveis no SUS para o tratamento de depressão maior: revisão rápida de evidências / Effectiveness and safety of Duloxetine compared to other antidepressant agents available in Brazilian Public Health for treatment of major depression: rapid response review of evidence

Tecnologia: Duloxetina e outros antidepressivos disponíveis no Sistema Único de Saúde (amitriptilina, nortriptilina, clomipramina, fluoxetina e bupropiona). Indicação: Tratamento do primeiro episódio depressivo no transtorno de depressão maior em adultos. Pergunta: A duloxetina é mais eficaz e tolerável que a amitriptilina, nortriptilina, clomipramina, fluoxetina e bupropiona para o tratamento do primeiro episódio de depressão maior em adultos? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews). Resultados: Foi selecionada 1 revisão sistemática, que atendia aos critérios de inclusão. Conclusão: Os antidepressivos, comparados ao placebo, tinham maior taxa de resposta, taxa de remissão e taxa de descontinuação devido a efeitos colaterais, no tratamento de curto prazo. Duloxetina tinha taxa de resposta similar a amitriptilina, clomipramina, fluoxetina e bupropiona. Duloxetina e amitriptilina tinham maior taxa de remissão que fluoxetina. Comparando-se as taxas de abandono de tratamento devido a efeitos colaterais, clomipramina era menos seguro, amitriptilina, bupropiona e duloxetina eram parecidos entre si, e fluoxetina era o antidepressivo mais seguro

Technology: Duloxetine and other antidepressants available in the Brazilian Public Health System (amitriptyline, nortriptyline, clomipramine, fluoxetine and bupropion). Indication: Treatment of the first depressive episode in adult major depressive disorder. Question: Is duloxetine more effective and tolerable than amitriptyline, nortriptyline, clomipramine, fluoxetine and bupropion for the treatment of first episode of major depression in adults? Methods: Rapid response review of evidence (overview) from systematic reviews, with a bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (Methodological Quality Assessment of Systematic Reviews). Results: One systematic review was selected, which met the inclusion criteria. Conclusion: In short-term treatment, antidepressants, compared to placebo, had a higher rate of response, rate of remission and rate drop-out due to side effects. Duloxetine had a similar response rate to amitriptyline, clomipramine, fluoxetine and bupropion. Duloxetine and amitriptyline had higher remission rates than fluoxetine. Comparing rates of dropout due to side effects, clomipramine had the worst rates, amitriptyline, bupropion, and duloxetine were similar to each other, and fluoxetine had the better rates

Lisdexanfetamina comparada a Metilfenidato ou antidepressivos no tratamento de TDAH em crianças e adolescentes: revisão rápida de evidências / Lisdexamfetamine compared to Methylphenidate or antidepressants for treatment of ADHD: rapid response review of evidence

Lisdexanfetamina e drogas disponíveis no SUS (metilfenidato, bupropiona, amitriptilina, clomipramina, nortriptilina). Indicação: Transtorno do Déficit de Atenção e Hiperatividade (TDAH) em crianças e adolescentes. Pergunta: Lisdexanfetamina é eficaz e segura para melhoria de sintomática, comparada ao placebo e medicações disponíveis no SUS, no tratamento de crianças e adolescentes com TDAH? Métodos: Revisão rápida de evidências (overview) de revisões sistemáticas, com levantamento bibliográfico realizado na base de dados PUBMED, utilizando estratégia estruturada de busca. A qualidade metodológica das revisões sistemáticas foi avaliada com AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews). Resultados: Foram selecionadas 3 revisões sistemáticas, que atenderam aos critérios de inclusão. Conclusão: Lisdexanfetamina e metilfenidato são mais eficazes que placebo, e similares entre si, para reduzir sintomas em escalas de avaliação. Lisdexanfetamina e metilfenidato têm risco similar ao placebo de abandono do tratamento devido a efeitos adversos. Bupropiona não é mais eficaz que placebo para alívio sintomático. Lisdexanfetamina tem efeitos adversos de redução do apetite e insônia/ dificuldades do sono. Não foram encontradas evidências na literatura sobre os efeitos terapêuticos de amitriptilina, clomipramina e nortriptilina no tratamento de crianças e adolescentes com TDAH

Lisdexamfetamine and drugs available in the Brazilian Public Health System (BPHS) (methylphenidate, bupropion, amitriptyline, clomipramine, nortriptyline, bupropion). Indication: Children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD). Question: Lisdexamfetamine is effective and safe for symptomatic improvement, compared to placebo and drugs available in the BPHS, for treatment of children and adolescents with ADHD? Methods: Rapid response review of evidence (overview) of systematic reviews, with bibliographic search in the PUBMED database, using a structured strategy. The methodological quality of systematic reviews was assessed with AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews). Results: 3 systematic reviews met the inclusion criteria and were selected. Conclusion: Lisdexamfetamine and methylphenidate are more effective than placebo, and similar to each other, to reduce symptoms on rating scales. Lisdexamfetamine and methylphenidate are not different from placebo in the risk of treatment discontinuation due to adverse effects. Bupropion is no more effective than placebo for symptomatic relief. Lisdexamfetamine has adverse effects of decreased appetite and insomnia/sleep troubles. No evidence was found in the literature about therapeutic effects of amitriptyline, clomipramine and nortriptyline for treatment of children and adolescents with ADHD

Clomipramine and alprazolam to treat noise phobia in a dog: case report / Uso de clomipramina e alprazolam no tratamento de cão com sensibilidade à ruídos: relato de caso

Behavioral disorders, including noise phobia, have a great impact on small animals internal medicine, impairing their quality of life as well as their life expectancy. The objective of this work is to report the case of a male dog who suffered from noise phobia and panic attacks triggered by thunderstorms and fireworks, and did not respond to previous training and treatment. After clinical and laboratory evaluations, he was treated with 2mg/kg clomipramine twice daily for 90 days associated with 0.06mg/kg alprazolam as needed on those days of intense fear. During the first week of treatment, a significant improvement could already be observed, with reduction in destructive behaviors, which lingered on for up to eight months of follow-up. The treatment stabilized the clinical condition and improved the patient’s quality of life.

Os distúrbios de comportamento, entre eles o medo de ruídos, apresentam um grande impacto na clínica de peque-nos animais, acarretando em decréscimo na qualidade e expectativa de vida. O objetivo deste trabalho é relatar o caso de um cão, macho, com histórico de medo de ruídos, que apresentava quadros de pânico desencadeados por trovões e fogos de arti-fício, sendo refratário a tentativas prévias de adestramento e tratamento medicamentoso. Após avaliação clínica e laboratorial, instituiu-se tratamento com clomipramina 2mg/kg BID durante 90 dias associada à administração de alprazolam 0,06mg/kg conforme necessário nos dias de medo intensificado. Na primeira semana de tratamento observou-se melhora significativa, com redução dos comportamentos destrutivos, se estendendo até 8 meses de acompanhamento. O tratamento realizado proporcio-nou estabilização do quadro clínico e incremento na qualidade de vida do paciente. informação a ser inserida pelos autores.

Clomipramine and alprazolam to treat noise phobia in a dog: case report / Uso de clomipramina e alprazolam no tratamento de cão com sensibilidade à ruídos: relato de caso

Behavioral disorders, including noise phobia, have a great impact on small animals internal medicine, impairing their quality of life as well as their life expectancy. The objective of this work is to report the case of a male dog who suffered from noise phobia and panic attacks triggered by thunderstorms and fireworks, and did not respond to previous training and treatment. After clinical and laboratory evaluations, he was treated with 2mg/kg clomipramine twice daily for 90 days associated with 0.06mg/kg alprazolam as needed on those days of intense fear. During the first week of treatment, a significant improvement could already be observed, with reduction in destructive behaviors, which lingered on for up to eight months of follow-up. The treatment stabilized the clinical condition and improved the patients quality of life.(AU)

Os distúrbios de comportamento, entre eles o medo de ruídos, apresentam um grande impacto na clínica de peque-nos animais, acarretando em decréscimo na qualidade e expectativa de vida. O objetivo deste trabalho é relatar o caso de um cão, macho, com histórico de medo de ruídos, que apresentava quadros de pânico desencadeados por trovões e fogos de arti-fício, sendo refratário a tentativas prévias de adestramento e tratamento medicamentoso. Após avaliação clínica e laboratorial, instituiu-se tratamento com clomipramina 2mg/kg BID durante 90 dias associada à administração de alprazolam 0,06mg/kg conforme necessário nos dias de medo intensificado. Na primeira semana de tratamento observou-se melhora significativa, com redução dos comportamentos destrutivos, se estendendo até 8 meses de acompanhamento. O tratamento realizado proporcio-nou estabilização do quadro clínico e incremento na qualidade de vida do paciente. informação a ser inserida pelos autores.(AU)

Pharmacological and behavioral treatment for trichotillomania: An updated systematic review with meta-analysis.

BACKGROUND: Trichotillomania (TTM) is a difficult-to-treat psychiatric condition with no first-line medications approved by the Food and Drug Administration. Individuals with TTM often feel that clinicians know little about this disorder. Here, we present an updated meta-analysis of randomized controlled trials (RCTs) examining treatments for TTM. METHODS: Pubmed, PsychINFO, Embase, and CENTRAL were searched with the terms "Trichotillomania OR Hair Pulling Disorder" to identify randomized controlled clinical trials evaluating treatments for TTM. RESULTS: Twenty-four trials involving 26 comparisons and 857 participants were included in this meta-analysis. Behavioral therapy with habit-reversal training components (BT-HRT) demonstrated a large benefit compared to control conditions (standardized mean difference [SMD] [95% CI] = -1.22 [-1.71, -0.73], p < .0001) for improving TTM symptoms. Clomipramine (SMD [95% CI] = -0.71 [-1.38, -0.05], p = .036), N-acetylcysteine (SMD [95% CI] = -0.75 [-1.36, -0.13], p = .017) and olanzapine (SMD [95% CI] = -0.94 [-1.77, -0.12], p = .025) demonstrated significant benefits compared to placebo in RCTs. CONCLUSIONS: BT-HRT has demonstrated the largest treatment effects and has the strongest evidence base for reducing TTM symptoms. In contrast, several pharmacological agents have demonstrated efficacy in single randomized clinical trials that would benefit from replication. Additional trials are needed to identify other effective medications for TTM and determine the relative efficacy of available agents.

Clomipramina no tratamento da perseguição compulsiva da cauda em Bull Terrier - relato de caso / Clomipramine in the treatment of compulsive tail pursuit in bull terrier - case report

A perseguição compulsiva da cauda consiste em um distúrbio caracterizado por movimentos giratórios em círculos, lentos a rápidos com ou sem foco na cauda. É uma desordem comportamental comumente observada em cães da raça Bull Terrier, sendo mais frequente em machos, com início entre três e seis meses de idade. O diagnóstico é realizado com base no histórico do paciente junto com exames físico, neurológico e laboratoriais. O tratamento pode ser feito por meio do manejo ambiental e da retirada de fatores estressantes aliados a medicamentos antidepressivos. O objetivo deste artigo é relatar o caso de um Bull Terrier que apresentava perseguição compulsiva da cauda e teve evidente melhora clínica 75 dias após início do tratamento com clomipramina. A melhora foi ainda maior após a orquiectomia. A clomipramina consiste em um antidepressivo tricíclico promissor no tratamento de perseguição compulsiva da cauda em cães, devendo-se associar alteração no manejo ambiental e evitar gatilhos que induzam frustração, ansiedade e conflito.(AU)

The compulsive pursuit of the tail is characterized by a rotating movement in circles, slow to fast with or without focus on the tail. It is a disorder commonly observed in bull terrier dogs, being more frequent in males, beginning between 3 and 6 months of age. Diagnosis can be made based on patient history along with physical, neurological, and laboratory tests. Treatment can be done through environmental management and withdrawal of stressors allied with antidepressant drugs. The objective of this article is to report the case of a Bull Terrier that had compulsive pursuit of the tail and had evident clinical improvement 75 days after starting treatment with clomipramine. The improvement was even greater after orchiectomy. Clomipramine is the promising tricyclic antidepressant in the treatment of compulsive tail chasing in dogs. It should be associated with changes in environmental management and avoid triggers that induce frustration, anxiety and conflict.(AU)

Clomipramina no tratamento da perseguição compulsiva da cauda em Bull Terrier - relato de caso / Clomipramine in the treatment of compulsive tail pursuit in bull terrier - case report

A perseguição compulsiva da cauda consiste em um distúrbio caracterizado por movimentos giratórios em círculos, lentos a rápidos com ou sem foco na cauda. É uma desordem comportamental comumente observada em cães da raça Bull Terrier, sendo mais frequente em machos, com início entre três e seis meses de idade. O diagnóstico é realizado com base no histórico do paciente junto com exames físico, neurológico e laboratoriais. O tratamento pode ser feito por meio do manejo ambiental e da retirada de fatores estressantes aliados a medicamentos antidepressivos. O objetivo deste artigo é relatar o caso de um Bull Terrier que apresentava perseguição compulsiva da cauda e teve evidente melhora clínica 75 dias após início do tratamento com clomipramina. A melhora foi ainda maior após a orquiectomia. A clomipramina consiste em um antidepressivo tricíclico promissor no tratamento de perseguição compulsiva da cauda em cães, devendo-se associar alteração no manejo ambiental e evitar gatilhos que induzam frustração, ansiedade e conflito.(AU)

The compulsive pursuit of the tail is characterized by a rotating movement in circles, slow to fast with or without focus on the tail. It is a disorder commonly observed in bull terrier dogs, being more frequent in males, beginning between 3 and 6 months of age. Diagnosis can be made based on patient history along with physical, neurological, and laboratory tests. Treatment can be done through environmental management and withdrawal of stressors allied with antidepressant drugs. The objective of this article is to report the case of a Bull Terrier that had compulsive pursuit of the tail and had evident clinical improvement 75 days after starting treatment with clomipramine. The improvement was even greater after orchiectomy. Clomipramine is the promising tricyclic antidepressant in the treatment of compulsive tail chasing in dogs. It should be associated with changes in environmental management and avoid triggers that induce frustration, anxiety and conflict.(AU)

Distúrbio compulsivo em cadela da raça Border Collie / Compulsive disorder in Border Collie bitch

Background: Compulsive disorders are excessive and repetitive behaviors that jeopardize the quality of life of both animaland guardian. It generally affects dogs between 6 and 36 months of age and its etiology is associated to stress, anxiety andgenetic predisposition. Clinical manifestations are the usual behaviors of the dog, but overly and inappropriately done.Diagnosis is based on a history of repetitive behavior and on clinical and complementary exams to discard other diseases.The aim of this study is to report a case of compulsive disorder in a female Border Collie dog, including diagnostic andtherapeutic approaches.Case: A 5-month-old, female, Border Collie dog was presented to Uberabas Veterinary Hospital owing to a chasingshadows behavior that started as a playtime activity but intensified to the point of becoming a repetitive and excessive act,followed by self-trauma and excessive barking. Clinical examination showed lesions in nasal planum region. No alterationswere observed on neurological examination apart from the chasing of shadows that also happened in the consultation room.Therefore, since there were no other findings on clinical and neurological exams, and since the manifestation occurredas a response to environmental stimuli (presence of shadows), it was established a presumptive diagnosis of compulsivedisorder. Treatment with trazodone chlorhydrate was performed, and it was indicated ovariohysterectomy, a follow-upwith a professional behaviorist and trainer and environment modifications. After a fortnight, it was observed a discreetimprovement of the clinical signs, hence a second anxiolytic, clomipramine, was added to the treatment. Approximately3 months after the beggining of therapy, there was improvement of the animals clinical picture...(AU)

The neonatal treatment with clomipramine decreases sexual motivation and increases estrogen receptors expression in the septum of male rats: Effects of the apomorphine.

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 ERß 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 ERß, only in septum area. These data indicate that neonatal treatment with CMI altered the expression of mRNA ERα and ERß in the septum, which participates in regulating the motivational component of sexual behavior.

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain.

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 ED50 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 ED50. 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 α2 -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.

The antidepressant clomipramine induces programmed cell death in Leishmania amazonensis through a mitochondrial pathway.

Despite many efforts, the currently available treatments for leishmaniasis are not fully effective. To discover new medications, drug repurposing arises as a promising strategy. We present data that supports the use of the antidepressant clomipramine against Leishmania amazonensis. The drug presented selective activity at micromolar range against both the parasite forms and stimulated nitric oxide production in host macrophages. Regarding the mechanism of action, clomipramine led parasites do mitochondrial depolarization, which coupled with the inhibition of trypanothione reductase induced strong oxidative stress in the parasites. The effects observed in promastigotes included lipoperoxidation, plasma membrane permeabilization, and apoptosis hallmarks (i.e., DNA fragmentation, phosphatidylserine exposure, and cell shrinkage). The mechanism of action in both parasitic forms was quite similar, but amastigotes also exhibited energetic stress, reflected by a reduction of adenosine triphosphate levels. Such differential effects might be attributable to the metabolic particularities of each form of the parasitic. Ultrastructural alterations of the endomembrane system and autophagy were also observed, possibly indicating an adaptive response to oxidative stress. Our results suggest that clomipramine interferes with the redox metabolism of L. amazonensis. In spite of the cellular responses to recover the cellular homeostasis, parasites underwent programmed cell death.

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression.

Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

Distúrbio compulsivo em cadela da raça Border Collie / Compulsive disorder in Border Collie bitch

Background: Compulsive disorders are excessive and repetitive behaviors that jeopardize the quality of life of both animaland guardian. It generally affects dogs between 6 and 36 months of age and its etiology is associated to stress, anxiety andgenetic predisposition. Clinical manifestations are the usual behaviors of the dog, but overly and inappropriately done.Diagnosis is based on a history of repetitive behavior and on clinical and complementary exams to discard other diseases.The aim of this study is to report a case of compulsive disorder in a female Border Collie dog, including diagnostic andtherapeutic approaches.Case: A 5-month-old, female, Border Collie dog was presented to Uberaba’s Veterinary Hospital owing to a chasingshadows behavior that started as a playtime activity but intensified to the point of becoming a repetitive and excessive act,followed by self-trauma and excessive barking. Clinical examination showed lesions in nasal planum region. No alterationswere observed on neurological examination apart from the chasing of shadows that also happened in the consultation room.Therefore, since there were no other findings on clinical and neurological exams, and since the manifestation occurredas a response to environmental stimuli (presence of shadows), it was established a presumptive diagnosis of compulsivedisorder. Treatment with trazodone chlorhydrate was performed, and it was indicated ovariohysterectomy, a follow-upwith a professional behaviorist and trainer and environment modifications. After a fortnight, it was observed a discreetimprovement of the clinical signs, hence a second anxiolytic, clomipramine, was added to the treatment. Approximately3 months after the beggining of therapy, there was improvement of the animal’s clinical picture...

In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach.

Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.

Early postnatal treatment with clomipramine induces female sexual behavior and estrous cycle impairment.

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.

Análisis de impacto presupuestal de citalopram, clomipramina escitalopram, paroxetina, fluvoxamina, fluoxetina y sertralina para pacientes con Trastorno Obsesivo Compulsivo en Colombia / Budget impact analysis of citalopram, clomipramine escitalopram, paroxetine, fluvoxamine, fluoxetine and sertraline for patients with Obsessive Compulsive Disorder in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) del citalopram, clomipramina, escitalopram, paroxetina, fluvoxamida, fluoxetina y sertralina para pacientes con trastorno obsesivo compulsivo (TOC) en Colombia, se desarrolló en el marco del mecanismo técnico-científico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015 (1). Estas tecnologías fueron seleccionadas por la Dirección de Beneficios, Costos y Tarifas del Aseguramiento en Salud del Ministerio de Salud y Protección Social (MinSalud), y remitidas al Instituto de Evaluación Tecnológica en Salud (IETS) para su evaluación. El TOC es un trastorno de ansiedad que se caracteriza por pensamientos intrusivos, recurrentes (obsesiones) y persistentes, que producen inquietud, temor o preocupación y comportamientos repetitivos (compulsiones) dirigidos a reducir la ansiedad asociada. Afectan el rendimiento laboral, académico y las relaciones interpersonales, generando un deterioro en la calidad de vida de los pacientes, así como el desarrollo de ideas o comportamientos suicidas. Se estima que la prevalencia del TOC en la población general a nivel mundial es de 1,6%, siendo uno de los principales trastornos que afecta a niños y adolescentes (3). La prevalencia de TOC en Colombia oscila entre el 0,9% y el 2,4% (4); se ha observado una mayor incidencia de este trastorno en las mujeres que en los hombres, en quienes se evidencia una fuerte relación de episodios psicóticos con otros tipos de trastornos como la esquizofrenia (5,6).Según los reportes del Sistema Integral de Información de la Protección Social (SISPRO), entre los años 2009 y 2013, se diagnosticaron en promedio 1194 casos nuevos de pacientes con TOC en Colombia. Adicionalmente, se ha encontrado que el 55 % de los casos reportados han sido en pacientes entre los 27 a 59 años de edad. El DSM-IV establece como criterio para el diagnóstico de TOC, que las obsesiones y compulsiones resulten excesivas o irracionales para el paciente, aunque aclara que este criterio no es aplicable a los menores, ya que es frecuente que estos síntomas sean ego sintónicos para los niños e incluso para algunos adolescentes (8). En la actualidad, el TOC es entendido como un único trastorno sea cual sea la edad en el que aparezca, aunque en el 80% de los casos el inicio del trastorno ocurre antes de los 18 años. Este documento describe la metodología desarrollada para realizar el análisis de impacto presupuestal de citalopram y clomipramina para pacientes con TOC que requieren manejo farmacológico en Colombia. Este informe, sigue los lineamientos propuestos en el Manual para la Elaboración de Análisis de Impacto Presupuestal y en el Manual de Participación y Deliberación publicados por IETS. TECNOLOGÍAS EVALUADAS: En el escenario actual se incluyeron las tecnologías que se encuentran cubiertas por el Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) para el TOC. Así mismo, se definieron los tratamientos farmacológicos para primera y segunda línea del TOC a partir de consideraciones clínicas expuestas por los expertos temáticos. Los tratamientos farmacológicos con las tecnologías que se encuentran dentro del escenario actual son: Tratamiento de primera línea: sertralina y fluoxetina. Tratamiento de segunda línea: no se identificó ninguna tecnología. INSUMOS Y MÉTODOS: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal. Cada una de las fuentes de información, estructuración de casos tipo y supuestos de modelación que fueron discutidos con el grupo de expertos temáticos en espacios de participación promovidos por el IETS. DISTRIBUCIÓN DE LA POBLACIÓN EN EL ESCENARIO ACTUAL: De acuerdo a la Base de Datos Única de Afiliados del Sistema General en Salud (BDUA) para el año 2017 se registran 32.768.685 personas mayores de 18 años en Colombia; al aplicar la prevalencia de TOC identificada previamente, se estimaron 1.540.128,195 casos. Considerando que entre estos pacientes el 33% presentan comorbilidades, el número de casos que tendrían únicamente diagnóstico de TOC correspondería a 508.242 casos. Para establecer la probabilidad de requerir tratamiento farmacológico en los pacientes con diagnóstico de TOC, el consenso de expertos y el estudio publicado por Martin P, en el año 2003 establecen que aproximadamente el 68% de los pacientes con TAG requieren tratamiento farmacológico de primera línea (22); tomando esta probabilidad se estiman para Colombia 345.605 casos de TOC como población objetivo para el presente AIP. Para establecer la probabilidad de requerir tratamiento farmacológico de segunda línea en los pacientes con diagnóstico de TOC, se extrajeron las probabilidades de respuesta a los tratamientos de primera línea reportadas en el análisis de costo-efectividad de escitalopram comparado con paroxetina, fluoxetina, sertralina, fluvoxamina y clomipramina como terapia de mantenimiento para pacientes con trastorno obsesivo compulsivo en Colombia (21). Considerando este estudio, se estableció que la probabilidad de respuesta a los tratamientos de primera línea es de 0,515, por lo tanto, por propiedades de probabilidades complementarias, se estimó que el 48% (1-p) de los pacientes requerirían tratamiento de segunda línea, dando como resultado una estimación de 165.890 casos. MÉTODOS DE COSTEO Y COSTOS: Se obtuvo como primera medida los registros sanitarios vigentes por parte del INVIMA para el primer semestre del 2017. Para la valoración de los medicamentos se utilizó SISMED para el año 2016 (enero-diciembre), tomando como base el canal institucional laboratorio. Para cada tratamiento se identificó la dosis promedio recomendada para cada tecnología sugerida en la fuente de información Micromedex ® 2017 (23), la periodicidad y la duración del tratamiento. El precio promedio, mínimo y máximo por tableta o unidad calculada corresponde al precio ponderado de las diferentes presentaciones del medicamento, el cual comprende tanto los genéricos como las moléculas originales. Con lo anterior se buscó determinar un precio ponderado del principio activo, y no de una molécula en particular. Adicionalmente se revisaron las circulares de regulación de precios del Ministerio de Salud, con el fin de identificar si a la fecha existe un precio máximo regulado de alguna de las alternativas de comparación. El procedimiento para calcular los precios de los medicamentos siguió las recomendaciones del manual metodológico para la elaboración de evaluaciones económicas del IETS. RESULTADOS: Los resultados que se presentan en el informe corresponde al impacto presupuestal total e incremental obtenidos en los escenarios 1 y 2 para los tratamientos de TOC de primera y segunda línea.

Análisis de costo-efectividad de escitalopram comparado con paroxetina, fluoxetina, sertralina, fluvoxamina y clomipramina como terapia de mantenimiento para pacientes con trastorno obsesivo compulsivo en Colombia / Cost-effectiveness analysis of escitalopram compared to paroxetine, fluoxetine, sertraline, fluvoxamine and clomipramine as maintenance therapy for patients with obsessive-compulsive disorder in Colombia

Problema de investigación: Analizar los costos y la efectividad del escitalopram comparado con paroxetina, sertralina, fluoxetina, fluvoxamina y clomipramina como terapia de mantenimiento de primera línea en pacientes con trastorno obsesivo compulsivo en Colombia. Tipo de evaluación económica: Análisis de costo-efectividad. Población objetivo: Pacientes mayores de 18 años con diagnóstico de trastorno obsesivo compulsivo. Intervención y comparadores: Comparadores: paroxetina, sertralina, fluoxetina, fluvoxamina y clomipramina. Horizonte temporal: 32 semanas. Perspectiva: Sistema General de Seguridad Social en Salud (SGSSS). Tasa de descuento: No aplica. Estructura del modelo: Árbol de decisión. Fuentes de datos de efectividad y seguridad: Reporte de efectividad y seguridad, Ensayos clínicos aleatorios. Desenlaces y valoración: Años de vida ajustados por calidad (AVAC). Costos incluidos: Costo de los medicamentos, Costo de procedimientos, Costo de los eventos adversos. Fuentes de datos de costos: SISMED, Manual tarifario ISS 2001. Resultados del caso base: En el escenario del caso base, fluvoxamina, fluoxetina, paroxetina y clomipramina son dominados por sertralina y escitalopram. El costo por AVAC es $16.084.456 de escitalopram comparado con sertralina. Análisis de sensibilidad: Los análisis de sensibilidad y el diagrama de tornado mostraron que las variables con mayor impacto sobre las estimaciones de costo-efectividad del escitalopram son la probabilidad de respuesta y retiro por eventos adversos del medicamento sertralina. Conclusiones y discusión: Escitalopram parece ofrecer una mejor relación entre costos y efectividad respecto a sus comparadores. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo. La principal limitación de este estudio se centra en la ausencia de ensayos clínicos de no inferioridad con un horizonte de largo plazo.(AU)