Current Treatment Strategies of Obsessive- Compulsive Disorder.

In the last decades, the treatment of obsessive-compulsive disorder (OCD) has dramatically improved with the introduction into the clinical practice of the selective serotonin reuptake inhibitors (SSRIs). However, a large part of patients do not respond to first-line drugs and different augmentation strategies have been proposed. More recently, some non-pharmacological techniques have been proposed, but the evidence of effectiveness is just preliminary. In this paper, the most recent works on pharmacological and alternative treatments of OCD will be reviewed.

Serotonin Syndrome after Clomipramine Overdose in a Child

Serotonin syndrome (SS) is a potentially life-threatening condition associated with increased serotonergic activity in central nervous system and may occur during the use of serotonergic drugs. Although increasing frequency of serotonergic drug use in children, pediatricians, emergency medicine and pediatric intensive care specialists have not enough knowledge and experience about SS that is a potentially life-threatening condition. A 12-year-old girl patient was admitted to our emergency room with the history of involuntary contractions on her extremities and alteration of consciousness. Her physical examination showed agitation, hyperthermia, dilated pupils, tremor, increased deep tendon reflexes, positive spontaneous clonus, agitation, flushed skin and diaphoresis, excessive perspiration, and continuous horizontal ocular movements. The patient diagnosed as SS by clinical history, physical and laboratory findings. In this paper, we will discuss SS occurred in a 12-year-old girl after concurrent clomipramine and risperidone use.

Simultaneous determination of clomipramine and four benzodiazepines in human plasma by HPLC-DAD after solid phase extraction / 中国药理学通报

Aim To establish a novel,highly sensitive,rapid and cost-effective HPLC method to simultaneously determine tri-cyclic antidepressant clomipramine and four benzodiazepines of diazepam,alprazolam,clonazepam,oxazepam in human plasma pretreated by solid phase extraction.Methods The assay was achieved by using C8 column (4.6 mm ×1 50 mm,5 μm)kept at 45 ℃,mobile phase 73.2:26.8 V/V (50 mmol·L -1 ,pH 3.0 phosphate buffer:acetonitrile)with flow rate of 1 .2 ml· min -1 ,and UV detection was set at λ220 nm.Solid phase ex-traction was performed on C1 cartridges.Results The calibra-tion curve was demonstrated to be linear (r >0.9994)in the ranges of 5 ~200 μg·L -1 for alprazolam and clonazepam,1 0 ~500 μg·L -1 for diazepam,20 ~500 μg· L -1 for clomipra-mine,and 7.5 ~2000 μg·L -1 for oxazepam;the limit of detec-tion (LOD)was 1 .5,1 .4,3.0,5.5 and 2.2 μg·L -1 for al-prazolam,clonazepam,diazepam,clomipramine and oxazepam respectively.Intra-day and inter-day precision revealed a coeffi-cient of variation of 2.2% ~1 2.6% and 2.1 % ~1 3.2%,re-spectively.Extraction yield ranged from 81 .1 % ~1 00.1 % for all analytes.Conclusion The developed method is accurate, reproducible,convenient,and suitable for routine therapeutic drug monitoring of clomipramine and the four benzodiazepines.

Effect of clomipramine combine sleep deprivation on depression rat behavior and hippocampal CA3 neuron apoptosis / 中华行为医学与脑科学杂志

Objective To analyze the effect of clomipramine combine sleep deprivation on depression rat behavior and hippocampal CA3 neuron apoptosis.Methods Chronic unpredictable mild stimulation was used to establish 40 depression model rats.They were randomly divided into depression group,clomipramine group (5 mg/kg orally),sleep deprivation group (36 h continuous full sleep deprivation),chlorpromazine combination of sleep deprivation group,and then selected 10 rats as control group.Open-field test and water maze test were used to test rats' behavioral change after 28 days intervention.RT-PCR,Western blot were used to detect the GDNF and Bcl-2 expression of hippocampal CA3 neurons.TUNEL assay was performed to test hippocampal CA3 neuron apoptosis ratios in each group.Results Open-field test level score,vertical score and latency of combination group were (75.6±7.3),(26.4±4.3),(1.1±0.2),and showed no significant difference with those of control group((79.4 ±6.8),(28.6±5.7),(1.0±0.4)) after 28 d intervention (P＞0.05),while the level score,vertical score were significantly higher than those in other three groups(P＜0.05),and the latency period was significantly lower than that in other three groups (P＜0.05).The combined group showed a trend of gradually shortened in water maze escape latency.GDNF,Bcl-2 expression of control group and combined group was significantly higher than those in other three groups (P＜0.05),while the difference between the two groups was not statistically significant (P＞0.05).Sleep deprivation group' apoptotic rate was the highest (55±6)％,significantly higher than the control group and the combination group ((14±3) ％ and (19±4)％).Conclusion Clomipramine combined sleep deprivation can improve the ability of rat model of depression and suppression of acts of hippocampal CA3 neuron apoptosis,and its effect may be related to increased hippocampal CA3 GDNF,Bcl-2 level.

Rhabdomyolysis as a manifestation of clomipramine poisoning / Rabdomiolise como manifestacao de intoxicacao por clomipramina

CONTEXT: Tricyclic antidepressive agents are widely used in suicide attempts and present a variety of deleterious effects. Rhabdomyolysis is a rare complication of such poisoning. CASE REPORT: A 55-year-old woman ingested 120 pills of 25 mg clomipramine in a suicide attempt two days before admission. After gastric lavage in another emergency department on the day of intake, 80 pills were removed. On admission to our department, she was disoriented, complaining of a dry mouth and tremors at the extremities. An electrocardiogram showed a sinus rhythm with narrow QRS complexes. Laboratory results showed high creatine phosphokinase (CK = 15,094 U/l on admission; normal range = 26 to 140 U/l), hypocalcemia, slightly increased serum transaminases and mild metabolic acidosis. The patient's medical history included depression with previous suicide attempts, obsessive-compulsive disorder, hypothyroidism and osteoporosis. She presented cardiac arrest with pulseless electric activity for seven minutes and afterwards, without sedation, showed continuous side-to-side eye movement. She developed refractory hypotension, with need for vasopressors. Ceftriaxone and clindamycin administration was started because of a hypothesis of bronchoaspiration. The patient remained unresponsive even without sedation, with continuous side-to-side eye movement and a decerebrate posture. She died two months later. Rhabdomyolysis is a very rare complication of poisoning due to tricyclic drugs. It had only previously been described after an overdose of cyclobenzaprine, which has a toxicity profile similar to tricyclic drugs. CONCLUSIONS: Although arrhythmia is the most important complication, rhabdomyolysis should be investigated in cases of clomipramine poisoning. .

CONTEXTO: Antidepressivos tricíclicos são amplamente utilizados em tentativas de suicídio e apresentam diversos efeitos deletérios, sendo a rabdomiólise uma complicação rara dessa intoxicação. RELATO DO CASO: Uma mulher de 55 anos ingeriu 120 comprimidos de clomipramina de 25 mg numa tentativa de suicídio dois dias antes da admissão. Após lavagem gástrica em outro serviço de urgência no dia da ingestão, 80 comprimidos foram retirados. Na admissão em nosso serviço, a paciente estava desorientada, queixando-se de boca seca e tremores de extremidades. O eletrocardiograma mostrou ritmo sinusal com complexos QRS estreitos. Exames laboratoriais evidenciaram aumento de creatinofosfoquinase (CK = 15.094 U/L na admissão; intervalo da normalidade = 26 a 140 U/L), hipocalcemia, discreto aumento das transaminases e leve acidose metabólica. Antecedentes pessoais incluíam depressão com tentativas de suicídio prévias, transtorno obsessivo compulsivo, hipotireoidismo e osteoporose. A paciente apresentou parada cardiorrespiratória com atividade elétrica sem pulso por sete minutos e, posteriormente, sem sedação, foi observado olhar em varredura. A paciente evoluiu com hipotensão refratária, necessitando de vasopressores. Ceftriaxone e clindamicina foram iniciados pela hipótese de broncoaspiração. A paciente permaneceu irresponsiva mesmo sem sedação, com olhar em varredura contínuo e postura descerebrada. A paciente evoluiu para óbito dois meses após. Rabdomiólise é uma complicação rara da intoxicação por tricíclicos, e só foi descrita em overdose de ciclobenzaprina, a qual tem um perfil de toxicidade semelhante aos tricíclicos. CONCLUSÕES: Apesar de as arritmias serem as complicações mais temidas, ...

Effect of clomipramine in a dog with cataplexy / 대한수의학회지

A 5-year-old, castrated male, Maltese was presented with history of acute flaccid paralysis. The dog was presented with sudden loss of muscle tone and involuntary movements of hind limbs. Neurologic examination revealed reduced postural reaction in the bilateral hind limbs. MRI of brain showed moderate hydrocephalus, but other examination results were normal. Based on the characteristic episodes and examination results, canine cataplexy was suspected. Treatment was initiated with clomipramine as cataplexy control. Clinical signs resolved with 3-month medication. This case demonstrates therapeutic diagnosis of cataplexy. To the author's knowledge, this is the first report of cataplexy treating with clomipramine.

Clomipramine treatment of acral lick dermatitis in a dog / 대한수의학회지

An 11-year-old, toy poodle dog was presented with dermatologic lesions and mammary gland tumor (MGT) evaluation. A solitary, lobulated MGT (size 2.5 x 3.5 cm) was affecting the 5th left mammary gland. Firm, oval plaque skin lesions were present on the left dorsal carpal area. The skin lesions were alopecic and salivary staining. The dog had historical separation anxiety and excessive licking of skin lesions were observed. Based on the clinical and histopathologic examinations, MGT was diagnosed with mammary complex adenoma and the skin lesions were diagnosed with acral lick dermatitis. Behavior modification treatment using oral clomipramine was effective.

Neonatal treatment with clomipramine and depression: A review of behavioral and physiological findings

Many times in science, the discovery of a treatment that has certain effect happens accidentally while the scientists are investigating another phenomenon. This is the case of the discovery of a possible animal model of depression by the administration of clomipramine (CLI) during neonatal days. Adult animals exposed to CLI in neonatal days showed alterations in REM sleep (for example, the decrease of REM latency); lower weight, disruptions in locomotor activity (the increase in activity depend on the dark / light phase in which the test starts, when the animals were tested in the light phase they found increase in activity, but no changes were observed when the animals were tested in the dark phase); less intracraneal self-stimulation, lower saccharin and sucrose consumption, less suppression of the consummatory behavior, sexual alterations in males (for example, expressed as a lower number of mounts and ejaculations; no alterations were found in the activity of the Hypothalamic - Pituitary - Gonadal axis and the level of testosterone was normal), higher alcohol consumption, disruptions in the agonistic response (CLI - treated animals were significantly less aggressive than control groups) and in learning (in the passive avoidance task and 8 radial arm maze) compared to untreated animals (rats that received vehicle during neonatal days). Several of these abnormalities could be reversed with those treatments that are effective for treating depression in humans (antidepressive drugs, nicotine and REM sleep deprivation treatment). These results were obtained in male rats of different strains and in hamsters, and at different months, the majority of them at 3-4 months, and some of them after the sixth, this could be because some changes were caused with the decrement in the age of the animals, although further research is needed to elucidate this issue. Neuroendocrinal alterations analogous to those found in human depression were also discovered in CLI - treated rats, although the data is contradictory. These include Hypothalamic - Pituitary - Adrenal axis alterations; while it is true that some experimental results found that CLI - treated rats have a higher basal level of corticosterone than controls, others found that not only do they differ in basal level, also during the stress situation; circulating corticosterone increases less and returns more rapidly to basal levels than control groups. For this reason, we can conclude that if alterations in the HPA axis indeed exist in CLI - treated animals, it is still unclear in which way the deregulation is manifested. Other results support the hypothesis that alterations found in CLI - treated animals are due to alterations in serotoninergic transmission during a critical period of development, such as the neonatal stage; more specifically, a reduction in the hypothalamic concentration of serotonin, like a decrease in the neuronal firing in the dorsal raphe nucleus. An increase in cholinergic activity was also found, although the data in this field is not as vast as that found in relation to the neurotransmission of serotonin. All of these results suggest that rats treated with CLI during neonatal days present alterations in adulthood analogous to human depression, however other findings indicate that is not yet a valid model. Further research is needed, and we have to be cautious with the conclusions because there is some evidence suggesting that this is a promising model but other does not support its validity. If a model like the neonatal administration of CLI achieves the reproduction of some symptoms, neurophysiological and behavioral alterations of depression, the advantages are invaluable. In this sense, neonatal treatment with CLI is a very promising animal model for the study of depression.

El presente trabajo describe los principales resultados acerca de un nuevo y probable modelo animal de depresión. Este modelo se basa, paradójicamente, en la administración de un antidepresivo, clomipramina, a ratas neonatas. Cuando los animales alcanzan la adultez, muestran alteraciones comportamentales que pueden ser interpretadas como depresivas, como hiperactividad, descenso en la búsqueda de placer, anormalidades en el sueño, entre otras. Se analizan los posibles mecanismos neurofisiológicos y neuroendocrinos involucrados. A pesar de las limitaciones que ofrece un modelo animal, es importante cómo logra reproducir algunos síntomas hallados en la depresión y debido a esto las ventajas del mismo son invaluables. Además, pueden estudiarse los mecanismos cerebrales implicados en la patogénesis y tratamiento del trastorno que por razones éticas son impensables de llevar a cabo en humanos. Por ello, se considera de gran valor el estudio realizado con el modelo de clomipramina con la perspectiva de que se siga trabajando en la validación del mismo.

Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment / Estudo de associação entre polimorfismos genéticos monoaminérgicos e resposta à clomipramina no tratamento do TOC

In the present paper, we investigated the 5HTTLPR and STin2 polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4), the G861C polymorphism (rs6296) of the serotonin receptor 1D beta (HTR1B), the T102C (rs6113) and C516T (rs6305) polymorphisms of the serotonin receptor gene subtype 2A (HTR2A), the DAT UTR, DAT intron 8 and DAT intron 14 of the dopamine transporter gene (SLC6A3), the Val-158-Met (rs4680) polymorphism of the COMT and the silent mutation G1287A (rs5569) in the norepinephrine transporter gene (SLC6A2). We genotyped 41 obsessive-compulsive disorder (OCD) outpatients, classified as good-responders (n=27) and poor-responders (n=14) to treatment with clomipramine according to the Yale Brown Obsessive-Compulsive Scale (YBOCS). Patients who achieved a reduction in symptoms of 40 percent or more in YBOCS after 14 weeks of treatment were considered good-responders. Genotypes and alleles distribution of the investigated polymorphisms were compared between both groups. We did not find association between the studied polymorphisms and clomipramine response in our sample.

No presente estudo, investigaram-se os polimorfismos 5HTTLPR e STin2 da região promotora do gene transportador de serotonina (SLC6A4), o G861C (rs6296) do receptor de serotonina 1D beta (HTR1B), os polimorfismos T102C (rs6113) e C516T (rs6305) do gene do receptor da serotonina subtipo 2A (HTR2A), os polimorfismos UTR, intron 8 e intron 14 do gene transportador de dopamina (SLC6A3), o Val-158-Met (rs4680) da COMT e a mutação G1287A (rs5569) do gene do transportador de norepinefrina (SLC6A2). Foram genotipados 41 pacientes com transtorno obsessivo-compulsivo (TOC), classificados como bons-respondedores (n=27) e maus-respondedores (n=14) ao tratamento com clomipramina, por meio do uso da Escala de Sintomas Obsessivos-Compulsivos Yale Brown (YBOCS). Foram considerados bons-respondedores os pacientes que tiveram redução nos sintomas em 40 por cento ou mais na YBOCS, após 14 semanas de tratamento. A distribuição dos genótipos e alelos estudados foi comparada entre os dois grupos. Não foi encontrada associação entre estes polimorfismos investigados e a resposta à clomipramina na amostra estudada.

Padrões de funcionamento cerebral em voluntários saudáveis antes e após o uso de antidepressivo: estudo de ressonância magnética funcional durante indução emocional através de estimulação visual / Patterns of brain functioning in healthy volunteers before and after the use of antidepressant: a study of functional magnetic resonance imaging during emotional induction through visual stimulation

INTRODUÇÃO: O processamento emocional pelo cérebro humano tem sido atualmente investigado através do uso de ressônancia magnética funcional (RMf). A RMf possibilita o estudo in vivo e não invasivo de mudanças na atividade cerebral regional em voluntários humanos saudáveis. O processamento emocional pode ser modulado através do uso de antidepressivos que influenciam sistemas neurais relacionados ao processamento emocional, através da modulação da ação de neurotransmissores como a serotonina e a noradrenalina. A clomipramina, um antidepressivo tricíclico, tem sido relacionada com efeitos de resposta clínica mesmo em voluntários saudáveis. Estudos utilizando a RMf permitem a investigação do efeito de antidepressivos nos sistemas neurais envolvidos no processamento emocional em indivíduos saudáveis que apresentam resposta ao uso destes medicamentos comparados a sujeitos que não apresentam resposta ao tratamento. MÉTODOS: Nesta tese, dezoito voluntários saudáveis foram investigados em relação a mudanças de atividade neural em resposta à indução emocional através da apresentação de fotografias do International Affective Pictures System (IAPS). Foram estudadas particularmente as emoções de raiva, felicidade e medo. Os voluntários foram submetidos ao tratamento prolongado com doses baixas de clomipramina por quatro semanas. A amostra foi subdividida em respondedores (n=6) e não respondedores (n=12) ao tratamento com clomipramina. A atividade neural foi estimada com o uso da RMf, através da mensuração do efeito blood oxygenation level dependent (BOLD). As imagens foram processadas e analisadas usando o programa Statistical Parametric Mapping (SPM). Indivíduos não respondedores foram comparados sob o efeito e na ausência de efeito da clomipramina, através de comparações planejadas utilizando t-teste pareado. Indivíduos respondedores foram comparados com os não respondedores sob o efeito da clomipramina através de t-teste não pareado. RESULTADOS: Nos voluntários...

INTRODUCTION: The emotional processing by the human brain has now been investigated through the use of functional magnetic resonance imaging (fMRI). The fMRI technique allows the noninvasive study of in vivo changes in regional brain activity in healthy human volunteers. The emotional processing may be modulated through the use of antidepressants that influence neural systems linked to emotional processing, by modulating the action of neurotransmitters such as serotonin and norepinephrine. Clomipramine, a tricyclic antidepressant, has been reported to elicit clinical response even in healthy volunteers. Studies using fMRI allow the investigation of the effect of antidepressants on neural systems involved in emotional processing in healthy subjects showing response to the use of antidepressant drugs compared to subjects who do not respond to treatment. METHODS: In this thesis, eighteen healthy volunteers were investigated in relation to changes in neural activity in response to emotional induction through the presentation of photos of the International Affective Picture System (IAPS). We studied especially the emotions of anger, happiness and fear. The volunteers were subjected to prolonged treatment with low doses of clomipramine for four weeks. The sample was divided into responders (n = 6) and non-responders (n = 12) to treatment with clomipramine. The neural activity was estimated by using fMRI, by measuring the blood oxygenation level dependent effect (BOLD). Images were processed and analyzed using the Statistical Parametric Mapping (SPM) program. Non-responders were compared under two conditions: when using clomipramine, and after drug washout, using paired t-tests. Individuals who responded to clomipramine treatment were compared with non-responders under the effect of the drug by independent t-test. RESULTS: In volunteers not responding to clomipramine, a comparison between the non-medicated versus medicated states showed less neural activity...

The Comparative Study on Treatment of Depressive Disorder with Jieyu Huatan Mixture / 国际中医中药杂志

Objective Through observing clinical effects of Western medicine,Chinese medicine and Chinese combined with western medicine in the treatment of depressive disorder (DD),the author tried to investigate a safer,more effective and obedient therapeutic method. Methods 120 DD patients were randomly recruited into three groups.Patients in group A were orally given clomipramine 25mg,3/d and Jieyu Huatan mixture 50ml,2/d;Patients in group B were orally given Jieyu Huatan mixture 50ml,2/d;Patients in group C were orally given clomipramine 25rag,3/d.After 6 weeks,Hamilton's depression (HAMD) and treatment emergent symptom scale (TESS) scale were used to assess the efficacy and safety.Results Altogether116 patients completed the whole treatment.Total clinical effective rate,effective rate of symptom improvement,and HAMD total cut-rate were 95.00%,92.50%,69.13±29.47% in the group A,69.23%,64.10%,53.22±25.78 % in the group,and 70.27%,64.87%,53.47±26.29% in the group C respectively.Patients in the group A were significantly better than the other two groups (P＜0.01) in terms of the indications mentioned above,while no significant difference showed between the group B and the group C (P＞0.05).Meanwhile the TESS score in the group A and B was lower than the group C (P＜0.01),and there was no significant difference between the group A and the group B (P＞0.05).Conelusion The treatment of Jieyu Huatan mixture combined with clomipramine is more effective and faster onset of action,having fewer side effects and reasonable cost.This method is a good way in the treatment of depressive disorder.

Cost-Effectiveness Analysis of 3 Therapeutic Regimes for Depression / 中国药房

0.05),respectively,and the cost-effectiveness ratios were 743.62,1 032.40 and 738.03,respectively.CONCLUSION:Group C is superior in terms of the cost-effectiveness ratios among the 3 regimes for depression.

Intravenous Anti-obsessive Agents : A Review / 대한정신약물학회지

Oral (p.o.) administration has a delayed onset time of several weeks and moderate efficacy in obsessive-compulsive disorder (OCD), therefore a more rapidly effective treatment is required. The aim of this paper was to review available data detailing the clinical outcome of intravenously (i.v.) administered antiobsessional drug in OCD patients. Review of the research indicates that i.v. administration exhibits a faster onset and greater improvement than p.o. administration. I.v. pulse administration showed clinically significantly faster onset than i.v. gradual administration. I.v. administration was safe and rapidly effective in treatment resistant OCD patients and might be a valuable new treatment.

Preparation and Release Rate in Vitro of Clomipramine Hydrochloride Sustained-release Tablets / 中国药房

OBJECTIVE: To prepare clomipramine hydrochloride sustained release tablet and study its in vitro release rate.METHODS: Orthogonal experiment was carried out to optimize the formulation and the preparation was prepared taking by the formula dosage of HPMC,lactose and amylum pregelatinisatum as factors and the in vitro release rate as index.The in vitro drug release rate was investigated as well.RESULTS: The optimal formulation was as follows: HPMC 45 mg,lactose 35 mg,and amylum pregelatinisatum 40 mg.The preparation prepared in the optimal formulation had a sustained release of 24 h and the release behavior of the tablets followed the zero order equation.CONCLUSION: The formula of the sustained release tablets is reasonable and which had satisfactory sustained release efficacy.

Cost-effectiveness Analysis of3Therapeutic Regimes for Depression / 中国药房

0.05),re-spectively,and the cost-effectiveness ratios were9.12,12.29and8.50,respectively.CONCLUSION:Group C is superior in terms of the cost-effectiveness ratio among the3regimes for depression.

A Case of Clomipramine-Induced Chronic Dilated Cardiomyopathy

Dilated cardiomyopathy is a primary myocardial disease characterized by ventricular dilatation and impaired ventricular contractility. The etiology of dilated cardiomyopathy has not been known yet, but toxin such as alcohol, thiamine deficiency, endocrine disorder, viral or bacterial infection, hereditary disorder, and muscular dystrophy may be related to dilated cardiomyopathy. Cocaine abuse and anticancer drugs (especially doxorubicin) were reported as the causes of drugs of dilated cardiomyopathy also. Recently we experinced a case of dilated cardiomyopathy in 30 years old man who developed dilated cardiomyopathy on chronic clomipramine (one of trcyclic antidepressant drugs) treatment for a obsessive-compulsive disorder. He became asymptomatic and normalization of left ventricular diameters and function was evidenced echocardiographically after withdrawal of the drug. The possible association of cardiomyopathy and tricyclic antidepressant drugs and possibility of functional improvement after tricyclic antidepressant drugs withdrawal should be kept in mind.