Intravenous Clomipramine Research Articles

P.2.f.028 - Intravenous clomipramine for treatment resistant depression

P.2.f.028 - Intravenous clomipramine for treatment resistant depression

Clinical practice guidelines for Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a common psychiatric illness with lifetime prevalence of 1-3% [1]. It is the fourth-most common psychiatric illness and a leading cause of disability. OCD is associated with significant impairment in functioning, quality of life and disability. If untreated, OCD is a chronic illness with a waxing and waning of symptoms. A recent meta-analysis of long-term naturalistic prospective studies demonstrated that nearly a half of patients experience remission with much higher rates of remission in Indian patients compared to those in the west [2]. Early diagnosis and appropriate treatment may improve outcomes. Despite OCD being a common mental illness, most seek treatment after several years of suffering. Those who suffer from OCD tend to be secretive about their symptoms and suffer from shame and embarrassment. Less than a third of OCD sufferers receive appropriate pharmacotherapy and even less receive evidence-based psychotherapy. Symptoms The hallmarks of OCD are presence of obsessions and compulsions. Obsessions are repetitive, unwanted, intrusive thoughts, images or urges that are mostly ego-dystonic and cause severe distress or anxiety. Compulsions (or rituals) are repetitive behaviours or mental acts that are performed in response to an obsession to reduce anxiety/distress or prevent a dreaded consequence. Obsessions and compulsions are time consuming, distressing and are often resisted unsuccessfully. Clinical manifestations of OCD are remarkably similar across cultures and geographic locations. Common obsessions and compulsions and symptom dimensions identified through factor-analytical studies are shown in Table 1. Table 1 Common symptoms of OCD

CITALOPRAM PULSE-LOADING FOR TREATMENT-RESITANT OBSESSIVE-COMPULSIVE DISORDER: PRELIMINARY DATA FROM AN OPEN-LABEL TRIAL

Purpose of the study Treatment resistance is a frequent situation in Obsessive Compulsive Disorder (OCD), occurring in 40–60% of patients. However, in the current literature there are only a few evidence-based options for treatment resistant patients. Pulse-loading treatment consists in a rapid titration of the pharmacological agent in the first days of treatment. A few studies suggested that this kind of titration with intravenous clomipramine could result in a greater and faster response than with a standard titration in OCD resistant patients Koran, 2006 , Grassi, 2013 . The aim of this open-label trial was to investigate the effectiveness and tolerability of a citalopram pulse-loading protocol in severe treatment-resistant OCD patients. Methods We enrolled 7 severe treatment-resistant OCD patients. Treatment-resistance was defined as non-response to two Serotonin Re-uptake Inhibitors (SRIs) trials, one antipsychotic augmentation trial and a non-response to 16 sessions of Cognitive-Behavioral Therapy (CBT) (Pallanti et al., 2002) . After a 2-week washout period from previous SRIs medications, patients were treated with intravenous citalopram starting with 40 mg for 3 days and increasing the dose up to 80 mg from the fourth day. The patients continued the treatment with 80 mg of intravenous citalopram for 18 days (a total of 21 days of intravenous treatment), then they switched to oral treatment (80 mg of oral citalopram). The patients treated with an antipsychotic augmentation, continued their antipsychotic treatment without any change during all the treatment protocol. No cognitive or behavioral psychotherapy was allowed during the intravenous or oral citalopram treatment period. We assessed treatment response using the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and the Clinical Global Impression – Improvement scale (CGI-I) at baseline, week 3 and week 12. The pulse-loading protocol incorporated standard criteria for treatment response (>35% improvement in baseline Y-BOCS scores and a CGI-I of 1 or 2), partial response (≥ 25% improvement in baseline Y-BOCS scores), and non-response ( [3] . Tolerability was assessed with a clinical report form. We assessed putative cardiac side effects with an electrocardiography at baseline, after the fourth day of infusion and before switching to oral therapy, monitoring any QTc change. We also monitored sodium levels during all the course of treatment. Results During the pulse-loading treatment no patients showed significant adverse events. No patients showed clinical significant change of the QTc interval and/or of the sodium levels. Four out of seven patients had a partial or full response at the end-point (3 patients had a full response and 1 patient had a partial response) and one of these had remission. Pulse-loading treatment seemed to induce a faster improvement respect to a standard titration, since the responder patients showed a significant improvement already after 3 weeks. Three out of seven patients did not respond. Conclusion Taking into account the very limited sample size, this case series suggests that this treatment approach deserves further controlled studies.

Citalopram Pulse-loading for Treatment-resitant Obsessive-compulsive Disorder: Preliminary Data From an Open-label Trial

Introduction Pulse-loading treatment consists in a rapid titration of the pharmacological agent in the first days of treatment. A few studies suggested that this kind of titration with intravenous clomipramine could result in a greater and faster response than with a standard titration in obsessive-compulsive disorder (OCD) resistant patients. The aim of this open-label trial was to investigate the effectiveness and tolerability of a citalopram pulse-loading protocol in severe treatment-resistant OCD patients. Methods We enrolled 8 severe treatment-resistant OCD patients. Patients were treated with intravenous citalopram starting with 40 mg for 3 days and increasing the dose up to 80 mg from the fourth day. The patients continued the treatment with 80 mg of intravenous citalopram for 18 days (a total of 21 days of intravenous treatment), then they switched to oral treatment (80 mg of oral citalopram). Results During the pulse-loading treatment no patients showed significant adverse events. No patients showed clinical significant change of the QTc interval and/or of the sodium levels. Five out of eight patients had a partial or full response at the end-point (4 patients had a full response and 1 patient had a partial response) and two of these had remission. Pulse-loading treatment seemed to induce a faster improvement respect to a standard titration, since the responder patients showed a significant improvement already after 3 weeks. Three out of eight patients did not respond. Conclusion Taking into account the very limited sample size, this case series suggests that this treatment approach deserves further controlled studies

Intravenous lipid emulsion-augmented plasma exchange in a rabbit model of clomipramine toxicity; survival, but no sink

Introduction. Intravenous lipid emulsion (ILE) has been shown to ameliorate toxicity from lipophilic xenobiotics, attributed in part through sequestration to circulating lipid droplets (sink). We postulated additional benefit with plasma exchange therapy undertaken subsequent to lipid injection, hypothesising enhanced blood carriage of lipophilic toxin to increase yield when combined with an extracorporeal method of elimination. Methods. Instrumented rabbits underwent clomipramine infusion at 3.2 mg/kg/min to target mean arterial pressure (MAP) of 50% baseline, then continuously at 2 mg/kg/min to death or 90 min. Resuscitation with saline (Control), sodium bicarbonate (BIC), ILE, or lipid emulsion plus cycled plasma exchange (LEPE), was commenced on attaining target MAP. Results. Greater survival was observed in animals receiving lipid emulsion from both LE and LEPE groups (Control median 12.0 [IQR 10.5–20] min, BIC median 30 [IQR 19–33] min, LE 85 [IQR 30–90] min, LEPE 90 min; P < 0.0001). No difference was observed in MAP, Heart Rate, or Electrocardiograph QRS duration between surviving LE and LEPE animals at 90 min. Mean plasma exchange of 52%circulating plasma volume returned only 0.04% of the administered clomipramine load in LEPE group animals. Conclusions. Infusion of lipid emulsion resulted in greater survival in this rabbit model of intravenous clomipramine toxicity. Plasma exchange performed in conjunction with administration of lipid emulsion failed to result in significant extracorporeal clomipramine elimination. Intravascular lipid sequestration of clomipramine appears an inadequate sole explanation for the beneficial effects of lipid emulsion.

NEWS ON THERAPEUTIC MANAGEMENT OF OBSESSIVE

The purpose of this article is to inform the reader on an evidence based medical treatment algorithm in order to be used in patients with obsessive-compulsive disorder (OCD). Relevant studies were identified through a comprehensive review and were classified according to the type of patients being investigated, the quality of the study design and function of invasiveness, availability and complexity of therapeutic approach. When ineffective first-line therapeutic trials (such as selective serotonin reuptake inhibitors [SSRIs] and venlafaxina) or the cognitive-behavioral therapy, they should be followed by other therapeutic approaches, such as clomipramine, adding antipsychotics or pindolol, or the use of high doses of SSRIs. These therapeutic should be useful for most patients with OCD. Additional approaches include intravenous clomipramine, oral morphine, heroic drug strategies deep brain stimulation and functional neurosurgery. Independent studies are urgently needed to help identify the most promising therapeutic sequences for treatment of OCD.

The utility of intravenous clomipramine in a case of Cotard's syndrome

The utility of intravenous clomipramine in a case of Cotard's syndrome

Citalopram Pulse-Loading for Severe Treatment-Resistant OCD: A Case Series of Acute Response, One Year Follow-Up and Tolerability

Background: Treatment resistance is a frequent situation in Obsessive Compulsive Disorder (OCD), occurring in 40-60% of patients. However, in the current literature there are only a few evidence-based options for treatmentresistant patients. Pulse-loading treatment consists in a rapid titration of the pharmacological agent in the first days of treatment. A few studies suggested that this kind of titration with intravenous clomipramine could result in a greater and faster response than with a standard titration in OCD resistant patients. The main aim of this case series was to investigate the effectiveness and tolerability of a citalopram pulse-loading protocol in severe treatment-resistant OCD patients. Methods: We treated 5 severe treatment-resistant OCD patients with intravenous citalopram starting with 40 mg for 3 days and increasing the dose up to 80 mg from the fourth day. The patients continued the treatment with 80 mgof intravenous citalopram for 18 days (a total of 21 days of intravenous treatment), then they switched to oral treatment (80 mg of oral citalopram). We assessed acute and one-year follow-up efficacy and tolerability. Results: During the pulse-loading treatment no patients showed significant adverse events. Two of five patients had a full response and one of these had remission. Furthermore, these two patients did not have any relapse of OC symptoms during the 1-year follow-up. One of five patients had a partial response after 12 weeks and a full response during the 1-year follow-up period after switching from quetiapine to aripiprazole and after a CBT trial. Two of five patients did not respond. No patients showed clinical significant changes of the QTc interval. No patients showed significant changes of the sodium levels. Conclusion: Taking into account the very limited sample size, this case series suggests that this treatment approach deserves further controlled studies.

P-1095 - Use of intravenous clomipramine in psychiatric patients in a general hospital

Background Clomipramine is a tricyclic antidepressant with potent serotonin reuptake blockade. It is one of a few antidepressant medications available in the intravenous form and is the only one available in Tan Tock Seng Hospital (TTSH), Singapore. Studies have provided evidence that intravenous clomipramine is useful in the treatment of major depression and obsessive-compulsive disorders. Other possible indications include post-traumatic stress disorder and anxiety disorder. Methods of delivering intravenous clomipramine varied in the literature, with starting doses ranging from 25 mg per day to 150 mg per day and final dosages ranging from 150 mg per day to 250 mg per day, either via pulse loading or gradual loading. Objectives The study aimed to analyze the demographics, indications for treatment, dosage and frequency of administration, complications of treatment and co-morbid psychiatric conditions of patients who were treated with intravenous clomipramine in TTSH over the period from January 2007 to December 2011. Methods A retrospective study was performed on all inpatients admitted under the Department of Psychological Medicine in TTSH who were treated with intravenous clomipramine over the specified period. Results The common indications for treatment include mood and anxiety disorders. The dosage given per day ranged from 25 mg to 150 mg. No mortality or severe adverse events resulted from the treatment. Conclusions The use of intravenous clomipramine may provide clinicians with a safe, fast-acting and efficacious therapy modality for acute management of several psychiatric disorders. Further large-scale studies will be useful in providing evidence to support its clinical use in psychiatry.

Prolactin and Cortisol Responses to Acute Intravenous Clomipramine Challenge in Patients with Mania, Depression and Healthy Controls: Evidence for Reduced Serotonergic Responsivity

Serotonergic dysregulation has been shown to be involved in the pathophysiology of unipolar and bipolar depression. Neuroendocrine challenge tests have been extensively used to investigate serotonin functioning in the brain. Although the role of serotonin has received a great deal of attention using neuroendocrine challenge paradigms, little effort has been made to explore the role of serotonin in mania. We assessed serotonergic neuroendocrine responsivity in patients with depression (n = 22), mania (n = 11) and 15 healthy controls by measuring the prolactin (PRL) and cortisol responses to i.v. clomipramine (CMI) and searched for possible differences among the groups. Blunted PRL responses to CMI in manic and depressed patients compared to healthy controls were found. The response to CMI disclosed similar results for the 2 patient groups. No significant differences were found among the 3 subject groups in the cortisol response to CMI. The blunted PRL responses to CMI in patients with mania and depression suggest that serotonergic functioning in mania and depression is similarly impaired, at least at the level of hypothalamus-hypophysis.

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

Long-Term Follow-Up Study of Patients With Refractory Obsessive-Compulsive Disorder

The authors prospectively followed patients with treatment-resistant obsessive-compulsive disorder (OCD). Between 1988 and 1995, 56 patients with a history of inadequate response to oral clomipramine received 14 infusions of intravenous clomipramine. The follow-up period ranged from 4 to 11 years after treatment. Of the 44 subjects interviewed at follow-up, 70.5% had current OCD and 29.5% had sub-threshold OCD. Almost half reported feeling much improved or very much improved compared to their state prior to treatment with intravenous clomipramine.

Pulse Intravenous Clomipramine as an alternative antidepressant treatment to ECT: A pilot study

- Background and Objectives: The aim of the study was to examine the antifecrt of a single pulse dose of intravenous clomipramine (200 mg i.v.) foldepressant effect of a single pulse dose of intravenous clomipramine (2UU mg i.v.) followed by oral administration as an alternative method to electroconvulsive therapy. Methods: Twenty-one inpatients (8 male, 13 female) with major depression were included. Depression severity was measured by Montgomery Asberg Rating Scale (MADRS) and Clinical Global Impression severity scale (CGI-S) before the pulse dose and 1 week after. The day after the pulse dose, the patient was medicated with 75 mg of oral clomipramine and from day two with 150 mg clomipramine daily. Results: The MADRS score dropped with 39% ± 22% and the CGI score with 28% ± 19% in one week. The improvement of the MADRS score after one week was 13.1 (C.I.9.5-17.0). CGI-ratings dropped from a mean of 5.5 (SD 1.2) to 3.9 (SD 1.1), an improvement of 28% ± 19%.(C.I. 1.0-2.1). Both improvements were significant (p<000.1). Conclusions: Single pulse dose clomipramine administration ameliorates depressive symptoms, and may be an alternative to ECT.

An update on the pharmacological treatment of obsessive-compulsive disorder

The purpose of this article is to introduce the reader to an updated evidence-based drug treatment algorithm to be employed in patients with obsessive-compulsive disorder (OCD). Relevant studies were identified through a comprehensive review and classified according to the type of patients enrolled, the quality of the study design and the invasiveness, availability and complexity of the therapeutic approach. When ineffective, therapeutic trials with first-line strategies (such as the selective serotonin re-uptake inhibitors [SSRIs] and venlafaxine) should be followed by treatment approaches such as clomipramine, augmentation with antipsychotics or pindolol, SSRI megadoses or cognitive behavioral therapy. These therapeutic strategies are expected to help most patients with OCD. Additional approaches include intravenous clomipramine, oral morphine, ‘heroic drug strategies’, deep brain stimulation and functional neurosurgery. Independent studies are urgently needed to help identify the most promising drug treatment sequences for OCD.

Pharmacokinetics of clomipramine and desmethylclomipramine after single‐dose intravenous and oral administrations in cats

A cross-over study was performed in six adult spayed cats to determine the pharmacokinetics of clomipramine and its metabolite, desmethylclomipramine (DCMP) after intravenous (0.25 mg/kg) and oral (0.5 mg/kg) single-dose administrations. Plasma clomipramine and DCMP were measured by high-performance liquid chromatography at regular intervals for up to 30 h. Intravenous clomipramine best fit a two-compartmental model yielding an elimination rate constant of 0.037-0.09 h(-1) from which a mean half-life of 12.3 h was calculated. Mean clomipramine AUC(0--infinity) (ngxh/mL), clearance (L/hxkg), V(ss) (L/kg) and MRT (h) values were 652.5, 0.393, 5.0, and 13.5, respectively. Compartmental modeling for clomipramine, after oral administration, and DCMP after both administrations, produced wide parameter estimates and plots of residuals indicated poor goodness of fit. Noncompartmental analysis yielded mean AUC(0--30 h) (ngxh/mL), C(max) (ng/mL) and T(max) (h) of 948.3, 87.5 and 6.2 for clomipramine, and 613.8, 34.8, and 12.8 for DCMP respectively after oral administration. Clomipramine bioavailability was 90%. The present study showed marked pharmacokinetic variability for clomipramine and DCMP through biphasic absorption and potential genetic variability in clomipramine metabolism. It was concluded that population pharmacokinetics would allow better characterization of clomipramine variability that may explain the variability in clinical response noted in cats.

Pulse-Loaded Intravenous Clomipramine in Treatment-Resistant Obsessive-Compulsive Disorder

Small studies have suggested that intravenous clomipramine (CMI) may be more effective and induce faster improvement in obsessive-compulsive disorder than do orally administered serotonin reuptake inhibitors. To test these hypotheses, we conducted a randomized, double-blind, double-dummy study of pulse-loaded intravenous versus oral CMI, followed by open-label oral CMI for 12 weeks. We enrolled a volunteer and referred group of 34 adults with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition obsessive-compulsive disorder of > or =1-year duration and Yale-Brown Obsessive Scale score of > or =20. Eligible subjects had failed > or =2 adequate serotonin reuptake inhibitor trials. Subjects received pulse loaded CMI 150 mg by vein or by mouth on day 1 and 200 mg on day 2. Oral CMI began on day 6 at 200 mg/d and was increased by 25 mg every 4 days to 250 mg/d, as tolerated, for 12 weeks. Adverse events led to one withdrawal during oral pulse loading and 5 during open-label oral treatment. Intravenous pulse loading did not induce a more rapid or greater Yale-Brown Obsessive Scale score decrease than oral pulse loading at day 6 or by week 12. Day 6 and week 12 improvement were unrelated to plasma drug or metabolite concentrations. Pulse loading itself seemed to induce more rapid and greater improvement than expected in treatment-resistant obsessive-compulsive disorder. Further investigation of oral pulse-loading regimens in treatment-resistant obsessive-compulsive disorder is warranted.

Successful use of intravenous clomipramine in depressive–catatonic state associated with corticosteroid treatment

We report two female patients who deteriorated to depressive–catatonic state after interepisode recovery from a hypomanic episode induced by corticosteroid treatment. Their symptoms developed during maintenance treatment with a low dose of prednisolone in Case 1 and after discontinuation of betamethasone in Case 2. Intravenous clomipramine successfully relieved their symptoms including reduction in contact and reactivity, immobility and mutism. These two patients showed no schizophrenic symptoms such as hallucinations and delusions. Corticosteroid-induced mood disorder can deteriorate into depressive stupor, severe depressive episode with catatonic features in DSM-IV. Clomipramine, a tricyclic antidepressant with relatively stronger serotonin reuptake inhibition, is one of the useful treatment options for corticosteroid-induced depression even in severe cases.

Clomipramine use in obsessive–compulsive disorder

The serotonin reuptake inhibitor, clomipramine and newer selective serotonin reuptake inhibitors have become recognized as the most effective monotherapy for obsessive–compulsive disorder. Meta-analyses have suggested that clomipramine may be superior to other selective serotonin reuptake inhibitors in treating obsessive–compulsive disorder. Double-blind, direct comparisons of the selective serotonin reuptake inhibitors and clomipramine, have demonstrated equal efficacy, fewer side effects and lower medication discontinuation rates in selective serotonin reuptake inhibitor patients. However, clomipramine continues to play a vital role in the pharmacotherapy of obsessive–compulsive disorder, being used when two or more selective serotonin reuptake inhibitor trials have not been sufficiently effective, which can occur in up to a third of patients. Recent investigation suggests potential roles for intravenous clomipramine and the combination of oral clomipramine with selective serotonin reuptake inhibitors and other medications in treatment-refractory obsessive–compulsive disorder patients.

Citalopram Treatment of Compulsive Shopping

Article AbstractBackground: Treatment with intravenous clomipramine is rapidly effective in some obsessive-compulsive disorder (OCD) patients unresponsive to orally administered serotonin reuptake inhibitors (SRIs). The selective serotonin reuptake inhibitor citalopram is effective for OCD when administered orally. We investigated whether intravenous citalopram would rapidly benefit OCD patients unresponsive to orally administered SRIs. Method: Thirty-nine adult outpatients participated in a 3-week open-label trial of intravenous citalopram. Eligible patients had moderate-to-severe DSM-IV OCD of >=1 year's duration, a baseline Yale-Brown Obsessive Compulsive Scale (YBOCS) score >=25, and no other active Axis I diagnosis and had failed at least 2 adequate oral SRI trials, excluding citalopram. Intravenous citalopram was administered daily for 21 days, followed by oral citalopram until treatment day 84. Intravenous citalopram was started at 20 mg/day and was increased to 40 to 80 mg/day as tolerated. Results: Intravenous citalopram was well tolerated even at higher doses (dropout rate=2.6%). At day 21, 23 (59%) of the 39 patients had YBOCS score decreases of >=25%, of whom 4 had decreases of >=35%. Twenty-seven patients with YBOCS score decreases of >=20% were allowed to continue on treatment with oral citalopram, and by day 84, all had substantial further improvement. All 27 patients also showed significant improvement in several dimensions of quality of life. Conclusion: Intravenous citalopram was safe and rapidly effective in a group of treatment-resistant OCD patients. The early onset of response suggests a means of accelerating OCD symptom relief and predicting response to oral citalopram treatment. Double-blind, double-dummy, placebo-controlled trials of intravenous versus oral citalopram in patients with treatment-resistant OCD are indicated.

Intravenous clomipramine decreases excitability of human motor cortex. A study with paired magnetic stimulation

Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). In these studies, paired magnetic stimulation has been used in normal subjects and on patients who were taking different antiepileptic drugs. The aim of our study was to investigate motor area excitability on depressed patients after intravenous administration of a single dose of clomipramine, a tricyclic antidepressant. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation (TMS) before and after 4, 8 and 24 h from intravenous administration of 25 mg of clomipramine. Cortical excitability was measured using different TMS parameters: motor threshold (MT), motor evoked potential (MEP) amplitude, duration of cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF). Spinal excitability and peripheral nerve conduction was measured by F response and M wave. A temporary but significant increase of motor threshold and intracortical inhibition and a decrease of intracortical facilitation were observed 4 h following drug administration. MEP amplitude, cortical silent period, F response and M wave were not significantly affected by drug injection. Our findings suggest that a single intravenous dose of clomipramine can exert a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of neuropsychiatric drugs used in psychiatric disease.