Abrupt Withdrawal Research Articles

Guidelines on oral anticoagulation (warfarin): third edition – 2005 update

The British Committee for Standards in Haematology (BCSH) published its third edition of Guidelines on Oral Anticoagulation in 1998 (British Committee for Standards in Haematology, 1998). Most of the recommendations made in 1998 remain unchanged and a fourth edition of the guideline is considered unnecessary at the time of writing (June 2005). However, we draw attention to those areas where new informative data have been published. As in the original guideline, the term ‘oral anticoagulant’ used in this update refers to oral vitamin K antagonists (VKA), such as warfarin. New oral non-VKA are currently being evaluated in clinical trials but are not yet licensed for use in the UK. When these drugs become available new guidance will be issued specifically for the use of those drugs. The guideline group was selected to be representative of UKbased medical experts. The drafting group met and communicated by email. MEDLINE was searched systematically for publications in English from 1998. The writing group convenor (T. Baglin) produced the draft guidelines which were subsequently revised by consensus. The guideline was reviewed by a multidisciplinary sounding board, the BCSH and the British Society for Haematology (BSH) and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as in Appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The target audience for this guideline is healthcare professionals involved in the management of patients receiving oral anticoagulant therapy.

Effects of JDTic, a selective κ-opioid receptor antagonist, on the development and expression of physical dependence on morphine using a rat continuous-infusion model

JDTic, (3 R)-7-hydroxy- N-{(1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide, is a potent and selective κ -opioid antagonist with a very long duration of action [Carroll, F.I., Thomas, J.B., Dykstra, L.A., Granger, A.L., Allen, R.M., Howard, J.L., Pollard, G.T., Aceto, M.D., Harris, L.S., 2004. Pharmacological properties of JDTic: A novel k-opioid receptor antagonist. Eur. J. Pharmacol. 501, 111–119.]. When given 24 h prior to a continuous 4-day infusion of morphine sulfate in rats, JDTic did not prevent the stereotypy that developed during the infusion of morphine. It had no effect on the dramatic loss of body weight associated with the abrupt withdrawal of morphine. However, it decreased the number of important withdrawal signs designated wet-dog shakes and facial rubs. These data suggest that JDTic may find some application in the treatment of opiate abuse.

Splenic macrophages and B cells mediate immunosuppression following abrupt withdrawal from morphine

We have previously shown that abrupt withdrawal (AW) from morphine induces greater than 80% immunosuppression in murine spleen cells, as assessed by the capacity to mount an in vitro plaque-forming cell response to sheep red blood cells. Present studies about the mechanisms of immunosuppression following AW showed that addition of highly enriched (CD11b+) splenic macrophages (obtained by cell sorting or magnetic separation) from AW mice to cultures of normal, unfractionated spleen cells suppressed immune responses. Further, addition of highly enriched (CD19+) B cells (but not T cells) from AW mice to normal cells was also immunosuppressive. B cells from AW mice were also able to inhibit the proliferative response of normal spleen cells to concanavalin A but not to lipopolysaccharide. Overall, the data suggest that immunosuppression by AW spleen cells is a result of active suppression by macrophages and B cells.

Bupropion attenuates nicotine abstinence syndrome in the rat

Bupropion reduces discomfort and craving associated with smoking cessation. This study determined whether a rat model of nicotine dependence could detect such nicotine abstinence-alleviating effects. Experiments determined whether the abstinence-alleviating effects of bupropion were detectable by (1) behavioral abstinence signs precipitated by the nicotinic antagonist mecamylamine, (2) place aversion conditioned to mecamylamine-precipitated nicotine abstinence, and (3) spontaneous behavioral abstinence signs after abrupt nicotine withdrawal. In experiments 1 and 2, nicotine-dependent rats were coinfused for 7 days with 3.15 mg/kg/day nicotine and 20 mg/kg/day bupropion or with nicotine alone. They were then challenged with 1 mg/kg mecamylamine and observed for behavioral abstinence signs (experiment 1) or place aversion conditioned to precipitated abstinence (experiment 2). In experiment 3, rats were nicotine-infused for 7 days as above. A day after termination of nicotine infusion, rats were observed for spontaneous nicotine abstinence signs before and after injection with saline or bupropion. In experiment 1, rats coinfused with nicotine and bupropion had significantly fewer mecamylamine-precipitated abstinence signs than rats infused with nicotine alone but similar numbers to rats infused with saline alone. In experiment 2, bupropion pretreatment significantly reduced the aversiveness of mecamylamine-precipitated nicotine abstinence. In experiment 3, a single bupropion injection dose-dependently alleviated spontaneous nicotine abstinence syndrome. These results suggest that these rat models of nicotine dependence and abstinence syndrome may be useful in detecting nicotine abstinence-alleviating effects of potential medications for smoking cessation. The effects of acute bupropion administration raise interesting questions regarding bupropion's mechanism of action.

Zopiclone withdrawal: an unusual cause of delirium in the elderly

We report a case of an elderly lady who was admitted for congestive heart failure. She developed delirium during the course of her hospital stay. Multiple investigations were performed but were unremarkable. Finally, a diagnosis of abrupt zopiclone withdrawal causing delirium was made. Zopiclone was resumed at a lower dose and delirium resolved completely.

Tardive dystonia

Tardive dyskinesia is a movement disorder that develops after exposure to dopamine receptor blocking agents. Less well-appreciated are other, more recently described tardive syndromes that are phenomenologically distinct from tardive dyskinesia and respond to different treatments. Patients may simultaneously have more than one tardive syndrome. Major subtypes of tardive syndromes include tardive dyskinesia, characterized by orobuccolingual, truncal, or appendicular, choreiform movements; tardive dystonia, characterized by sustained, stereotyped muscle spasms of a twisting or turning character; and tardive akathisia, characterized by an inner sense of restlessness or unease. The sensation often is unpleasant and may be accompanied by repetitive, purposeless movements (stereotypies), such as pacing. Less common tardive syndromes include tardive myoclonus, tardive tourettism, and tardive tremor. Tardive syndromes often are a source of great distress and disability to patients and may be permanent, despite discontinuing the responsible medication. Prevention, early detection, and prompt management are the major clinical focus. When a patient develops a tardive syndrome appropriate actions include 1) review of the primary diagnosis that prompted starting a dopamine receptor blocking agent; 2) characterization of the movement disorder(s); 3) where possible, discontinuation of dopamine blocking agent or replacement with a less potent alternative agent; 4) gradual withdrawl of the offending drug because some patients have an exacerbation of a tardive syndrome after abrupt withdrawal; and 5) assessment of the severity of symptoms and development of a treatment plan based on the phenomenology, with the goal of maximizing patient comfort and function. Although tardive dyskinesia typically develops after chronic exposure to dopamine receptor blocking agents, it, and other variants (such as tardive dystonia) can develop very rapidly after treatment. There seems to be no minimal safe duration of exposure for the development of a tardive syndrome. It is important to recognize that anti-emetics, which are dopamine receptor blockers, such as prochlorperazine, promethazine and metoclopramide, can cause tardive syndromes. Clinicians should become familiar with antipsychotic agents that have a lower risk of causing tardive syndromes, such as clozapine, quetiapine, and olanzapine. We review treatment options for tardive dystonia.

Alteration of kappa-opioid receptor system expression in distinct brain regions of a genetic model of enhanced ethanol withdrawal severity

Abrupt withdrawal from chronic alcohol exposure can produce convulsions that are likely due to ethanol (EtOH) neuroadaptations. While significant efforts have focused on elucidating dependence mechanisms, the alterations contributing to EtOH withdrawal severity are less well characterized. The present studies examined the kappa-opioid receptor (KOP-R) system in Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice, selected lines that display severe and mild convulsions upon removal from chronic EtOH exposure. Previous data demonstrated significant increases in whole brain prodynorphin ( Pdyn) mRNA in WSP mice only during EtOH withdrawal. No significant effects of EtOH exposure or withdrawal were observed in WSR mice. The present study characterized Pdyn mRNA and the KOP-R in WSP and WSR mice during EtOH withdrawal using in situ hybridization (ISH) and KOP-R autoradiography. Analyses were performed in brain regions that express Pdyn mRNA and/or KOP-R and that might participate in seizure circuitry: the piriform cortex, olfactory tubercle, nucleus accumbens, caudate–putamen, claustrum, dorsal endopiriform nucleus, and cingulate cortex. ISH analyses confirmed previous findings; EtOH withdrawal increased Pdyn mRNA in multiple brain regions of WSP mice, but not WSR. Basal KOP-R binding was higher in WSR mice than in WSP mice, suggesting an anti-convulsant role for receptor activation. Finally, increased KOP-R density was present during EtOH withdrawal in WSP mice. These data suggest that differences in the KOP-R system among the lines might contribute to their selected difference in EtOH withdrawal severity.

Long‐term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas

Reports suggest that up to 70% of patients with microprolactinomas treated with dopamine agonist therapy may achieve long-term normoprolactinaemic remission following drug withdrawal. Yet, there is no consensus on the duration of therapy nor is therapeutic interruption universally practised. We have assessed remission rates in a large cohort of treatment-naive subjects with microprolactinomas. Subjects received dopamine agonist (DA) therapy with either cabergoline or bromocriptine for a period of 2 to 3 years in the majority of cases, followed by a trial of treatment withdrawal. Retrospective analysis of clinic records of 89 patients (mean age 32.7 +/- 8.4 years, 84 women and 5 men) who had received either cabergoline (n = 67) (0.5-3 mg weekly) or bromocriptine (n = 22) (2.5-10 mg daily) for a mean duration of 3.1 years. Following withdrawal of therapy, 57 subjects developed recurrence (64%) and the mean time to recurrence was 9.6 months (range 1-44 months), while 32 subjects (36%) remained in remission beyond 1 year (mean 3.6 years, range 1-7 years). There was no difference in remission rates between subjects treated with cabergoline (n = 21) and bromocriptine (n = 11), but a direct relationship between pretreatment prolactin concentration and risk of recurrent symptomatic hyperprolactinaemia was observed. No subjects developed clinical features to suggest tumour expansion following therapeutic discontinuation. This study confirms that abrupt withdrawal of chronic dopamine agonist therapy, following 2 to 3 years of treatment is safe and associated with long-term remission in 30-40% of subjects with microprolactinomas. This therapeutic strategy is convenient and applicable in clinical practice.

Role of B-Type Natriuretic Peptide and Effect of Nesiritide After Total Cardiac Replacement With the AbioCor Total Artificial Heart

Endogenous B-type natriuretic peptide (BNP) is thought to be produced in the cardiac ventricles. After sub-total cardiectomy and implantation of a total artificial heart (TAH), the abrupt withdrawal of BNP impairs renal function despite normal hemodynamic variables. We hypothesized that abrupt withdrawal of endogenous BNP may impair renal function and volume homeostasis and BNP may have a direct renal influence unrelated to its cardiovascular effect. Nesiritide infusion should be supplemented in the interim and weaned slowly until BNP levels normalize, which suggests that BNP is produced in tissues other than the cardiac ventricles.

Withdrawal syndrome following cessation of antihypertensive drug therapy

In this study, a review of the available information concerning abrupt withdrawal of antihypertensive drug therapy is presented. Abrupt withdrawal of these drugs can produce a syndrome of sympathetic overactivity that includes nervousness, tachycardia, headache, agitation and nausea 36-72 h after cessation of the drug. A withdrawal syndrome may occur after discontinuation of almost all types of antihypertensive drugs, but mostly occurs with clonidine, beta-blockers, methyldopa and guanabenz. Less commonly can produce a rapid increase of the blood pressure to pre-treatment levels or above, or both and/or myocardial ischaemia. Although the exact incidence of the syndrome is not known, it appears to be rare, at least in patients receiving standard doses of the above antihypertensive drugs. The best treatment is prevention. In this study regarding the withdrawal syndrome that follows cessation of antihypertensive drugs therapy, a reference to the abrupt discontinuation of the main categories of antihypertensive drugs is also attempted.

SSRI and statin use increases the risk for vasospasm after subarachnoid hemorrhage

Use of medications with vasoconstrictive or vasodilatory effects can potentially affect the risk for vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Using International Classification of Diseases-9 diagnostic codes followed by medical record review, the authors identified 514 patients with SAH admitted between 1995 and 2003 who were evaluated for vasospasm between days 4 and 14. The authors determined risks for vasospasm, symptomatic vasospasm, and poor clinical outcomes in patients with documented pre-hemorrhagic use of calcium channel blockers, beta-receptor blockers, ACE inhibitors, aspirin, selective serotonin reuptake inhibitors (SSRIs), non-SSRI vasoactive antidepressants, or statins. Vasospasm developed in 62%, and symptomatic vasospasm in 29% of the cohort. On univariate analysis, the risk for all vasospasm tended to increase in patients taking SSRIs (p = 0.09) and statins (p = 0.05); SSRI use increased the risk for symptomatic vasospasm (p = 0.028). The Cochran-Armitage trend test showed that the proportion of patients taking SSRIs and statins increased significantly across three worsening categories (none, asymptomatic, symptomatic) of vasospasm. Logistic regression analysis showed that SSRI use tended to predict all vasospasm (O.R. 2.01 [0.91 to 4.45]), and predicted symptomatic vasospasm (O.R. 1.42 [1.06 to 4.33]). Statin exposure increased the risk for vasospasm (O.R. 2.75 [1.16 to 6.50]), perhaps from abrupt statin withdrawal (O.R. 2.54 [0.78 to 8.28]). Age < 50 years, Hunt-Hess grade 4 or 5, and Fisher Group 3 independently predicted all vasospasm, symptomatic vasospasm, poor discharge clinical status, and death. Selective serotonin reuptake inhibitor and statin users have a higher risk for subarachnoid hemorrhage-related vasospasm. Whether the underlying disease indication, direct actions, or rebound effects from abrupt drug withdrawal account for the associated risk warrants further investigation.

Risperidone Withdrawal-Related Respiratory Dyskinesia

Risperidone is a frequently used member of a new class of atypical antipsychotics-the serotonin-dopamine antagonists (SDAs)-due to its comparatively high efficacy and low D2/5HT2 binding ratio, which results in a low incidence of extrapyramidal side effects including tardive dyskinesia (TD). The authors present an elderly patient with mixed dementia who developed TD at multiple sites, (including respiratory dyskinesia [RD], limb dyskinesia, and orofacial dyskinesia) following abrupt withdrawal of risperidone therapy. RD is not a rare condition, but is often misdiagnosed and is potentially lethal. Therefore, clinicians should pay close attention to possible onset of RD in patients with multiple risk factors for TD, even when SDA therapy is used. If RD is suspected, assessment should include spirography combined with fibroscopy for examination of irregularities in the rate, rhythm, and depth of respiration.

Control of urine marking by use of long-term treatment with fluoxetine or clomipramine in cats

To determine whether clomipramine differs from fluoxetine in reducing feline urine marking; whether reduction of marking continues in cats treated >8 weeks; whether recurrence of marking, after abrupt drug withdrawal, is less in cats treated >8 weeks; and whether cats that are successfully treated but resume marking after drug withdrawal can be successfully treated again with the same drug regimen. Positive-controlled, double-masked clinical trial. 22 neutered cats (2 females, 20 males) > or =1 year old with objectionable urine marking. Cats that marked vertically > or =3 times/wk were treated with fluoxetine (1 mg/kg [0.45 mg/lb], q 24 h, PO) or clomipramine (0.5 mg/kg [0.23 mg/lb], q 24 h, PO) for 16 weeks, and efficacy was compared. Recurrence of marking was determined after abrupt withdrawal of fluoxetine at 16 or 32 weeks. Reduction in marking in cats treated with fluoxetine for 8 weeks after returning to marking following drug withdrawal was compared with the initial 8 weeks of successful treatment. Efficacy of fluoxetine and clomipramine was similar. Treatment >8 weeks revealed increasing efficacy in reduction of marking. Return of marking after termination of fluoxetine administration occurred in most cats. Cats successfully treated initially with fluoxetine responded similarly to repeated treatment. Clomipramine and fluoxetine were equivalent in treating urine marking. Longer treatment increased efficacy. Most cats return to marking after abrupt drug withdrawal. A second course of treatment can be expected to be as effective as the first.

Possible Neuroleptic Malignant Syndrome With Aripiprazole and Fluoxetine

Back to table of contents Previous article Next article Letter to the EditorFull AccessPossible Neuroleptic Malignant Syndrome With Aripiprazole and FluoxetineHARPREET S. DUGGAL, M.D., D.P.M., and JOSEPH KITHAS, M.D., HARPREET S. DUGGALSearch for more papers by this author, M.D., D.P.M., and JOSEPH KITHASSearch for more papers by this author, M.D., Pittsburgh, Pa.Published Online:1 Feb 2005https://doi.org/10.1176/appi.ajp.162.2.397-aAboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: There are rare reports of neuroleptic malignant syndrome occurring with a combination of atypical antipsychotics and selective serotonin reuptake inhibitors (1). We describe a similar case with a combination of aripiprazole and fluoxetine.Mr. A, a 43-year-old man, was admitted to our hospital with severe depression and psychotic symptoms. Three weeks before, he had been admitted to a different hospital for similar symptoms and had been given bupropion and risperidone, titrated up to 150 mg/day and 1 mg/day, respectively. However, for unapparent reasons, these medications were discontinued abruptly after a week, and Mr. A was given aripiprazole, started at 30 mg/day, and fluoxetine, 20 mg/day. A week later, Mr. A was discharged from the hospital with the same regimen. Subsequently, after taking these medications for about 2 weeks, Mr. A came to us with complaints of muscle stiffness, restlessness, and fever of a week’s duration. In addition, he also had depressive and some psychotic symptoms, but his family’s predominant concern was his physical symptoms.Upon examination, Mr. A exhibited marked psychomotor retardation, mask-like facies, and severe rigidity, with cog-wheeling, sialorrhea, tremors, and akathisia. He had fever (99.8°F), labile blood pressure (148/99–137/89 mm Hg), and tachycardia (110 bpm). He was fully oriented and did not display any cognitive deficits. Laboratory investigations revealed elevated creatine phosphokinase (248 IU/liter; normal range=0–200) and alanine aminotransferase (61 IU/liter; normal range=0–35) levels, whereas the results of renal function tests, a CBC, and a urine examination were normal. Although Mr. A had stopped taking aripiprazole 2 days before he came to visit us, his symptoms had shown little improvement. Fluoxetine was discontinued, and Mr. A was treated symptomatically with benztropine and acetaminophen and had an uneventful recovery within a week, with his creatine phosphokinase level returning to normal (138 IU/liter).Although this patient had the core symptoms of neuroleptic malignant syndrome, including rigidity, fever, and autonomic instability and met the DSM-IV criteria for neuroleptic malignant syndrome, the symptoms of severe neuroleptic malignant syndrome, such as a marked creatine phosphokinase elevation, hyperthermia, and an altered sensorium, were absent. Early recognition of this condition, the use of an atypical antipsychotic (aripiprazole), and the patient’s discontinuation of aripiprazole may have contributed to his mild presentation of neuroleptic malignant syndrome. Serotonin syndrome, another differential in this case, cannot be ruled out, but the patient did not exhibit autonomic features, such as hyperhidrosis and diarrhea, or muscular signs, such as hyperreflexia and myoclonus, which are typical of this syndrome. The Physicians’ Desk Reference documents that two “possible” cases of neuroleptic malignant syndrome occurred during aripiprazole treatment in a premarketing worldwide clinical database, although we found no reports of neuroleptic malignant syndrome occurring with aripiprazole on PUBMED. Given that aripiprazole is a functional dopamine receptor agonist in a hypodopaminergic state (as occurs in neuroleptic malignant syndrome), the presentation of this syndrome may be different from other atypical antipsychotics. Serotonin 5-HT1A agonism, another hypothetical mechanism for neuroleptic malignant syndrome (2), can also be implicated in this case because aripiprazole is a partial agonist at this receptor. Of interest, this is also the mechanism underlying serotonin syndrome (3), and both neuroleptic malignant syndrome and serotonin syndrome have been considered under the rubric of catatonic syndromes (4). Although fluoxetine (an inhibitor of CYP2D6) alone has been associated with neuroleptic malignant syndrome (5), it may have further increased levels of aripiprazole (which is metabolized by CYP2D6). This, compounded with the altered dopamine balance due to abrupt withdrawal of risperidone, may have made the patient more vulnerable to neuroleptic malignant syndrome, as supported by reports of neuroleptic malignant syndrome after withdrawal of atypical antipsychotics (6).

Effect of Anticholinergics in Preventing Acute Deterioration in Patients Undergoing Abrupt Clozapine Withdrawal

The most serious adverse effect of clozapine, agranulocytosis, was described for the first time in Finland in 1975. It caused the immediate withdrawal of clozapine from the market and immediate discontinuation of this medication in all patients. It is now known that abrupt withdrawal of clozapine may cause a rapid deterioration in psychotic symptoms. The aim of this retrospective study was to investigate the effect of abrupt clozapine withdrawal on psychiatric patients, and to examine whether anticholinergic drugs are effective in preventing acute deterioration. We reviewed the hospital case records from Pitkäniemi Psychiatric Hospital, Tampere, Finland, of the 28 patients with schizophrenia who had been receiving clozapine and from whom it was abruptly withdrawn due to the withdrawal of the drug from the market in the summer of 1975. We assessed the incidence of deterioration and whether or not patients in whom this occurred were receiving anticholinergic drugs. We found a rapid deterioration after clozapine withdrawal in almost half (46.4%; n = 13) of the patients. Patients receiving anticholinergic drugs (such as antiparkinsonians, tricyclic antidepressants and antipsychotics with anticholinergic properties) were significantly less likely to deteriorate than those not receiving these drugs (21.4% vs 71.4%, p = 0.008). The condition of the patients who deteriorated was poor for up to 1 month after discontinuation, but had improved slightly by the end of 1975. Anticholinergic medication should be considered for preventing possible symptom deterioration when clozapine is abruptly discontinued.

Interferon-γ-Dependent in vitro Model for the Putative Keratin 17 Autoimmune Loop in Psoriasis: Exploration of Pharmaco- and Gene-Therapeutic Effects

In 1999, A.S. Gudmundsdottir et al. have envisaged an epitope on keratin 17 (K17) as a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, we now demonstrate that IFN-γ and to a less extent also TNF-α and TGF-α are able to induce K17 protein expression, in contrast to IL-1α, IL-1β, IL-6, IL-8 and IL-18. This supports our hypothesis of an existing proinflammatory cytokine/K17 autoimmune loop as a presumptive positive feedback mechanism driving psoriasis etiopathogenesis. K17 overexpression was now found to also coincide with suppression of keratinocyte proliferation, e.g. induced by NF-kappa B inhibitors (Bay 11-7082 and Bay 11-7085), and thereby correlated hyperapoptosis to be encountered in psoriatic epidermis. Acitretin as an established antipsoriatic drug and the tyrosine kinase inhibitor imatinib decreased, whereas hydrocortisone as well as dexamethasone increased the IFN-γ-induced K17 overexpression. The latter might be another mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment. Finally, we defined a K17-directed and effective antisense oligodesoxynucleotide which may hold promise for future gene-therapeutic approaches in psoriasis.

Memories of Arabia and Empire: An Oral History of the British in Aden

The British ruled Aden in southern Arabia, together with the Western and Eastern Aden Protectorates, from 1839 to 1967. In the final years, an increasingly violent national liberation struggle forced an abrupt British withdrawal. Although some local people benefited from colonial rule, it was felt by many that the decolonisation process was unsatisfactory. By listening to the voices of a wide range of individuals, both British and Yemeni, who experienced the final years of British rule, the Aden oral history project shifts the focus from history's ‘grand narratives’ to the ‘smaller’, less familiar stories of enterprise, adventure and everyday survival.

Results of a follow-up investigation to a clinical trial testing the efficacy of clomipramine in the treatment of separation anxiety in dogs

The objective of the study was to investigate the incidence of adverse events and changes in behaviour after use of clomipramine to treat separation anxiety in dogs. This study was a follow-up investigation to a previously published clinical trial. In the main trial, dogs were randomised in a double-blinded manner to receive placebo, standard (1–2 mg/kg, q12h) or low (0.5–1 mg/kg, q12h) dosages of clomipramine for 2–3 months. All dogs received behavioural therapy. Follow-up questionnaires were completed in 76 out of 89 dogs between 5.5 and 16 months after completion of the main trial. Post study, 12 dogs at one site received clomipramine long term (>13–16 months). The clomipramine was tolerated well, no dogs had worsening of their behaviour and behaviour improved further in 10 (83%) dogs. An additional 16 dogs received clomipramine and/or other drugs for up to 30 weeks and 48 cases received no drugs post trial. Acute worsening of behaviour was noted in the first two weeks after stopping treatment in three cases receiving low dose clomipramine, but in no cases in the other groups. The worsening rate of separation anxiety >2 weeks after stopping therapy was 13% of dogs that had received standard-dose clomipramine, 15% of dogs that had received low dose clomipramine and 23% of dogs that had received placebo. The mean time to worsening was longer in dogs that had received standard-dose clomipramine (37 weeks), as compared to low dose clomipramine (11 weeks, P = 0.005) or placebo (11 weeks, P = 0.003). In conclusion, no undesirable long term effects were detected in the use of standard-dose (1–2 mg/kg, q12h) clomipramine for the treatment of separation anxiety in dogs. Abrupt withdrawal of a sub-optimal dose of clomipramine (0.5–1 mg/kg, q12h) before signs of anxiety have been well controlled is not recommended.

Life after clozapine.

We consider the reasons underlying clozapine withdrawal in a group of hospitalised schizophrenic inpatients and review clinical outcome following clozapine withdrawal. A retrospective case note study was undertaken of all patients (n=41) registered at the State Hospital, Carstairs, with the Clozaril Patient Monitoring Service between 1990 and 2001 whose clozapine therapy had either been withdrawn or never initiated following registration. Twelve patients refused to commence clozapine following registration: twenty-nine patients were subsequently studied. Thirteen patients stopped clozapine owing to non-compliance, whereas seven had clozapine withdrawn due to a clinically inadequate response. Eleven patients were withdrawn primarily because of an unacceptable side-effect burden, although only four had a 'red alert'. In twenty patients, abrupt clozapine withdrawal resulted in a marked, immediate deterioration in their mental state. Twenty-three patients remained at the State Hospital at a mean follow-up period of 75 months. The study highlights the relevance of psychoeducation for clozapine patients in the maintenance phase of treatment, the importance of minimising the side-effect burden by clozapine monotherapy, the effectiveness of clozapine serum level monitoring and the evidence base for adjuvant treatment.

Recurrent, persisting panic attacks after sudden discontinuation of mirtazapine treatment: A case report

A 53-year-old woman with depressive symptoms and sleep problems, diagnosed as adjustment disorder with depressive reaction (ICD-10, F43.2), was treated with mirtazapine at a dose of 30 mg/day for a period of 10 weeks. In view of an imminent surgical intervention, the medication was than abruptly stopped. On the second day after discontinuation of mirtazapine, the patient developed a typical panic attack crisis with symptoms of palpitations, dyspnoea, retro-sternal pain, dizziness and nausea, blurred vision, anguish and fear of dying. During the next 5 days the patient suffered from severe, similar attacks recurring every 1–2 h, with each attack lasting about 20 min. Upon hospitalization and minor surgical intervention, the frequency and severity of symptoms regressed progressively, but the patient remained, with about one attack per week, not symptom free until the restitution of mirtazapine treatment at a dose of 30 mg/day. After re-introduction of mirtazapine panic attacks vanished, and during the entire follow-up period the patient remained symptom free. This case illustrates the risk of abrupt withdrawal of mirtazapine and indicates that, even after a medium-long therapy (10 weeks) with mirtazapine, progressive tapering-off of medication is advisable.