Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine

We report five cases of restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) that were probably associated with olanzapine. The first patient showed a good response to olanzapine, but the RLS symptoms associated with olanzapine resulted in poor long-term compliance, eventually leading to frequent relapse of psychotic symptoms. The second patient exhibited sudden PLMS following olanzapine injection. The third patient had been suffering from serious akathisia while on risperidone, and was cured after switching to olanzapine, but thereafter the patient suffered from RLS at nighttime. The fourth patient showed RLS symptoms that were initially caused by a 20-mg daily olanzapine dosage and were later mitigated when olanzapine was reduced and ropinirole was administered. The fifth patient exhibited paraesthesia and agitation caused by olanzapine that was misdiagnosed as psychotic agitation. Increasing the olanzapine dosage severely aggravated the symptoms of RLS. Antipsychotic-induced RLS and PLMS are not well-recognized side effects of antipsychotics, with the symptoms often misdiagnosed as psychotic agitation. These cases also suggest that the occurrence of RLS can cause noncompliance with antipsychotics in psychiatric patients, and thus aggravate their psychotic symptoms.     

Longer-term treatment of patients with bipolar disorder: a 9-month observational study in Central and Eastern Europe,the Middle East and Africa

ABSTRACT

Objective: To compare the longer-term outcomes of pharmacological treatment of patients with a diagnosis of bipolar affective disorder currently suffering a manic or hypomanic episode prescribed olanzapine or non-olanzapine medication in naturalistic, clinical practice settings in Bosnia-Herzegovina, Slovakia, Slovenia, Turkey, Saudi Arabia and Egypt.

Research design and methods: Prospective, observational, non-interventional study conducted over 9 months. Inpatients or outpatients who initiated or changed oral bipolar mania medication were grouped into (1) those prescribed olanzapine at baseline (n?=?569) and (2) those not prescribed olanzapine (n?=?325).

Main outcome measure(s): The change from baseline in the Clinical Global Impression Severity scale for bipolar disorder (CGI-BP-S), the rates of symptomatic response and remission (based on CGI-BP-S) and the frequency and nature of treatment-emergent adverse events. Analyses included (1) linear or logistic regression, with adjustment for confounders, based on the last observation carried forward and (2) weighted repeated measures models that adjusted for treatment switching and patient drop-out.

Results: When results were adjusted for treatment switching and patient drop-out, patients prescribed olanzapine had significantly better CGI-BP-S scores (mean difference?=??0.24; 95% confidence interval [CI] ?0.33, ?0.16; p?<?0.001) and significantly greater odds of treatment response (odds ratio [OR] =?1.86; 95% CI 1.31, 2.65; p?<?0.001) and symptom remission (OR?=?1.65; 95% CI 1.18–2.32; p?=?0.003) than those not prescribed olanzapine. The frequency of most adverse events decreased in both groups. Patients prescribed olanzapine had significantly greater weight gain from baseline (mean increase?=?2.66?kg; 95% CI 2.35, 2.98) compared with those not prescribed olanzapine (mean increase?=?1.85?kg; 95% CI 1.51, 2.19; p?<?0.001).

Conclusions: Inclusion of olanzapine is of benefit for pharmacological treatment of patients with bipolar disorder. However, the favourable outcomes observed cannot be directly attributed to olanzapine alone because of the high prevalence of polypharmacy in the patient population.     

Pramipexole for the treatment of restless legs syndrome

Restless legs syndrome (RLS) is a common disorder that is estimated to affect 10% of Americans. However, it remains largely undiagnosed and untreated by clinicians. The primary symptoms of this condition are leg discomfort or an urge to move that is temporarily relieved by movement and is worse at rest and at bedtime. RLS impacts the quality of life of the sufferer by disrupting sleep and disturbing or curtailing work and social activities. Approximately 80% of RLS sufferers also have periodic limb movements during sleep, in which repetitive leg movements fragment sleep and may result in daytime drowsiness. RLS may be treated by dopaminergic agents, benzodiazepines, anticonvulsants and opiates; dopamine agonists are currently considered first-line therapy for this condition. Pramipexole has been studied in the treatment of RLS since 1998. This article reviews the role of this medication in the management of this serious neurological disorder.     

Pramipexole for the treatment of restless legs syndrome

Restless legs syndrome (RLS) is a common disorder that is estimated to affect 10% of Americans. However, it remains largely undiagnosed and untreated by clinicians. The primary symptoms of this condition are leg discomfort or an urge to move that is temporarily relieved by movement and is worse at rest and at bedtime. RLS impacts the quality of life of the sufferer by disrupting sleep and disturbing or curtailing work and social activities. Approximately 80% of RLS sufferers also have periodic limb movements during sleep, in which repetitive leg movements fragment sleep and may result in daytime drowsiness. RLS may be treated by dopaminergic agents, benzodiazepines, anticonvulsants and opiates; dopamine agonists are currently considered first-line therapy for this condition. Pramipexole has been studied in the treatment of RLS since 1998. This article reviews the role of this medication in the management of this serious neurological disorder.     

Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia

There are reports of de novo development or exacerbation of obsessive-compulsive symptoms in patients with schizophrenia treated with atypical antipsychotics, although this is widely debated. We report one such case where a patient with a primary diagnosis of schizophrenia, treated with olanzapine, developed de novo obsessive-compulsive disorder, with convincing evidence for its causality due to the drug.KEY WORDS: Obsessive-compulsive disorder, olanzapine, schizophrenia     

Restless legs syndrome.

PURPOSE: The signs and symptoms, epidemiology, etiology, pathophysiology, diagnosis, pharmacologic and nonpharmacologic treatments, and options and guidelines for the treatment of restless legs syndrome (RLS) are reviewed. SUMMARY: RLS was first described in the 17th century and further characterized in 1945. RLS is a common disorder, occurring in about 10% of the population. Patients with RLS often describe the urge to move, uncomfortable sensations, and pain, which begin or worsen during rest or inactivity such as lying or sitting. Symptoms of RLS make sleeping difficult for many patients, and significant daytime difficulties result from the condition. RLS can either be primary or arise from secondary causes that lead to iron deficiency. There is a familial component in primary RLS, but its underlying mechanisms remain unknown. Of individuals with conditions associated with iron-deficiency states, including pregnancy, renal failure, and anemia, 25-30% may develop RLS. The goals of RLS treatment include improving its symptoms and the patient's quality of life. There are limited data on the treatment of RLS. Pharmacologic therapies include iron replacement, dopaminergic agents (e.g., levodopa), dopamine agonists, anticonvulsants, opioids, and benzodiazepines. There have been no systematic trials of nonpharmacologic therapies for RLS, but good sleep hygiene and avoidance of alcohol, caffeine, and nicotine may improve symptoms. CONCLUSION: RLS is a common disorder thought to involve abnormal iron metabolism and dopaminergic systems. Nonpharmacologic therapy should be suggested for all patients with RLS, but pharmacologic therapy may be required, and evidence is strongest for levodopa and dopamine agonists.     

Black hairy tongue associated with olanzapine treatment: a case report

Olanzapine is an atypical antipsychotic drug approved for acute and long-term treatment of bipolar disorder. Although relatively safe as compared to other classical antipsychotic medications, there are a number of uncommon adverse effects of olanzapine such as oral cavity lesions. In addition to the relatively common side effect of dry mouth, several articles have reported an association between olanzapine treatment and the development of oral lesions such as apthous stomatitis, pharyngitis, glossitis and oral ulceration. Although there are several cases in which the tongue was affected in conjunction with stomatitis or pharyngitis, we could not find a case report indicating a direct relationship between olanzapine use and a tongue lesion. We present here the case of a patient with bipolar disorder, who developed recurrent black hairy tongue on two different occasions following the addition of olanzapine to lithium treatment. In the present case, xerostomia (dry mouth), which is an adverse reaction of both olanzapine and lithium, may have played a role in the development of black hairy tongue. All agents with a possible side effect of xerostomia may predispose patients to black hairy tongue, especially when they are administered in combination. To preclude the development of this complication with such drugs, extra time and effort should be given to improving oral hygiene.     

Restless legs syndrome in the older adult: diagnosis and management

Restless legs syndrome (RLS) is common in the elderly, with an estimated prevalence of 10 to 35% in individuals over 65 years of age. RLS is characterised by paraesthesias and dysaesthesias of the legs, typically occurring in the evening. The symptoms occur at rest and result in motor restlessness; movement often temporarily relieves the symptoms. Patients with poorly controlled RLS may develop related problems including insomnia (due to sleep-onset restlessness or periodic limb movements or related sleep fragmentation) and depression. RLS can be a primary disorder that develops in the young and includes familial cases. Secondary RLS occurs in association with iron-deficiency anaemia, uraemia and polyneuropathies. Typically, RLS is misdiagnosed or undiagnosed for years. In the elderly, both primary and secondary types of the disorder are common. It is thought that RLS represents lower CNS levels of, or reduced responsiveness to, dopamine. The symptoms improve with dopaminergic therapy. Ergotamine dopamine-receptor agonists such as pergolide, and the non-ergotamine dopamine-receptor agonists pramipexole and ropinirole, are becoming more commonly used to treat RLS. The dopamine precursor levodopa, in combination with carbidopa, is another effective therapeutic agent. An advantage of levodopa is lower cost than non-ergotamine and ergotamine dopamine-receptor agonists. However, the adverse effect of symptom augmentation appears to develop more frequently with levodopa than dopamine-receptor agonists; therefore, levodopa may currently be used somewhat less often as first-line therapy. Patients with painful symptoms may respond favourably to the anticonvulsants gabapentin and carbamazepine. Opioids and hypnosedatives are helpful in selected patients; however, these agents may have troubling adverse effects in the elderly. Correction of iron deficiency improves symptoms in patients with low ferritin levels. Lifestyle modification may also be helpful. Therapy is directed at symptoms, and most symptomatic patients benefit from treatment. It is important to consider RLS in the differential diagnosis of any patient with paraesthesias of the limbs.     

Photo-onycholysis caused by olanzapine and aripiprazole

Photo-onycholysis associated with drugs is an uncommon disorder. We report the case of a woman who developed photo-onycholysis on multiple nails after uptake of olanzapine. Substitution of olanzapine with aripiprazole further exacerbated the problem. The possible mechanisms of photo-onycholysis development by modern atypical antipsychotics, modulating dopamine receptors, are discussed.     

不安腿综合征的药物治疗

不安腿综合征是一种常见的神经系统感觉运动障碍疾病,常伴有睡眠障碍。它可见于任何年龄,因缺乏特异性的实验室辅助诊断依据,大多数患者在发病数年后仍不能被识别,甚至被误诊,更得不到适当治疗。过去的数十年里,多个大型临床研究证实,几种类型的药物可用来改善患者症状,包括多巴胺能药物、抗癫痫药物、鸦片类药物和苯二氮革类药物。     

Opioids in the treatment of restless legs syndrome: pharmacological and clinical aspects

Introduction: Restless legs syndrome (RLS) is a common neurologic sensory-motor disorder that can have a negative impact on sleep, quality of life and health. In patients affected by severe RLS, pharmacological treatment is mandatory.

Areas covered: The present review is based on a search using PubMed from 1993 to 2016. It is focused on pharmacological and clinical aspects of opioids used for the treatment of RLS.

Expert opinion: The drugs currently available for the treatment of RLS do not always allow to obtain an optimal control of symptoms, in particular, when utilised for long-term treatment. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a phase III trial oxycodone-naloxone prolonged-release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatment. It was recently approved for the second-line symptomatic treatment of severe to very severe idiopathic RLS, after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone-naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α-2-δ ligands are needed.     

Current treatment options for restless legs syndrome

Restless legs syndrome (RLS) is a common but often underdiagnosed neurological disorder characterised by an imperative desire to move the extremities associated with paraesthesias, motor restlessness, worsening of symptoms at rest in the evening or at night and, as a consequence, sleep disturbances particulary. Additionally, most patients with RLS have periodic limb movements during sleep and relaxed wakefulness. The aetiology of RLS remains unknown. Treatment of RLS is generally symptomatic, a causal therapy is possible only in the secondary forms. Dopaminergic agents including levodopa and dopamine agonists such as pergolide, pramipexole, cabergoline and ropinirole are regarded as the treatment of choice for idiopathic RLS, however, the development of augmentation of symptoms, especially under levodopa therapy, may be a major problem. Except in special circumstances, opioids and anticonvulsants such as gabapentin or benzodiazepines, are regarded as second-line treatment. In secondary RLS, the underlying illness should first be treated, although dopaminergic drugs may also be helpful.     

Emerging drugs for restless legs syndrome

Restless legs syndrome (RLS) is a common, but often underdiagnosed, neurological disorder, which is characterised by an imperative urge to move the extremities associated with paraesthesias, worsening of symptoms at rest and in the evening or at night, and, as a consequence, sleep disturbances. RLS affects 1-10% of the population. The aetiology of RLS is unknown, but besides genetic factors the dopaminergic and opioidergic system may play a crucial role and new developments also point to an exciting iron-dopamine connection in the pathophysiology of this burdening disorder. Due to the limited disease-specific knowledge, current treatment strategies are not curative, but nevertheless may produce an effective and lasting relief of symptoms. Although clinically based treatment has focused on levodopa, opioids and benzodiazepines for a long time, evidence-based and clinical guidelines identify dopamine agonists as a first-line treatment for daily restless legs symptoms. These substances are now in the process of registration for this indication. Ropinirole is the first dopamine agonist that has been approved by the FDA in May 2005. In addition, several promising new therapies with nondopamine profiles are under development for RLS.     

Investigational approaches to therapies for restless legs syndrome

Introduction: Restless Legs Syndrome (RLS) is a common neurological disorder that impairs nocturnal rest, causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by severe RLS, pharmacological treatment is mandatory.

Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 – 2014. It focuses on drugs currently in development for the treatment of RLS.

Expert opinion: The drugs currently available for treating RLS do not always allow the patient to obtain a dose capable of controlling the symptoms, particularly in the long term. There is still the need for effective and well-tolerated new drugs. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS, sparing stronger dopaminergic agents for later stages of the disease. Oxycodone-naloxone has demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled with first-line drugs; it could be used as a long-term treatment option in severe cases of RLS for which alternative satisfactory drug regimens are unavailable. There is a paucity of data comparing medications in head-to-head trials to determine their relative effectiveness and adverse event profiles. Furthermore, there is also a need for further studies that evaluate nondopaminergic agonists and combination therapies for treating RLS.     

Pharmacologic Treatment of Restless Legs Syndrome

Restless legs syndrome (RLS)/Willis-Ekbom disease is a neurologic disorder characterized by a strong desire to move when at rest (usually in the evening) and paraesthesia in their lower legs. The most widely used therapies for first-line treatment of RLS are dopaminergic drugs; however, their long-term use can lead to augmentation. α2δ Ligands, opioids, iron, glutamatergic drugs, adenosine, and sleep aids have been investigated as alternatives. The pathogenesis of RLS is not well understood. Despite the efficacy of dopaminergic drugs in the treatment of this disorder, unlike in Parkinson’s disease dopaminergic cell loss in the substantia nigra has not been observed in RLS. The etiology of RLS is likely complex, involving multiple neural pathways. RLS-related genes identified in genome-wide association studies can provide insight into the mechanistic basis and pathophysiology of RLS. Here we review the current treatments and knowledge of the mechanisms underlying RLS.     

A suspected case of olanzapine induced hyponatremia

Here we report a case of a 63-year-old male diagnosed with recurrent depressive disorder and current episode of severe depression with psychotic symptoms, developed hyponatremia soon after addition of olanzapine and increasing the dose of escitalopram. A possible causality association was established with olanzapine, and the possible etiological reasons of this clinically significant risk were discussed.KEY WORDS: Antipsychotic, escitalopram, hyponatremia, olanzapine     

Human reward system activation is modulated by a single dose of olanzapine in healthy subjects in an event-related,double-blind,placebo-controlled fMRI study

Rationale Olanzapine is a neuroleptic drug widely prescribed to treat schizophrenia and bipolar disorder. Although it is long known that modulation of the dopamine system is a basic mechanism of action of neuroleptics, their impact on reward functions mediated by dopamine is still poorly understood. Objective Using functional magnetic resonance imaging (fMRI), we intended to reveal the effects of a single dose of olanzapine on reward-related brain activation. Methods Eight healthy subjects were each scanned twice, once 5 h after intake of 5 mg of olanzapine and once after intake of placebo in a double-blind cross-over design. Subjects performed a delayed incentive paradigm with monetary reward to investigate reward functions and a breath-holding task as a hypercapnic challenge to reveal unspecific drug effects on the fMRI signal. Results Reward-related brain activation in the ventral striatum, anterior cingulate and inferior frontal cortex was reduced on olanzapine compared to placebo. Only the differential effects (high>no reward) in the ventral striatum were independent of overall drug effects as measured with the breath-holding task. Parallel to the differential effects in the ventral striatum, the acceleration of reaction times in the trials with higher rewards was diminished in the olanzapine sessions. Conclusions Our behavioural and fMRI results can be interpreted as first evidence from neuroimaging that olanzapine affects the assignment of incentive salience represented by differential activation in dopaminergic brain areas and acceleration of reaction times. This can help to better understand neuroleptic effects in psychiatric diseases. Furthermore, we demonstrate the value of a hypercapnic challenge in functional pharmaco-MRI.