Factors associated with complex visual hallucinations during antidepressant treatment

Published case reports on complex visual hallucinations (CVH) occurring during antidepressant (AD) treatment were reviewed. Thirteen cases of CVH associated with SSRI treatment, 16 cases during tricyclic drug treatment and seven cases with other AD drug treatments were found. Nine patients were taking concomitant drugs while on therapy with SSRIs and four had a neurological disease in addition to depression. The cholinergic impoverishment occurring in dementia states or during concomitant therapy with anticholinergic drugs could increase the sensitivity to serotonergic agonists, triggering the manifestation of CVH. During tricyclic drug treatment, half of the reports were of hypnopompic or hypnagogic hallucinations and this can be associated with the effects of tricyclics (TCA) on sleep architecture. It is likely that the potent anticholinergic effect of amitriptyline was potentiated in a situation of a rapidly changing state of consciousness. In general, the review supports the view that an imbalance between serotonin and acetylcholine systems is at the root of AD-induced CVH, with a profile defined by a cholinergic hypoactivity and a serotonergic hyperactivity. Caution is needed when administering a combination of serotonergic and anticholinergic AD in the treatment of the demented population and in other already compromised patients because there is a risk of precipitating CVH.     

Pramipexole Overdose Associated with Visual Hallucinations,Agitation and Myoclonus

Introduction

Pramipexole is a dopamine D₂ receptor agonist used to treat idiopathic Parkinson’s disease and primary restless legs syndrome. There is limited information on pramipexole overdose.

Case Report

A 59-year-old male ingested 3 mg pramipexole, 2250 mg venlafaxine, 360 mg mirtazapine, with suicidal intent. He presented alert, had normal vital observations and normal pupillary reflexes. He was mildly agitated, reported visual hallucinations and was given 5 mg diazepam. He had a mildly elevated lactate of 1.7 mmol/L, but otherwise normal laboratory investigations. Overnight, he remained agitated with visual hallucinations and developed myoclonus while awake. He had increasing difficulty passing urine on a background of mild chronic urinary retention. On review, 14 h post-ingestion, he was hypervigilant, jittery and mildly agitated. He had pressured speech and difficulty focusing on questioning. He had a heart rate of 110 bpm, but had an otherwise normal examination, with no clonus or extrapyramidal effects. He was unable to mobilize due to dizziness and ataxia. Over the next few hours, he improved, the visual hallucinations and agitation resolved and he mobilized independently. Pramipexole was measured with liquid chromatography mass spectrometry. The initial plasma pramipexole concentration was 34.2 ng/mL (therapeutic range 0.2 to 7 ng/mL), 9 h post-overdose. Concentration time data fitted a one-compartment model with an estimated elimination half-life of 18 h.

Discussion

Pramipexole overdose with hallucination, agitation, and myoclonus is consistent with adverse effects reported with therapeutic toxicity, but mirtazapine and venlafaxine may have contributed. Pramipexole concentrations exceeded the therapeutic range for over 24 h. With the increasing use of pramipexole in restless legs syndrome, adult overdoses may become more common.

     

Ofloxacin-induced hallucinations

Drug-induced hallucinations are not uncommon, and may be misdiagnosed as psychiatric illness leading to unnecessary treatment with antipsychotics. If a temporal association of use of a drug having the potential to cause hallucinations is present, mere withdrawal of the drug causes complete improvement in the symptoms. There are reports of various untoward central nervous system adverse events following administration of fluoroquinolones, including delirium, hallucinations and psychosis, even after a single dose. We describe a 5-year-old girl who suffered visual hallucinations following ofloxacin use.KEY WORDS: Adverse events, hallucinations, ofloxacin     

Alendronate-induced auditory hallucinations and visual disturbances

A 79-year-old Caucasian woman who had been taking alendronate 10 mg/day for over 2 years to prevent osteoporosis reported hearing "voices in her head" along with red-colored visual disturbances. These auditory hallucinations and visual disturbances began shortly after her regimen was changed from alendronate 10 mg/day to 70 mg once/week. Assessment of causality using the Naranjo and Jones algorithms revealed a "probable" and "highly probable" relationship, respectively, between this adverse drug event and the switch from daily to weekly alendronate therapy. Other bisphosphonates, such as etidronate and pamidronate, have caused both reversible and irreversible auditory, visual, and olfactory hallucinations beginning 2 hours--1 week after drug administration. The mechanism behind these adverse effects is unknown but is thought to be independent of calcium homeostasis. Clinicians should be aware of central nervous system toxicity as a rare but potential adverse effect associated with bisphosphonates.     

Treatment of typical Charles Bonnet syndrome with donepezil

Charles Bonnet syndrome (CBS) is characterized by the presence of complex visual hallucinations in psychologically normal people. Although visual hallucinations in the elderly are often associated with dementia with Lewy body (DLB), Alzheimer's disease and delirium, they are excluded from the diagnosis of typical CBS, as are cognitive or psychiatric disturbances, sleep disorders and focal neurological lesions. Here, we describe a patient with typical CBS, who responded to donepezil, a cholinesterase inhibitor, and has not shown any symptoms suggestive of Alzheimer's disease or DLB for approximately the past 40 months. However, follow-up examination of her clinical symptoms is necessary for a definite exclusion of Alzheimer's disease and DLB. The effectiveness of donepezil indicates that the patient's visual hallucinations might be related to dysfunction of cholinergic neurones, although she did not exhibit any cognitive decline, or morphological and physiological brain pathology. Because donepezil has fewer adverse effects than anticonvulsants and neuroleptic drugs, it may be a safer option for the treatment of CBS in the elderly.     

Benefits and risks of pharmacotherapy for narcolepsy.

Narcolepsy is a life-long central nervous system (CNS) syndrome characterised by excessive sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed night-time sleep. Unsuccessfully treated narcolepsy confers increased risks on patients and on society due to the patient's increased chance of becoming involved in vehicle crashes and workplace mishaps. The syndrome may be diagnosed by a clinical history positive for cataplexy and excessive daytime sleepiness and negative for other more common sleep disorders such as sleep apnoea and sleep deprivation. Night-time polysomnography and multiple sleep latency testing are helpful in differentiating narcolepsy from other sleep problems. Recent data from canine, murine, and human forms of narcolepsy indicate that genetically or developmentally mediated deficits in the hypocretin neurotransmitter system may cause some, but not all, forms of narcolepsy. Pharmacotherapy for narcolepsy is required to control symptoms and involves the use of CNS stimulants or modafinil to control sleepiness and antidepressant medications or sodium oxybate to control cataplexy. Modafinil and sodium oxybate have been developed and approved specifically for the indication of narcolepsy based on large, double-blind, placebo-controlled, parallel group efficacy and safety studies. The efficacy of drugs in the treatment of narcolepsy is variable from patient to patient and usually associated with adverse effects that can limit patient compliance and, therefore, symptom control. Nevertheless, the benefits of pharmacotherapy are judged to outweigh the risks to the patient. The favourable benefit-risk ratio of pharmacotherapy is greater if one considers the reduced risk to society of vehicle crashes and workplace mishaps that might be precipitated by attentional lapses or sleep attacks in the untreated or under-treated patient with narcolepsy.     

The Clinical and Forensic Toxicology of Z-drugs

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1–7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography–mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.     

酒石酸唑吡坦与文拉法辛合用致幻觉

1例54岁女性患者,因焦虑状态给予文拉法辛75mg及酒石酸唑吡坦10mg睡前服用。约15min后出现幻觉,入睡后消失。随后症状加重。考虑该不良反应与两药合用有关,故改为分开服用,间隔大于2h。1周后症状消失。     

Modest abuse-related subjective effects of zolpidem in drug-naive volunteers

Recent case reports suggest that the short-acting benzodiazepine-like hypnotic, zolpidem, may have abuse potential among individuals who have no personal history of abusing drugs or alcohol, particularly at doses higher than those recommended for treating insomnia. This study recruited drug-naive volunteers to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg) administered in a within-subject double-blind design. Participants (n=11) answered computerized questionnaires (Addiction Research Center Inventory, visual analog scales, and a hypothetical Drug versus Money Choice) to address the hypothesis that a supratherapeutic dose (20 mg) would increase ratings of abuse-related subjective effects, while lower therapeutic doses (5 and 10 mg) would not. Although participants rated some effects as negative at 10 and 20 mg, the highest dose engendered predominantly positive abuse-like effects such as 'High', 'Like', and 'Good Effects'. However, no dose of zolpidem was chosen over money ($0.35-$10) when participants made hypothetical choices between them. Results suggest that although individuals without a drug abuse history are not inclined to choose zolpidem when presented with an alternative reinforcer such as money, it may possess moderate abuse potential that limits its clinical utility.     

Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine omega 1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20 mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.     

Clinically important drug interactions with zopiclone,zolpidem and zaleplon

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The fact that these drugs are newer to the market and have not been as extensively studied as the conventional benzodiazepines may be the reason for this. Another explanation may be a difference in CYP metabolism. While triazolam and midazolam are biotransformed almost entirely via CYP3A4, the newer hypnosedatives are biotransformed by several CYP isozymes in addition to CYP3A4, resulting in CYP3A4 inhibitors and inducers having a lesser effect on their biotransformation.     

Temazepam,but not zolpidem,causes orthostatic hypotension in astronauts after spaceflight

Insomnia is a common symptom, not only in the adult population but also in many astronauts. Hypnotics, such as temazepam (a benzodiazepine) and zolpidem (an imidazopyridine), are often taken to relieve insomnia. Temazepam has been shown clinically to have hemodynamic side effects, particularly in the elderly; however, the mechanism is not clear. Zolpidem does not cause hemodynamic side effects. The purpose of this study was to determine whether the use of different hypnotics during spaceflight might contribute significantly to the high incidence of postflight orthostatic hypotension, and to compare the findings in astronauts with clinical research. Astronauts were separated into three groups: control (n = 40), temazepam (15 or 30 mg; n = 9), and zolpidem (5 or 10 mg; n = 8). In this study, temazepam and zolpidem were only taken the night before landing. The systolic and diastolic blood pressures and heart rates of the astronauts were measured during stand tests before spaceflight and on landing day. On landing day, systolic pressure decreased significantly and heart rate increased significantly in the temazepam group, but not in the control group or in the zolpidem group. Temazepam may aggravate orthostatic hypotension after spaceflight when astronauts are hemodynamically compromised. Temazepam should not be the initial choice as a sleeping aid for astronauts. These results in astronauts may help to explain the hemodynamic side effects in the elderly who are also compromised. Zolpidem may be a better choice as a sleeping aid in these populations.     

The effects of repeated zolpidem treatment on tolerance,withdrawal-like symptoms,and GABAA receptor mRNAs profile expression in mice: Comparison with diazepam

Rationale

Zolpidem is a short-acting, non-benzodiazepine hypnotic that acts as a full agonist at α1-containing GABA_A receptors. Overall, zolpidem purportedly has fewer instances of abuse and dependence than traditionally used benzodiazepines. However, several studies have shown that zolpidem may be more similar to benzodiazepines in terms of behavioral tolerance and withdrawal symptoms.

Objectives

In the current study, we examined whether subchronic zolpidem or diazepam administration produced deficits in zolpidem’s locomotor-impairing effects, anxiety-like behaviors, and changes in GABA_AR subunit messenger RNA (mRNA).

Methods

Mice were given subchronic injections of either zolpidem (10 mg/kg), diazepam (20 mg/kg), or vehicle twice daily for 7 days. On day 8, mice were given a challenge dose of zolpidem (2 mg/kg) or vehicle before open field testing. Another set of mice underwent the same injection regimen but were sacrificed on day 8 for qRT-PCR analysis.

Results

We found that subchronic zolpidem and diazepam administration produced deficits in the acute locomotor-impairing effects of zolpidem and increased anxiety-like behaviors 1 day after drug termination. In addition, we found that subchronic treatment of zolpidem and diazepam induced distinct but overlapping GABA_AR subunit mRNA changes in the cortex but few changes in the hippocampus, amygdala, or prefrontal cortex. Levels of mRNA measured in separate mice after a single injection of either zolpidem or diazepam revealed no mRNA changes.

Conclusions

In mice, subchronic treatment of zolpidem and diazepam can produce deficits in the locomotor-impairing effects of zolpidem, anxiety-like withdrawal symptoms, and subunit-specific mRNA changes.     

Benefit-risk considerations in the treatment of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a relatively recently characterised syndrome with clinical and pathological features that distinguish it from classical Alzheimer's disease. These characteristics include more rapid decline, spontaneous features of parkinsonism, visual hallucinations and fluctuating cognition. This article reviews the clinical syndrome of DLB and the agents used to treat its cognitive, motor and behavioural manifestations. Benefit-risk issues regarding the treatment of DLB are discussed based upon limited randomised, controlled clinical trials with some speculative conclusions being drawn from case reports and case series. We conclude that patients with DLB may respond better to cholinesterase inhibitors than patients with Alzheimer's disease on both cognitive and behavioural measures. Cholinesterase inhibitor therapy may result in reduced caregiver burden and less time institutionalised. These agents are well tolerated with the majority of adverse effects being gastrointestinal in nature. Although neuropsychiatric manifestations are numerous in patients with DLB, antipsychotics should be used infrequently and with caution, although atypical antipsychotics are better tolerated than conventional antipsychotics. Physicians should exhibit caution when prescribing these agents because of the increased risk of extrapyramidal adverse effects. Limited data suggest that the use of levodopa or other dopaminergic agents may be of benefit for the treatment of the parkinsonism that is associated with DLB. However, the increased risk of hallucinations and neuropsychiatric symptoms may negate the potential benefits of increased mobility. There is insufficient evidence to draw conclusions about the use of antidepressants; however, selective serotonin reuptake inhibitors may be of benefit.     

Charles Bonnet Syndrome: successful treatment of visual hallucinations due to vision loss with selective serotonin reuptake inhibitors

Visual hallucinations are a common and often distressing consequence of vision loss, particularly in age-related macular degeneration. Charles Bonnet Syndrome (CBS) is defined by the triad of complex visual hallucinations, ocular pathology causing visual deterioration and preserved cognitive status. So far, although this condition is frequent, no established treatment for CBS has been stated. We report here the case of a 78-year-old woman, who came in our hospital because of a 4-week long mild depressive symptomatology. For 1 year she experienced daily sudden, unexpected, vivid and elaborate hallucinations. Insight was completely present, so the patient stated that the hallucinations were unreal and that the faces, geometrical figures and animals she saw every day were possibly due to her vision loss. The Mini Mental State Examination, digit span and verbal fluency were administered and no cognitive impairment was reported. The visual acuity was hand motion. After 4 days of treatment with venlafaxine the hallucinations completely disappeared. This is the first case to show that selective serotonin (and noradrenalin) reuptake inhibitors may be an effective and well-tolerated treatment for visual hallucinations associated with vision loss, and it adds to evidence implicating serotonergic pathways in the pathogenesis of visual hallucinations.     

Emerging drugs for narcolepsy

Narcolepsy is characterised by excessive daytime sleepiness, usually associated with cataplexy, hypnagogic hallucinations, sleep paralysis and fragmented nocturnal sleep. Although uncommon, it results in significant disability. Most cases occur sporadically, but genetic factors probably form a susceptibility background on which unknown environmental triggers act. The hypocretin system is strongly implicated in the development of narcolepsy. Cerebrospinal fluid levels of hypocretin-1 are significantly reduced in narcoleptic subjects with cataplexy. Despite the advances in our understanding of narcolepsy, current therapy is primarily symptomatic. Stimulants (standard and novel) combat excessive daytime sleepiness. Antidepressants (tricyclics, dual-action or selective serotonin re-uptake inhibitors) and sodium oxybate are anticataplexy agents. Hypnagogic hallucinations and sleep paralysis respond to antidepressants. Sodium oxybate consolidates sleep. Novel and experimental treatments include histamine antagonists, hypocretin agonists, slow-wave sleep enhancers, intravenous gamma-globulin, tramadol and corticosteroids.     

Voriconazole-associated visual disturbances and hallucinations

Voriconazole is a second-generation azole widely used for the prevention and treatment of fungal infection in leukemia patients. Voriconazole is considered the primary antifungal agent for invasive aspergillosis. We report a case of 16-year-old girl who developed visual disturbance and visual and auditory hallucinations after intravenous voriconazole treatment for invasive pulmonary aspergillosis. Due to the visual hallucinations and visual disturbance began acutely and shortly after the initiation of voriconazole, and no other cause could be determined, the symptoms were considered to be the side effects of voriconazole. Simultaneous development of visual side effects and hallucinations rarely have been reported before.     

Pharmacoepidemiological characterisation of zolpidem and zopiclone usage

Purpose

Zolpidem and zopiclone are two widely used non-benzodiazepine hypnotics whose usage seems to be associated to pharmacodependence. However, to our knowledge, there has as yet been no published epidemiological study which has compared their abuse or dependence potential. We used a pharmacoepidemiological approach to identify and characterise zolpidem and zopiclone users in real life situations.

Methods

Regular users of zolpidem or zopiclone were identified in the database of a French regional health insurance organisation. A latent class analysis (LCA) was used to identify different subgroups of users of these two hypnotics.

Results

The study cohort comprised 25,168 patients who regularly used zolpidem and 21,860 who regularly used zopiclone. The results of the latent class analysis, which enables subgroups with similar patterns of response to be identified, revealed four clinical subtypes of users of zolpidem: non-problematic users, users with associations with hypnotics/anxiolytics or with associated mental disorders, and problematic users. Only three subgroups were identified for zopiclone, and LCA did not discriminate a special class of problematic users for this drug.

Conclusion

Our analysis indicates that there is a subclass of zolpidem user suggestive of abuse; this was not the case for zopiclone. This methodology is very interesting because it allows analysis of databases and determination of a specific signature of drugs potentially leading to abuse or dependence.     

Cholecystokinin,cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease

Cholecystokinin modulates the release of dopamine and dopamine-related behaviours in the mesolimbic pathway, where cholecystokinin and dopamine coexist in dopaminergic neurones. Because cholecystokinin and its receptors (A and B) have a functional interaction with dopaminergic neurotransmission, alterations in them may constitute a predisposition for Parkinson's disease. We performed a case-control study to investigate the association between the cholecystokinin system and Parkinson's disease using genetic markers for three genes: cholecystokinin and its two receptors (A and B). One hundred and sixty patients with Parkinson's disease and 160 controls, matched for age, gender, ethnic origin and area of residence, were recruited. Cholecystokinin -45C>T, cholecystokinin-A receptor 779T>C and cholecystokinin-B receptor 1550G>A gene polymorphisms were studied using polymerase chain reaction-restriction fragment length polymorphism analyses. These three gene polymorphisms showed no correlation with risk of Parkinson's disease; however, the cholecystokinin CT/TT genotype was associated with a 4.429-fold increased risk for visual hallucinations in Parkinson's disease. Cholecystokinin-A receptor and B receptor polymorphisms, considered alone, showed no correlation with hallucinations in Parkinson's disease; however, a combined effect was found in patients with hallucinations harboring both the cholecystokinin CT/TT and cholecystokinin-A receptor TC/CC genotypes. Parkinson's disease patients harboring this genotype have a 5.922-fold increased risk for developing visual hallucinations. These results suggest that, in Chinese, visual hallucinations in Parkinson's disease are associated with cholecystokinin -45C>T polymorphism, and this association was still observed in the presence of the cholecystokinin-A receptor TC/CC genotype, indicating a possible interaction of these two genes in the visual hallucinogenesis in Parkinson's disease.