Virginie-Anne Chouinard

Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes

movement disorder(s) (DIMD) has continuously decreased with atypical antipsychotics, DIMD persist as do psychiatric and psychiatric-like symptoms associated with DIMD, and these must also be identified and evaluated. Persistent DIMD have been found to be a predictor of the later emergence of tardive dyskinesia (TD) and supersensitivity psychosis [4] . At present, we need to determine the relative risk of iatrogenic discontinuation syndromes, DIMD and DIMD psychiatric symptoms resulting from atypical antipsychotics. Although atypical antipsychotics are now most commonly prescribed, a debate has emerged on the differences between classical and atypical antipsychotics following the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [5] . The question that comes to the forefront is why recent studies are no longer finding well-established differences between these two generations in terms of efficacy and DIMD. Reasons to explain why recent schizophrenia studies have found reduced drug and placebo differences were examined at the International Society for CNS Clinical Trials and Methodology Annual Mid-Year Conference [6] . Chronic illness can result in chronicity of clinical practice. As we have moved away from prescribing classical antipsychotics and tricyclic antidepressants, issues remain with the use of atypical antipsychotics and second-generation antidepressants that need to be addressed, namely, iatrogenic discontinuation syndromes and supersensitivity psychiatric symptoms. An optimal maintenance drug treatment consists of regular attempts to reduce the dose by finding a minimal therapeutic dose, regularly asking the question of when to reduce or withdraw treatment and for which patients, and moreover, why it is difficult to decrease a given drug treatment. Recently, Falloon [1] proposed that maintenance pharmacotherapy in schizophrenia will depend on finally finding minimally effective doses through ‘extensive training in stress management’. In the long-term treatment of major depression, Fava [2] has hypothesized that antidepressants can aggravate the course of depressive illness. Lambert [3] recently suggested that ‘antipsychotic-switching syndromes’, which include discontinuation syndromes, are a ‘major barrier’ to adjusting antipsychotic treatment. In this paper, we propose that to achieve optimal maintenance treatment with antipsychotics, and to reduce or withdraw antipsychotics effectively, we must distinguish syndromes associated with discontinuing antipsychotics, such as supersensitivity psychosis, from true relapse. While the prevalence and incidence of drug-induced Published online: January 25, 2008

Is DSM-IV bereavement exclusion for major depressive episode relevant to severity and pattern of symptoms? A case-control, cross-sectional study.

OBJECTIVE To assess the DSM-IV major depressive episode (MDE) bereavement exclusion criterion by comparing severity and pattern of symptoms in bereavement-excluded individuals satisfying all other DSM-IV MDE criteria to these same variables in MDE controls. METHOD A case-control, cross-sectional study of self-referred individuals seeking treatment for depressive symptoms was conducted. A total of 17,988 subjects met DSM-IV MDE symptom criteria. Of these, 1,521 individuals (8.5%) met all MDE criteria except the bereavement exclusion. They were matched by age, gender, marital status, and educational level with 1,521 MDE controls. Among the MDE controls, 292 had a recent bereavement and 1,229 did not. Severity of depression was measured by the number of MDE symptoms and the Montgomery-Asberg Depression Rating Scale (MADRS) score. Symptom cues of the bereavement-exclusion criterion were analyzed. The study was conducted between September 2003 and May 2004. RESULTS Bereavement-excluded subjects were more severely depressed than MDE controls without bereavement and similar to MDE controls with bereavement. Two symptom cues, suicidal ideation and worthlessness, and the majority of other depressive symptoms were more pronounced in bereavement-excluded individuals than in MDE controls. CONCLUSIONS Symptom cues of the DSM-IV MDE bereavement exclusion criterion should be modified since they could result in patients failing to be correctly diagnosed and treated.

New Classification of Selective Serotonin Reuptake Inhibitor Withdrawal

inal symptoms at the same intensity as before treatment, entailing a return of the same episode and a new episode of illness, respectively [6, 9] . When treatment with a CNS drug is discontinued, patients can experience classic new withdrawal symptoms, rebound and/or persistent postwithdrawal disorders, or relapse/recurrence of the original illness [6, 9, 14] . New and rebound symptoms can occur for up to 6 weeks after drug withdrawal, depending on the drug elimination half-life [2, 3] , while persistent postwithdrawal or tardive disorders associated with longlasting receptor changes may persist for more than 6 weeks after drug discontinuation. Initial withdrawal symptoms from CNS drugs have been reported to be more frequent and severe when high-potency drugs and drugs with a short elimination half-life have been used [9, 10] . CNS drugs with a shorter elimination half-life and rapid onset of action also carry a higher risk of dependency and high-dose use [9, 10] . Withdrawal symptoms can be relatively short-lasting, lasting for a few hours to a few weeks with complete recovery, while others may persist and last for several months [1, 15, 16] . Fava et al. [1] have proposed using the terminology ‘withdrawal syndrome’ to replace the term ‘discontinuation syndrome’, which has been most often used to describe SSRI withdrawal. They have recommended the Selective serotonin reuptake inhibitors (SSRIs) are widely used in clinical practice, and have advanced the treatment of depression and other mental disorders. However, more studies are needed on the effects of decreasing and discontinuing these medications after their long-term use [1] . Withdrawal symptoms may occur with all SSRIs and serotonin-noradrenaline reuptake inhibitors (SNRIs) [1] , similarly to other CNS drugs, including benzodiazepines [2–4] and antipsychotics [5, 6] . Withdrawal from SSRIs and other CNS drugs produces psychiatric symptoms that can be confounded with true relapse or recurrence of the original illness [1, 2, 7] . When discontinuing or decreasing SSRIs, withdrawal symptoms must be identified to avoid prolonging treatment or giving unnecessarily high doses [6, 8] . Different types of syndromes have been described with the withdrawal from SSRIs and other CNS drug classes, including benzodiazepines, antipsychotics, antidepressants, opiates, barbiturates, and alcohol: (1) new withdrawal symptoms (classic withdrawal symptoms from CNS drugs) [1, 4–6, 9–12] , (2) rebound [2, 6, 9, 13–16] , and (3) persistent postwithdrawal disorders [7, 17, 18] ( table 1 ). These types of withdrawal need to be differentiated from relapse and recurrence of the original illness. Relapse and recurrence are the gradual return of the origReceived: October 12, 2014 Accepted after revision: January 6, 2015 Published online: February 21, 2015

Patient Online Report of Selective Serotonin Reuptake Inhibitor-Induced Persistent Postwithdrawal Anxiety and Mood Disorders

In general, most studies have looked only at minor new symptoms of the CNS depressant withdrawal type [6] , but there are some exceptions which examined SSRI postwithdrawal emergent persistent disorders [7–9] . In the present study, we looked at both new SSRI withdrawal symptoms [6] and postwithdrawal persistent symptoms. Between February 2010 and September 2010, qualitative Google searches of 8 websites including Paxilprogress.org, ehealthforum.com, depressionforums.org, about.com, medhelp. org, drugLib.com, topix.com and survigingantidepressant.org were carried out in English, using keywords as ‘SSRIs withdrawal syndrome’, ‘Paxil withdrawal’, ‘SSRIs forums’. Links from the above websites/forums and other related material were also followed. In table 1 , we list selected online patient self-reporting of physical and psychiatric withdrawal symptoms for each of the 6 SSRIs: paroxetine (n = 3), sertraline (n = 2), citalopram (n = 2), fluoxetine (n = 1), fluvoxamine (n = 1) and escitalopram (n = 3), which we thought reflected best patient self-reporting of SSRI withdrawal symptoms. From online information available, gender is known for 4 patients (2 men and 2 women), the mean length of SSRI treatment (n = 9) was 5.13 years, range 0.25–15 years, median 4.5, and the mean duration of withdrawal symptoms (n = 7) was 2.5 years, range 0.125–6 years, median 2.1 years. As can be seen in table 1 , 58% of patients (7 out of 12) reported persistent postwithdrawal symptoms: 3 of 3 paroxetine patients, 2 of 2 citalopram, 1 of 1 fluvoxamine, 1 of 3 escitalopram and none of both sertraline and fluoxetine patients. We note in table 1 , persistent postwithdrawal disorders, which occur after 6 weeks of drug withdrawal, rarely disappear spontaneously, and are sufficiently severe and disabling to have patients returned to previous drug treatment. When their drug treatment is not restarted, postwithdrawal disorders may last several months to years. Significant persistent postwithdrawal emergent symptoms noted consist of anxiety disorders, including generalized anxiety and panic attacks, tardive insomnia, and depressive disorders including major depression and bipolar illness. Anxiety, disturbed mood, depression, mood swings, emotional liability, persistent insomnia, irritability, poor stress tolerance, impaired concentration and impaired memory are the more frequent postwithdrawal symptoms reported online. In the Fava et al. [8] gradual SSRI discontinuation controlled study on panic disorders, 9 of 20 patients (45%) had new withdrawal symptoms and 3 of the 9 (33%) paroxetinetreated patients had persistent emergent postwithdrawal disorders, consisting of bipolar spectrum disorder (n = 2) and major depressive disorder (n = 1) during a 1-year postwithdrawal fol low-up. Recently, Schifano et al. [1] analyzed online self-reporting of misuse of pregabalin, and found psychedelic dissociative effects induced by pregabalin in this selected population of drug abusers, information that apparently can only be obtained at least initially through online self-reporting studies [1] . In the present study, we analyze online self-reporting from a variety of websites visited by patients who had discontinued selective serotonin reuptake inhibitor (SSRI) antidepressants and were reporting, spontaneously on those internet forums, significant withdrawal symptoms and postwithdrawal psychopathology, that they attributed to discontinuation of their SSRI antidepressants. SSRI withdrawal, like for other classes of CNS depressant type (alcohol, benzodiazepine, barbituric, narcotic, antipsychotic, antidepressant), needs to be divided into two phases: the immediate withdrawal phase consisting of new and rebound symptoms, occurring up to 6 weeks after drug withdrawal, depending on the drug elimination half-life [2, 3] , and the postwithdrawal phase, consisting of tardive receptor supersensitivity disorders, occurring after 6 weeks of drug withdrawal [4] . One example of self-reporting new withdrawal symptoms of the CNS depressant type is the publication by Shoenberger [5] , which described new withdrawal symptoms (headaches, agitation, irritability, nausea, insomnia) as listed in controlled studies [6, 7] . Shoenberger self-reporting does not mention postwithdrawal disorders following withdrawal of paroxetine (taken for 3 years) [5] , but reports disturbing feelings of ‘zaps’, electric zapping sensations described as ‘washing over his entire body’ or ‘riding on a rollercoaster’ [5] , a withdrawal symptom of the CNS depressant type, which lasted into the fourth week of withdrawal. Zajecka et al. [6] had already listed ‘electric sensations’ as one of new withdrawal symptoms included in four published case reports. Received: January 19, 2012 Accepted after revision: June 5, 2012 Published online: September 6, 2012

Factors associated with overweight and obesity in schizophrenia, schizoaffective and bipolar disorders.

Evidence suggests abnormal bioenergetic status throughout the body in psychotic disorders. The present study examined predictors of elevated body mass index (BMI) across diagnostic categories of schizophrenia, schizoaffective and bipolar disorders. In a cross-sectional study, we studied demographic and clinical risk factors for overweight and obesity in a well-characterized sample of 262 inpatients and outpatients with schizophrenia (n=59), schizoaffective disorder (n=81) and bipolar I disorder (n=122). Across the three diagnostic categories, the prevalence of overweight (29.4%) and obesity (33.2%) combined was 62.6% (164/262). Logistic regression analyses, adjusted for age, sex and ethnicity, showed that schizoaffective disorder, lifetime major depressive episode, presence of prior suicide attempt, and more than 5 lifetime hospitalizations were significantly associated with BMI≥25. Patients with schizophrenia had significantly lower risk for overweight and obesity. Overall, we found that affective components of illness were associated with elevated BMI in our cross-diagnostic sample. Our results show that patients with schizoaffective disorder have a greater risk for obesity. Identifying predictors of elevated BMI in patients with psychotic and mood disorders will help prevent obesity and related cardiovascular and cerebral complications. Future studies are needed to elucidate the mechanistic nature of the relationship between obesity and psychiatric illness.

Diffusion tensor imaging in first degree relatives of schizophrenia and bipolar disorder patients

OBJECTIVES White matter (WM) abnormalities are one of the most widely and consistently reported findings in schizophrenia (SZ) and bipolar disorder (BD). If these abnormalities are inherited determinants of illness, suitable to be classified as an endophenotype, relatives of patients must also have them at higher rate compared to the general population. In this review, we evaluate published diffusion tensor imaging (DTI) studies comparing first degree relatives of SZ and BD patients and healthy control subjects. METHODS We searched PubMed, Embase and PsychInfo for DTI studies which included an unaffected relative and a healthy comparison group. RESULTS 22 studies fulfilled the inclusion criteria. WM abnormalities were found in many diverse regions in relatives of SZ patients. Although the findings were not completely consistent across studies, the most implicated areas were the frontal and temporal WM regions and the corpus callosum. Studies in relatives of BD patients were fewer in number with less consistent findings reported across studies. CONCLUSIONS Our review supports the concept of WM abnormalities as an endophenotype in SZ, with somewhat weaker evidence in BD, but larger and higher quality studies are needed to make a definitive comment.

Psychosis associated with elevated trough tacrolimus blood concentrations after combined kidney-pancreas transplant

Neurotoxicity and delirium have been reported to occur with the macrolide immunosuppressive tacrolimus in hepatic and kidney allograph transplantation (Beresford, 2001; Oliveiro et al., 2000). High tacrolimus blood concentrations were found to be correlated with nephrotoxicity and anxiety in renal transplantation (Di Martini et al., 1996; Venkataramanan et al., 2001).

Cognitive Impairment in Systemic Lupus Erythematosus Women with Elevated Autoantibodies and Normal Single Photon Emission Computerized Tomography

Background: Systemic lupus erythematosus (SLE) is known to induce psychiatric disorders, from psychoses to maladaptive coping. Brain autoantibodies were proposed to explain SLE neuropsychiatric disorders and found to be elevated before the onset of clinical symptoms. We assessed cognition in Caucasian SLE women with elevated autoantibodies without overt neuropsychiatric syndromes, in conjunction with single photon emission computerized tomography (SPECT). Methods: 31 women meeting SLE criteria of the American College of Rheumatology (ACR) were included. Patients who met the ACR neuropsychiatric definition were excluded. Matched controls were 23 healthy women from the Champagne-Ardenne region, France. Participants completed neuropsychological and autoantibodies measurements, and 19 completed SPECT. Results: 61% (19/31) of women with SLE and 53% (9/17) of those with normal SPECT had significant global cognitive impairment defined as 4 T-scores <40 in cognitive tests, compared to 0% (0/23) of controls. SLE women also had significantly greater cognitive dysfunction (mean T-score) on the Wechsler Adult Intelligence Scale (WAIS) visual backspan, Trail Making Test A and B, WAIS Digit Symbol Substitution Test and Stroop Interference, compared to controls. Elevated antinuclear antibody correlated with impairment in the WAIS visual span, WAIS visual backspan, and cancellation task; elevated anti-double-stranded DNA antibody and anticardiolipin correlated respectively with impairment in the Trail Making Test A and WAIS auditive backspan. Two SLE women had abnormal SPECT. Conclusions: A high prevalence of cognitive deficits was found in Caucasian SLE women compared to normal women, which included impairment in cognitive domains important for daily activities. Elevated autoantibodies tended to correlate with cognitive dysfunction.

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

Normal and Pathological Aging of Attention in Presymptomatic Huntington’s, Huntington’s and Alzheimer’s Disease, and Nondemented Elderly Subjects

Background: Attention models view attention as having at least two components: endogenous attention defined as executive and directed by voluntary acts, and exogenous attention defined as automatic and directed by external stimulation. Methods: Three studies (2 of our own) were designed to evaluate the decline of these two components of attention in normal aging and two neurodegenerative diseases. Standardized tests derived from Posner’s model of visuospatial attention were administered to normal healthy elderly participants (n = 13), patients suffering from Huntington’s disease (HD; n = 17) and Alzheimer’s disease (n = 15), and matched control subjects (n = 57). Outcome measures were reaction time (RT) and RT difference score (defined as invalid RT minus valid RT). Results: In healthy elderly participants, the decline was more pronounced for endogenous attention in situations of perceptual conflict. In Alzheimer’s disease, there was a significant decline in both attention components, while in HD, voluntary attention was markedly impaired and automatic attention preserved. Conclusions: Normal aging and HD are characterized by decreased endogenous attention in situations of perceptual conflict. Our data support previous findings that older people display impairment of attention in complex perceptual situations. We propose a model which allows for the separation of attention pathologies, thus improving therapeutic strategies for patients and elderly.