Beyond the therapeutic shackles of the monoamines: New mechanisms in bipolar disorder biology.

Multiple novel biological mechanisms putatively involved in the etiology of bipolar disorders are being explored. These include oxidative stress, altered glutamatergic neurotransmission, mitochondrial dysfunction, inflammation, cell signaling, apoptosis and impaired neurogenesis. Important clinical translational potential exists for such mechanisms to help underpin development of novel therapeutics - much needed given limitations of current therapies. These new mechanisms also help improve our understanding of how current therapeutics might exert their effects. Lithium, for example, appears to have antioxidant, immunomodulatory, signaling, anti-apoptotic and neuroprotective properties. Similar properties have been attributed to other mood stabilizers such as valproate, lamotrigine, and quetiapine. Perhaps of greatest translational value has been the recognition of such mechanisms leading to the emergence of novel therapeutics for bipolar disorders. These include the antioxidant N-acetylcysteine, the anti-inflammatory celecoxib, and ketamine - with effects on the glutamatergic system and microglial inhibition. We review these novel mechanisms and emerging therapeutics, and comment on next steps in this space.

[Therapeutic management of bipolar disorder in France and Europe: a multinational longitudinal study (WAVE-bd)]. / Prise en charge thérapeutique des patients présentant un trouble bipolaire en France et en Europe : étude multinationale longitudinale WAVE-bd.

BACKGROUND: Bipolar disorder is a complex disease which requires multiple healthcare resources and complex medical care programs including pharmacological and non pharmacological treatment. If mood stabilizers remain the corner stone for bipolar disorder treatment, the development of atypical antipsychotics and their use as mood stabilizers has significantly modified therapeutic care. At the present time, psychiatrists have a large variety of psychotropic drugs for bipolar disorder: mood stabilizers, atypical antipsychotics, antidepressants, anxiolytics… However, despite the publication of guidelines on pharmacological treatment, with a high degree of consensus, everyday clinical practices remain heterogeneous. Moreover, there are few longitudinal studies to describe therapeutic management of bipolar disorder, whatever the phase of the disease is. Indeed, most of the studies are carried out on a specific phase of the disease or treatment. And there is no study comparing French and European practices. OBJECTIVES: In this paper, we aim to present the comparison of the management of pharmacological treatments of bipolar disorder between France and Europe, using the data of the observational Wide AmbispectiVE study of the clinical management and burden of bipolar disorder (WAVE-bd study). METHODS: The WAVE-bd study is a multinational, multicentre and non-interventional cohort study of patients diagnosed with BD type I or type II, according to DSM IV-TR criteria, in any phase of the disorder, who have experienced at least one mood event during the 12 months before enrolment. In total, 2507 patients have been included across 8 countries of Europe (480 in France). Data collection was retrospective (from 3 to 12 months), but also prospective (from 9 to 15 months) for a total study length of 12 to 27 months. Main outcome measures were the healthcare resource use and pharmacological treatments. RESULTS: Our results show differences in the therapeutic management of bipolar disorder between France and other European countries. Regarding healthcare resource use, our results show that French patients consult more frequently a psychiatrist or a psychologist and less frequently a general practitioner or the emergency ward in comparison with patients from other European countries. In the whole European population, including France, atypical antipsychotics are widely used. Only 25% of the patients receive lithium and more than 50% of the patients receive antidepressants, while their use in bipolar disorder remains controversial. Most of the patients receive polymedication. Considering all phases of the disease pooled, less lithium and less atypical antipsychotics are prescribed to French patients, whereas they receive more antidepressants and more benzodiazepines than patients from other European countries. On the over hand, prescription of anticonvulsants and electroconvulsive therapy are equal. Moreover, data analyses by polarity of the episodes globally confirm these trends. There are a few exceptions: mixed states, in which lithium is twice more prescribed in France in comparison to other countries; depressive states, in which antidepressants are even more prescribed in other countries than in France; and less prescription of anticonvulsants in manic, mixed and euthymic phases in France. CONCLUSION: The WAVE-bd study is the first observational study conducted on a large sample of bipolar I and II patients that compares therapeutic management between France and other European countries. The differences observed in therapeutic care across the different phases of the disease show that treatments differ depending on the countries studied, but also according to the preventive or curative phases, polarity of the bipolar disorder, comorbidities, impact of guidelines, and care organization. Although French patients have been treated by less lithium and less atypical antipsychotics than other European patients, they receive more antidepressants and more benzodiazepines. Finally, patients generally receive polymedication and the diversity in prescriptions shows how bipolar disorder is a complex disorder.

Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview.

OBJECTIVE: Historically, pharmacological treatments for bipolar disorders (BD) have been associated with neurocognitive side-effects. We reviewed studies which assessed the impact of several psychopharmacological drugs on the neurocognitive function of BD patients. METHOD: The PubMed database was searched for studies published between January 1980 and February 2011, using the following terms: bipolar, bipolar disorder, mania, manic episode, or bipolar depression, cross-referenced with cognitive, neurocognitive, or neuropsychological, cross-referenced with treatment. RESULTS: Despite methodological flaws in the older studies and insufficient research concerning the newer agents, some consistent findings emerged from the review; lithium appears to have definite, yet subtle, negative effects on psychomotor speed and verbal memory. Among the newer anticonvulsants, lamotrigine appears to have a better cognitive profile than carbamazepine, valproate, topiramate, and zonisamide. More long-term studies are needed to better understand the impact of atypical antipsychotics on BD patients' neurocognitive functioning, both in monotherapy and in association with other drugs. Other agents, like antidepressants and cognitive enhancers, have not been adequately studied in BD so far. CONCLUSION: Pharmacotherapies for BD should be chosen to minimize neurocognitive side-effects, which may already be compromised by the disease process itself. Neurocognitive evaluation should be considered in BD patients to better evaluate treatment impact on neurocognition. A comprehensive neuropsychological evaluation also addressing potential variables and key aspects such as more severe cognitive deficits, comorbidities, differential diagnosis, and evaluation of multiple cognitive domains in longitudinal follow-up studies are warranted.

Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) likely involves, at a molecular and cellular level, dysfunctions of critical neurotrophic, cellular plasticity and resilience pathways and neuroprotective processes. Therapeutic properties of mood stabilizers are presumed to result from a restoration of the function of these altered pathways and processes through a wide range of biochemical and molecular effects. We aimed to review the altered pathways and processes implicated in BD, such as neurotrophic factors, mitogen-activated protein kinases, Bcl-2, phosphoinositol signaling, intracellular calcium and glycogen synthase kinase-3. METHODS: We undertook a literature search of recent relevant journal articles, book chapter and reviews on neurodegeneration and neuroprotection in BD. Search words entered were 'brain-derived neurotrophic factor,''Bcl-2,''mitogen-activated protein kinases,''neuroprotection,''calcium,''bipolar disorder,''mania,' and 'depression.' RESULTS: The most consistent and replicated findings in the pathophysiology of BD may be classified as follows: i) calcium dysregulation, ii) mitochondrial/endoplasmic reticulum dysfunction, iii) glial and neuronal death/atrophy and iv) loss of neurotrophic/plasticity effects in brain areas critically involved in mood regulation. In addition, the evidence supports that treatment with mood stabilizers; in particular, lithium restores these pathophysiological changes. CONCLUSION: Bipolar disorder is associated with impairments in neurotrophic, cellular plasticity and resilience pathways as well as in neuroprotective processes. The evidence supports that treatment with mood stabilizers, in particular lithium, restores these pathophysiological changes. Studies that attempt to prevent (intervene before the onset of the molecular and cellular changes), treat (minimize severity of these deficits over time), and rectify (reverse molecular and cellular deficits) are promising therapeutic strategies for developing improved treatments for bipolar disorder.

Apathy in acute stroke patients.

BACKGROUND AND PURPOSE: Apathy is a frequent disturbance in stroke patients. The aim of this case-control study was to elucidate whether apathy: (i) was secondary to stroke or related to hospitalization, (ii) was related to thalamic and striatocapsular stroke lesions, (iii) was independent from cognitive impairment and depression in the acute phase of stroke, (iv) was associated with clinical and demographical variables and (v) was associated with a worse functional outcome at discharge. METHODS: We assessed a sample of 94 consecutive patients with an acute (≤4 days) stroke (22 intracerebral haemorrhages, 72 cerebral infarcts), and a control group of 50 patients with acute coronary syndrome, with the 10-item Apathy Evaluation Scale-Clinical. We related apathy with cognition (MMSE), depression (Montgomery Åsberg Depression Rating Scale) and with outcome (modified Rankin Scale). RESULTS: Apathy was present in 36 (38.3%) acute stroke patients but was also frequent in patients with acute coronary syndrome (24%). Stroke patients were more inaccurate in understanding their problems than patients with acute coronary syndrome (P=0.005). Logistic regression identified cerebral haemorrhage (OR=3.5), low educational level (OR=4.7) and a trend of right hemispherical lesion (OR=3.0) as independent predictors for apathy (R(2)=32.3%). Cognitive impairment and depression were not associated to apathy. Apathy was associated with a worse outcome (P=0.03). CONCLUSION: Apathy was frequent in acute stroke patients, and it was predicted by acute intracerebral haemorrhage and right hemispherical acute stroke lesion.

Neuropsychiatric disturbances in acute subarachnoid haemorrhage.

BACKGROUND: Acute and unexpected neuropsychiatric disturbances can herald subarachnoid haemorrhage (SAH). We investigated the risk factors for neuropsychiatric disturbances in acute SAH and analysed the relation between neuropsychiatric disturbances and location and amount of haematic densities and hydrocephalus. METHODS: We assessed a sample of 108 consecutive patients with an acute (≤ 4 days) SAH (61 aneurysmal, 47 non-aneurysmal SAH), before aneurysmal treatment, using DSM-IV-TR criteria and the Montgomery Åsberg Depression Rating Scale and Mania Rating Scale, the Denial of Illness Scale, the Catastrophic Reaction Scale and the Apathy Evaluation Scale, excluding patients with severe consciousness or language disturbance. Performance on each scale was related to (i) the total amount of haematic densities in 10 basal cisterns/fissures and in the four ventricles, using the Hijdra et al. rating scale, (ii) the haematic densities in the prepontine cistern and the convexity of the brain and (iii) hydrocephalus. RESULTS: Depression (45%), apathy (42%), denial (21%) and catastrophic reaction (17%) were frequent in acute SAH patients. Mania was present in two patients. Denial was associated with higher haematic densities in the left and right basal sylvian fissure and in the 4th ventricle (P < 0.01) and with hydrocephalus (P = 0.05). Catastrophic reaction and depression were associated with previous mood disorder (P < 0.007). Apathy was associated with blood in the left or right lateral ventricles (P < 0.03). CONCLUSIONS: In the first 4 days of SAH, depression, apathy, catastrophic reaction and denial were rather frequent. SAH haematic densities were associated with denial and apathy, but not with depression, mania or catastrophic reaction.

Cost-effectiveness and budget impact of long-acting risperidone in Portugal: a modeling exercise.

BACKGROUND: Previous analyses have shown that long-acting risperidone (LAR) is cost-effective in several Western countries. In Portugal, however, the costs of key services are lower. Therefore, available evidence in other countries may have limited relevance. OBJECTIVE: To estimate costs and effects of LAR versus a conventional depot and a short-acting oral atypical antipsychotic over a 5-year period in Portugal. METHODS: An existing discrete event model was adapted to reflect the Portuguese healthcare setting, based on expert opinion, clinical, epidemiological, and cost data. The model compares three scenarios. In scenario 1, patients start with a conventional depot; in scenario 2, with LAR; and in scenario 3, with oral risperidone. The model simulates individual patient histories while taking into account patient characteristics such as risk to society and side-effects. Subsequently, the model simulates patient histories in terms of outpatient appointments, psychotic episodes, treatment, compliance, symptom scores, lack of ability to take care presenting an actual risk, and treatment setting. Outcomes were number of psychotic episodes, cumulative symptom score and direct medical costs. Univariate sensitivity analyses were carried out. RESULTS: Compared to a conventional depot and an oral atypical, LAR was estimated to save approximately euro 3603 and euro 4682 per patient (respectively) and avoid 0.44 and 0.59 relapses per patient in 5 years. Sensitivity analyses showed that the outcome of dominance was only sensitive to estimates about unit costs of hospital/institutionalization, potential risk, and to the reduction in symptoms by use of atypicals. CONCLUSION: Based on this modeling exercise, it could be expected that LAR may be a cost-effective treatment with limited budget impact in Portugal. However, further studies are required to test the generalizability of the results of the present modeling study to the larger population of Portugal.

Delirium in acute stroke: a preliminary study of the role of anticholinergic medications.

The pathogenesis of delirium in acute stroke is incompletely understood. The use of medications with anticholinergic (ACH) activity is associated with an increased frequency of delirium. We hypothesized that the intake of medications with ACH activity is associated with delirium in acute stroke patients. Delirium was assessed using the DSM-IV-TR criteria and the Delirium Rating Scale, in a sample of consecutive patients with an acute (< or =4 days) cerebral infarct or intracerebral haemorrhage (ICH). We performed a gender and age matched case-control study. Twenty-two delirious stroke patients (cases) and 52 non-delirious patients (controls) were compared concerning the intake of ACH medications (i) before stroke, (ii) during hospitalization but before the assessment. The variables associated with delirium on bivariate analysis were entered in a stepwise logistic regression analysis. The final regression model (Nagelkerke R2 = 0.65) retained non-neuroleptics ACH medication during hospitalization (OR = 24.4; 95% CI = 2.18-250), medical complications (OR = 20.8; 95% CI = 3.46-125), ACH medication taken before stroke (OR = 17.5; 95% CI = 1.00-333.3) and ICH (OR = 16.9; 95% CI = 2.73-100) as independent predictors of delirium. This preliminary result indicates that drugs with subtle ACH activity play a role in the pathogeneses of delirium in acute stroke. Medication with ACH activity should be avoided in acute stroke patients.

Hyperhydricity in in vitro eggplant regenerated plants: structural characteristics and involvement of BiP (Binding Protein).

The hyperhydricity in eggplant (Solanum melongena L.) plants was monitored by the induction of the ER-luminal resident protein BiP. Although tissue culture conditions may induce BiP synthesis, the accumulation of BiP in hyperhydric shoots was consistently higher than in non-hyperhydric shoots. The leaf and stem anatomy in non-hyperhydric and hyperhydric eggplant was investigated aiming to identify structural changes associated with this phenomenon. In non-hyperhydric organs there were smaller and more organized cells, besides a more differentiated vascular system when compared with its hyperhydric counterpart. Scanning electron microscopy of leaves showed that leaf surface and stomata differentiation were also affected in hyperhydric plants.

Influence of the antibiotic timentin on plant regeneration of tomato (Lycopersicon esculentum Mill.) cultivars.

Cotyledon explants of tomato (Lycopersicon esculentum Mill. cvs 'Santa Clara', 'Firme' mutant, 'IPA-5' and 'IPA-6') were excised from 8- to 10-day-old in vitro-grown seedlings. Four different shoot induction media supplemented with timentin (300 mg l-1) were screened. When cotyledon explants were cultured on MS-based medium with 1.0 mg l-1 zeatin plus 0.1 mg l-1 IAA and supplemented with timentin, higher regeneration frequencies and a greater number of elongated shoots were obtained. It was observed that timentin caused an increase in the morphogenesis of in vitro cotyledon explants of tomato cultivars. In two of three cultivars tested, rooting of shoots was positively influenced, both in the presence and absence of timentin in the rooting medium, among shoots regenerated from explants derived from timentin-supplemented medium. The results confirm those of a previous investigation on the beneficial effects of this class of antibiotics on tomato regeneration and, consequently, its reliability for use in the transformation of this species.

Multicenter double-blind study of moclobemide and maprotiline.

A randomized double-blind, multicenter 6-week study was undertaken in 80 depressed patients to compare the effects of moclobemide, a selective and reversible monoamine oxidase-A inhibitor (300 mg daily), and maprotiline (75 mg daily). Efficacy was assessed by Hamilton Depression Rating Scale (HDRS) and Clinical Global Impression (CGI). Tolerability was assessed by adverse events reports. After 6 weeks of therapy, both groups of patients showed significant improvement in HDRS and CGI. Speed of onset of action was faster with moclobemide (significant difference at week 3, p = 0.025). There was a significant reduction of depression ratings (HDRS) in both the moclobemide and maprotiline group in all types of depression according to ICD-9 criteria (major depressive disorder, neurotic depression and adjustment-prolonged depressive reaction). Significantly fewer patients in the moclobemide group reported adverse events (28.9% compared with 70.2%) including weight gain (2.6% compared to 21.6%). Anticholinergic side effects were less frequent with moclobemide. It is concluded that both drugs are at least equivalent in terms of therapeutic efficacy, but moclobemide is better tolerated.

How do normal subjects learn a simple adaptative task: how and why do paranoid schizophrenic patients fail?

The authors studied the behavior of normal subjects and paranoid schizophrenic patients in a simple problem-solving situation. The schizophrenics were divided into two sample groups, one of individuals under treatment and the other of individuals not under treatment. The learning process involved in this problem-solving situation is very similar to an instrumental conditioning, and can be understood by means of the following assumptions: (1) the subjects use decision functions in reacting to the stimuli, although they may be not fully aware of this; (2) learning is the result of successive transformations of these decisions in the course of time; (3) the changes have specific probabilities and are related to (a) those responses which are made to the latest stimuli, and (b) a differential probability for decision functions which were effective, or only interrupted painful reinforcement, or were completely ineffective. In schizophrenics further factors of importance were (1) an 'inertia' factor and (2) the rigidly continued use of unsuccessfuly or only partially successful decision criteria. The authors used a systems theory based on Galois field theory and a calculus of operators specifying three groups of subjects. A computer program based on thses hypotheses was tested in a stimulation experiment. The statistical evaluation of the results showed a congruence between the theoretical approach and the experimental data.