The involvement of BDNF-CREB signaling pathways in the pharmacological mechanism of combined SSRI- antipsychotic treatment in schizophrenia.

Previous studies into the mechanism of SSRI-antipsychotic synergism in our laboratory identified unique changes in the brain, particularly in the γ-aminobutyric acid (GABA)-A receptor and its modulators. This study examined the role of brain derived neurotrophic factor (BDNF)-cAMP response element binding (CREB) protein signaling pathways, including protein kinase B (AKT), glycogen synthase kinase (GSK)-3ß and related molecules in the molecular response to haloperidol, fluvoxamine, combined haloperidol+fluvoxamine and clozapine treatments in rat frontal cortex, hippocampus and primary cortical neuronal cultures. The effect of fluvoxamine augmentation on BDNF-CREB pathways in peripheral mononuclear cells (PMC׳s) of medicated schizophrenia patients was also studied. Chronic haloperidol (1mg/kg) +fluvoxamine (10mg/kg) treatment increased TrkB receptor and BDNF expression levels, and the phosphorylation of AKT/CREB/GSK-3ß, compared to the individual drugs in rat brain. In addition, haloperidol+fluvoxamine treatment improved cognitive functions in rats, indicating that the molecular changes may have a role in behavioral improvement. In primary neuronal cell cultures, pretreatment with a selective PI3K inhibitor abolished the haloperidol+fluvoxamine-induced phosphorylation of AKT and GSK-3ß, but did not affect the upregulation of CREB phosphorylation. In the clinic, PMC׳s of treated patients showed upregulation of mRNA expression and protein levels of BDNF, CREB and AKT after addition of fluvoxamine. Analyses of PMC genes and proteins showed significant inter-correlations and some gene changes correlated with improvement in negative and cognitive symptoms. Our study provides new knowledge of the molecular mechanisms of symptom amelioration in schizophrenia and may advance development of new drugs for this disease and other neuropsychiatric disorders.

Colour influences perception of facial emotions but this effect is impaired in healthy ageing and schizophrenia.

INTRODUCTION: Social cognition is commonly assessed by identification of emotions in facial expressions. Presence of colour, a salient feature of stimuli, might influence emotional face perception. METHODS: We administered 2 tests of facial emotion recognition, the Emotion Recognition Test (ER40) using colour pictures and the Penn Emotional Acuity Test using monochromatic pictures, to 37 young healthy, 39 old healthy and 37 schizophrenic men. RESULTS: Among young healthy individuals recognition of emotions was more accurate and faster in colour than in monochromatic pictures. Compared to the younger group, older healthy individuals revealed impairment in identification of sad expressions in colour but not monochromatic pictures. Schizophrenia patients showed greater impairment in colour than monochromatic pictures of neutral and sad expressions and overall total score compared to both healthy groups. Patients showed significant correlations between cognitive impairment and perception of emotion in colour but not monochromatic pictures. CONCLUSIONS: Colour enhances perception of general emotional clues and this contextual effect is impaired in healthy ageing and schizophrenia. The effects of colour need to be considered in interpreting and comparing studies of emotion perception. Coloured face stimuli may be more sensitive to emotion processing impairments but less selective for emotion-specific information than monochromatic stimuli. This may impact on their utility in early detection of impairments and investigations of underlying mechanisms.

Improvement in verbal memory following SSRI augmentation of antipsychotic treatment is associated with changes in the expression of mRNA encoding for the GABA-A receptor and BDNF in PMC of schizophrenic patients.

Verbal memory impairment in schizophrenia is associated with abnormalities in gamma-aminobutyric acid (GABA)-ergic and brain-derived neurotrophic factor (BDNF) systems. Recent evidence from animal and clinical studies that adding fluvoxamine to antipsychotics alters the expression of transcripts encoding for the GABA-A receptor and BDNF led us to postulate that fluvoxamine augmentation may improve memory in schizophrenia. To test this, we examined the effect of add-on fluvoxamine on verbal memory and other cognitive functions and related it to the expression of mRNA coding for the GABA-A receptor and BDNF in peripheral mononuclear cells (PMC) of schizophrenic patients. Twenty-nine patients completed a 6-week study in which fluvoxamine (100 mg/day) was added to ongoing antipsychotic treatment. Verbal memory, abstraction working memory, object and face recognition, and psychomotor speed and clinical symptoms were assessed at baseline and after 3 and 6 weeks of treatment. Blood samples were taken at baseline and weeks 1, 3, and 6 and PMC was assayed for the GABA-A beta3 receptor and BDNF mRNA by quantitative real-time reverse transcription-PCR. Associative and logical verbal memory improved significantly and showed a significant correlation with changes in PMC BDNF and GABA-A beta3 receptor mRNA, which increased during treatment. Abstraction and object recognition improved, but this did not correlate with PMC measures. Negative and positive symptoms improved significantly; the latter showed significant correlations with changes in PMC measures. Addition of fluvoxamine to antipsychotics improves verbal memory. It is postulated that the mechanism involves enhanced GABA-A receptor/BDNF-dependent synaptic plasticity in the hippocampus.

Similar verbal memory impairments in schizophrenia and healthy aging. Implications for understanding of neural mechanisms.

Memory is impaired in schizophrenia patients but it is not clear whether this is specific to the illness and whether different types of memory (verbal and nonverbal) or memories in different cognitive domains (executive, object recognition) are similarly affected. To study relationships between memory impairments and schizophrenia we compared memory functions in 77 schizophrenia patients, 58 elderly healthy individuals and 41 young healthy individuals. Tests included verbal associative and logical memory and memory in executive and object recognition domains. We compared relationships of memory functions to each other and to other cognitive functions including psychomotor speed and verbal and spatial working memory. Compared to the young healthy group, schizophrenia patients and elderly healthy individuals showed similar severe impairment in logical memory and in the ability to learn new associations (NAL), and similar but less severe impairment in spatial working memory and executive and object memory. Verbal working memory was significantly more impaired in schizophrenia patients than in the healthy elderly. Verbal episodic memory impairment in schizophrenia may share common mechanisms with similar impairment in healthy aging. Impairment in verbal working memory in contrast may reflect mechanisms specific to schizophrenia. Study of verbal explicit memory impairment tapped by the NAL index may advance understanding of abnormal hippocampus dependent mechanisms common to schizophrenia and aging.

Social cognition in schizophrenia and healthy aging: differences and similarities.

UNLABELLED: Social cognition is impaired in schizophrenia but it is not clear whether this is specific for the illness and whether emotion perception is selectively affected. To study this we examined the perception of emotional and non-emotional clues in facial expressions, a key social cognitive skill, in schizophrenia patients and old healthy individuals using young healthy individuals as reference. Tests of object recognition, visual orientation, psychomotor speed, and working memory were included to allow multivariate analysis taking into account other cognitive functions RESULTS: Schizophrenia patients showed impairments in recognition of identity and emotional facial clues compared to young and old healthy groups. Severity was similar to that for object recognition and visuospatial processing. Older and younger healthy groups did not differ from each other on these tests. Schizophrenia patients and old healthy individuals were similarly impaired in the ability to automatically learn new faces during the testing procedure (measured by the CSTFAC index) compared to young healthy individuals. CONCLUSIONS: Social cognition is distinctly impaired in schizophrenia compared to healthy aging. Further study is needed to identify the mechanisms of automatic social cognitive learning impairment in schizophrenia patients and healthy aging individuals and determine whether similar neural systems are affected.

What is "effective treatment" for a schizophrenic inpatient with persistent treatment-resistant psychosis and severe violent behavior?: a case of ECT.

Aggressive behavior among treatment-resistant schizophrenic patients is a major clinical challenge whose prevalence is underestimated.In our 420-bed psychiatric hospital, some 15% of patients exhibit active psychosis and high rates of verbal/physical aggression necessitating physical restraints. In addition to their condition, these individuals endanger staff and other patients, consume extensive resources, and induce a sense of clinical helplessness.Physicians managing such complex patients face dilemmas regarding choice of treatment, criteria for treatment decisions, treatment goals, and outcome assessments. We address some of these by following the progress of a persistently psychotic severely aggressive treatment-resistant inpatient treated with repeated electroconvulsive therapy (ECT). The motivation for this report was our desire to examine whether there was objective evidence to support our clinically based treatment decisions.To this end, we compiled a retrospective chronological life chart recording ECT administrations and aggression using case note information. Physical restraint was chosen as the outcome measure, as it was accurately documented. Because it was used only after all other means failed, a recorded incident represents an extreme peak of ongoing aggressive behavior.

Pathways to similar executive impairment: comparison of schizophrenia patients and healthy aging individuals.

Executive impairment is prominent in schizophrenia, in conditions such as Parkinson's disease and dementia and in healthy aging. Identifying processes that critically constrain executive function can advance investigation of their biological basis and treatment planning. Recent findings that elderly healthy individuals showed similar impairment on conditional exclusion task as schizophrenia patients raised the question whether similar processes are impaired. To test this we compared 56 schizophrenia patients, 57 elderly and 77 young healthy individuals on three executive tests: conditional exclusion, abstraction and inhibition and tests of working memory and psychomotor speed. Schizophrenia patients performed worse than elderly healthy on abstraction, inhibition and verbal working memory. They were similarly impaired on Penn Conditional Exclusion Test (PCET) outcome measures but differed in performance characteristics. Schizophrenia patients needed relatively more trials to learn the first PCET category than the second or the third. This correlated with other cognitive impairments, particularly in working memory. Elderly healthy individuals found it most difficult to learn the last category. The two groups showed different error patterns. We propose that schizophrenia patients have particular difficulty in early (probabilistic) learning ("what to do") while aging individuals have selective impairment in executive integration. These constitute distinct targets for customized treatment in the two conditions.

The role of GABA-A receptor in the synergism between SSRI and antipsychotic in schizophrenia; implications for antipsychotic modes of actions.

Antipsychotics, old and new varieties, are effective against positive symptoms such as hallucination and delusions, but are often of limited value in treating core features of schizophrenia particularly negative symptoms. Developments of new drugs based on current dogmas have produced similar drugs with no breakthroughs in effectiveness. New knowledge as to which mechanisms are responsible for symptom productions and treatment is needed. There is evidence that response may improve when antipsychotics are augmented with selective serotonin reuptake inhibitor (SSRI). This augmenting effect cannot be explained by summating pharmacological effects of the individual drugs. In a series of laboratory and clinical studies, we identified unique biochemical effects of the SSRI-Antipsychotic combination, different from each individual drug and suggested that some of these may mediate the clinical effect. In this paper, we review these studies and propose that modulation of the gamma-aminobutyric acid (GABA)-A receptor and its regulating system is the mechanism by which SSRI antipsychotic synergism exerts its clinical efficacy.

Impairment in associative memory in healthy aging is distinct from that in other types of episodic memory.

There is evidence that age related changes in episodic memory are heterogeneous and result from diverse pathologies. To test this, we examined performance of healthy high-functioning younger (N=41, ages 18-60 y) and older (N=58, ages 61-83 y) individuals in tests of associative memory, logical memory and memory in executive and object-recognition domains. We compared their relationships to each other and to other cognitive functions, including, psychomotor speed and verbal and spatial working memory. Older individuals showed significantly greater reduction in an index of the ability to learn new associations (NAL) than for memory in executive and object-recognition domains. Age-related reduction in NAL and in logical memory was of similar severity, but the two measures showed only moderate correlation when age and other cognitive functions were controlled for. NAL shows an age-related pattern of change distinct from memory in executive and object-recognition domains and from logical (item) memory. We propose that in healthy well-functioning individuals, NAL taps processes which support binding of newly learned association in context of accumulating information, a key function of the hippocampus. NAL may thus serve as a selective marker of complex, hippocampus-based, cognitive functions in studies of normal cognitive aging and of its possible relationship to early dementia.

Chronic treatment with serotonin reuptake inhibitor antidepressant (SSRI) combined with an antipsychotic regulates GABA-A receptor in rat prefrontal cortex.

INTRODUCTION: The combination of selective serotonin reuptake inhibitor (SSRI) antidepressants and antipsychotics is currently used for the treatment of negative symptoms of schizophrenia. However, the biochemical mechanism mediating the clinical effectiveness of this treatment remains obscure. Previously, we have reported that acute haloperidol (HALO)-fluvoxamine (FLU) in vivo and in vitro treatment regulated GABA-Aß2/3 receptor subunits, and protein kinase C (PKC) and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) signaling pathways. FINDINGS: In the present study, we demonstrated that chronic HALO-FLU treatment, but not each drug alone, significantly decreased GABA-Aß2/3 receptor expression (25 ± 6.2% vs. control) and caused receptor translocation from the membrane to the cytosol in rat prefrontal cortex. Phosphorylation of PKC and ERK2 was affected differently by HALO-FLU combination than by the individual drug treatments. HALO and FLU each given alone increased PKC phosphorylation levels (29 ± 15% and 40 ± 11.8%, vs. control, respectively) and did not affect ERK2 phosphorylation, while HALO-FLU combined treatment did not alter PKC phosphorylation levels and significantly decreased ERK2 phosphorylation levels (58 ± 4.4% vs. control). GABA-A receptor downregulation in the brain was accompanied by a decrease in GABA-A function, as shown in muscimol-induced loss of righting reflex (22 ± 9.8 min). CONCLUSIONS: We provide a brief heuristic overview of our preclinical and clinical studies with the SSRI-antipsychotic combination and argue that the finding that it causes similar dynamic changes in laboratory and clinical domains, specifically in GABA-A ß2/3 receptor and PKC, strongly supports the hypothesis that the GABA-A receptors and their regulatory systems are involved in the molecular mechanisms underlying the clinical effectiveness of SSRI augmentation.

SSRI augmentation of antipsychotic alters expression of GABA(A) receptor and related genes in PMC of schizophrenia patients.

Clinical studies have shown that negative symptoms of schizophrenia unresponsive to antipsychotic given alone can improve after augmentation with SSRI antidepressant. Laboratory investigations into the mechanism of this synergism showed that co-administration of SSRI and antipsychotic produces changes in GABA(A) receptor and related systems, which differ from the effects of each drug alone. To examine the clinical relevance of these findings, the current study examined the effects of SSRI augmentation treatment on GABA(A) receptor and related systems in schizophrenia patients. Schizophrenia patients with high levels of negative symptoms unresponsive to antipsychotic treatment received add-on fluvoxamine (100 mg/d). Blood was taken before and 1, 3 and 6 wk after adding fluvoxamine and peripheral mononuclear cells (PMC) isolated. RNA encoding for GABA(A)ß3, 5-HT2A, and 5-HT7 receptors, PKCß2, and brain-derived neurotrophic factor (BDNF) was assayed with real-time RT-PCR. Plasma BDNF protein was assayed using ELISA. Clinical symptoms were assessed with validated rating scales. We found significant increase in mRNA encoding for GABA(A)ß3 and 5-HT2A, 5-HT7 receptors and BDNF and a reduction in PKCß2 mRNA. Plasma BDNF protein concentrations were increased. There were significant correlations among the genes. Clinical symptoms improved significantly. mRNA expression of PKCß2, 5-HT2A and 5-HT7 showed significant associations with clinical symptoms. Combined SSRI+antipsychotic treatment is associated with changes in GABA(A) receptor and in related signalling systems in patients. These changes may be part of the mechanism of clinically effective drug action and may prove to be biomarkers of pharmacological response.

The involvement of GABA(A) receptor in the molecular mechanisms of combined selective serotonin reuptake inhibitor-antipsychotic treatment.

There is evidence that combining selective serotonin reuptake inhibitor (SSRI) antidepressant and antipsychotic drugs may improve negative symptoms in schizophrenia and resistant symptoms in obsessive-compulsive and affective disorders. To examine the mechanism of action of this treatment we investigated the molecular modulation of γ-aminobutyric acid-A (GABA(A)) receptor components and biochemical pathways associated with GABA(A) receptor function following administration of the SSRI fluvoxamine (Flu) combined with the first-generation antipsychotic haloperidol (Hal) and compared it to the individual drugs and the atypical antipsychotic clozapine (Clz). We analysed prefrontal cortices of Sprague-Dawley rats injected intraperitoneally (i.p.) with the combination of Flu (10 mg/kg) and Hal (1 mg/kg), each drug alone, or Clz (10 mg/kg) after 30 min and 1 h. We found that haloperidol plus fluvoxamine (Hal-Flu) co-administration, and Clz, decreased the level of GABAAß2/3 receptor subunit in the cytosolic fraction, and increased it in the membrane compartment in rat PFC. Flu or Hal alone did not produce changes in GABAAß2/3 receptor protein expression. Additionally, Hal-Flu and Clz regulated molecular signalling pathways that modulate GABA(A) receptor function, including protein kinase C (PKC) and extracellular signal-regulated kinase-2 (ERK2). In primary cortical culture, short-term treatment (15 min) with Hal-Flu combination and Clz increased GABAAß subunit phosphorylation levels. Pretreatment of the cells with PKC inhibitor abolished the effect of the combined treatment, or Clz on phosphorylation of GABA(A) receptor. Inhibition of ERK2 did not alter the effect of drugs on GABA(A) receptor phosphorylation levels. Our findings provide evidence that the combined treatment regulates GABA(A) receptor function and does so via a PKC-dependent pathway.

'Executive' functions and normal aging: selective impairment in conditional exclusion compared to abstraction and inhibition.

BACKGROUND: Some executive functions may be selectively impaired in normal aging over and above the general cognitive decline. METHODS: We examined the performance of healthy high functioning young (n = 77) and older (n = 57) individuals on three 'executive' tests: conditional exclusion, abstraction, and inhibition of prepotent responses. We compared their relationships to each other and to other cognitive functions including attention, psychomotor speed and working memory. RESULTS: Conditional exclusion was significantly more impaired than abstraction or inhibition in the elderly compared to the younger group and unlike them, showed a nonlinear relationship with age. These findings were independent of other cognitive functions. Analysis of PCET performance characteristics showed that older individuals were particularly impaired in attaining the last of the three achievable categories, were slower, and had fewer error monitoring resources compared to the younger group. CONCLUSIONS: Conditional exclusion shows an age-related pattern of impairment distinct from inhibition and abstraction. We propose that in healthy well-functioning individuals, it taps processes integrating task set establishment and shifting in context of accumulating information. It may thus be useful as a specific marker of complex cognitive functions in studies of normal cognitive aging and in early detection of cognitive dysfunction.

Impaired recognition of happy, sad and neutral expressions in schizophrenia is emotion, but not valence, specific and context dependent.

It is not clear whether the deficits in emotion perception in schizophrenia are distinct from cognitive impairments or affect some emotions more than others. We tested the hypothesis that the emotion perception deficit in schizophrenia is valence specific. Participants comprised 75 chronic schizophrenia patients and 77 healthy controls who were asked to identify happy, sad and neutral facial emotional expressions. A test of facial identity recognition was also performed. Processing of happy, sad and neutral expressions differed in accuracy, processing strategy and efficiency. Patients were impaired on all parameters, but the valence-related pattern of performance did not differ in the two groups. Compared with healthy individuals, schizophrenia patients were more impaired in the processing of facial emotions than identity. Processing of neutral expressions was context dependent. Emotion impairment in schizophrenia appears to be selective for the emotion domain but not specific emotions. Test context influences how neutral facial expressions are processed.

Molecular mechanisms underlying synergistic effects of SSRI-antipsychotic augmentation in treatment of negative symptoms in schizophrenia.

Negative symptoms in schizophrenia respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRIs). The molecular mechanisms underlying the augmentation are unclear. Nevertheless, significant progress has been made, pointing to some candidate systems which may be involved in SSRI-antipsychotic synergism. Thus, the enhanced dopamine release by SSRI-antipsychotic treatment is modulated by specific serotonergic receptors and by tyrosine hydroxylase. There are modifications in gamma-aminobutyric acid system via glutamate decarboxylase 67, protein kinase C beta and the receptor for activated C-kinase 1 (Rack1). Some studies indicate the input of transcription and neurotrophic factors as phospho-cyclic adenosine monophosphate response element-binding protein, Fos and fibroblast growth factor-2. Alterations in calcium signaling (neurogranin, regulator of G-protein signaling and Rack1) and in cytokine receptors for interleukin-8 and chemokine have also been reported. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI-antipsychotic synergistic actions.

Age in high-functioning healthy men is associated with nonlinear decline in some 'executive' functions in late middle age.

BACKGROUND/AIM: Age-related cognitive decline might involve selective deterioration of specific brain systems. We studied the relationship between age and cognition by comparing cognitive function of older and younger high functioning men. METHODS: A cross-sectional study comparing neuropsychological test battery performance of younger (18-60 years) and older (61-85 years) men. RESULTS: Older men showed impaired psychomotor speed, working memory, attention, declarative verbal memory and executive functions. Impairment in executive function was prominent and not explained by psychomotor slowing, impaired working memory or attention. Regression models showed a non-linear relationship between age and executive function with a change of slopes in the mid-50s. The relationship of age with verbal memory was linear. CONCLUSIONS: The nonlinear change in late middle age is consistent with the hypothesis that an age-related selective diatheses impacts selectively on executive function.

Multifunctional pharmacotherapy: what can we learn from study of selective serotonin reuptake inhibitor augmentation of antipsychotics in negative-symptom schizophrenia?

Many patients suffering from major psychiatric disorders do not respond adequately to monotherapy and require additional drugs. To date, there are no objective guidelines for deciding which combination may be effective, and the choice is based on previous clinical experience and on trial and error. Even when combination drugs are effective, the biochemical mechanisms responsible for the value-added effect are unknown. Understanding the mechanism of such synergism may provide a rational basis for choosing drug combinations and for developing more effective drugs. In schizophrenia, negative symptoms respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRI). This augmenting effect cannot be explained by summating the pharmacological effects of the individual drugs. We proposed that the study of SSRI augmentation can serve as a window to understanding the biochemical mechanisms of clinically effective drug synergism. In a series of studies we identified unique biochemical effects of the combination, different from each individual drug, and proposed that some of these are involved in mediating the clinical effect. Here we review some of the findings and propose that the mechanism of action involves regionally selective modulation of the GABA system. The evidence indicates that the SSRI antidepressant-antipsychotic combination may be a useful paradigm for studying therapeutically effective synergistic drug interactions in schizophrenia. Although as yet limited in scope, the findings of definable molecular targets for synergistic SSRI-antipsychotic interaction provide new directions to inform future research and provide novel bio-molecular targets for drug development.

Analysis of cognitive performance in schizophrenia patients and healthy individuals with unsupervised clustering models.

Currently, assignment of cognitive test results to particular cognitive domains is guided by theoretical considerations and expert judgments which may vary. More objective means of classification may advance understanding of the relationships between test performance and the cognitive functions probed. We examined whether "atheoretical" analyses of cognitive test data can help identify potential hidden structures in cognitive performance. Novel data-mining methods which "let the data talk" without a priori theoretically bound constraints were used to analyze neuropsychological test results of 75 schizophrenia patients and 57 healthy individuals. The analyses were performed on the combined sample to maximize the "atheoretical" approach and allow it to reveal different structures of cognition in patients and controls. Analyses used unsupervised clustering methods, including hierarchical clustering, self-organizing maps (SOM), k-means and supermagnetic clustering (SPC). The model revealed two major clusters containing accuracy and reaction time measures respectively. The sensitivity (75% versus 52%) and specificity (95% versus 77% ) of these clusters for diagnosing schizophrenia differed. Downstream branching was influenced by stimulus domain. Predictions arising from this "atheoretical" model are supported by evidence from published studies. This preliminary study suggests that appropriate application of data-mining methods may contribute to investigation of cognitive functions.