The only widely confirmed sporadic AD genetic risk factor is carrying the apolipoprotein E ε4 allele. The results of numerous studies on various other genes are highly inconclusive. Genetic studies in mild cognitive impairment (MCI) are scarce.

To assess the influence of APOE, CYP46, PRNP, PRND genetic polymorphisms on the risk of AD and MCI.

To date, over 100 subjects with AD, amnestic form of MCI and cognitively healthy age-matched controls have been recruited for the study (ongoing recruitment). To increase the homogeneity of the studied population subjects with prominent comorbid vascular risk factors, family history of dementia or satisfying criteria for non-AD neurodegenerative dementias have been excluded from the study. RFLP and sequencing techniques were employed to assess polymorphic sites in the CYP46, PRNP, PRND and APOE genes.

As expected, the proportion of APOE ε4 carriers was significantly higher in the AD group compared to controls. No statistically significant influence of polymorphisms in the CYP46, PRNP and PRND genes on the risk of AD or MCI was observed. However, the odds ratio for PRNP codon 129 homozygosity was over fivefold higher in the AD group compared to other study groups.

The significance of APOE genotype as an AD risk factor seems to be beyond controversy. The role of other genes putatively involved in the pathobiology of neurodegenerative disorders seems vague at most. Studies on much larger populations are required to estimate true significance of those genetic variants in the etiology of AD.

Data on the prevalence of Dementia with Lewy Bodies (DLB) derive mostly from neuropathological data or community studies. There exist only limited data about the prevalence in the communal geriatric psychiatry service with 3% in a Chinese and 28% in a British study.

We applied the recently revised consensus criteria for DLB, One Day Fluctuation Assessment Scale (ODFAS) and Unified Parkinsons Disease Rating Scale (UPDRS) retrospectively (chart review) (n=58) and prospectively (n=54) on demented patients in a communal psychiatric service in Basel, Switzerland.

Prevalence in the prospective group was 19% and 5% in the retrospective group. The odds ratio between both groups is 5.1. If gender is considered odds ratio for women is 2.4 and for men 6.8.

Our study shows that in communal geriatric psychiatry a high prevalence of DLB is encountered and that prospective use of DLB diagnosis criteria in combination with scales for fluctuation and parkinsonism enhances the detection rate of DLB.

The MCI syndrome is precociously present in over 50% of the patients that develop Alzheimer's Disease (AD) in the following three years. The evolution rhythm can be precipitated by the intervention of some risk factors.

Retrospective study with 30 patients with their case histories and current AD diagnosis confirmed by CT and DSM IV, evolution stage medium to serious. The aim was emphasize risk factors:

1. • repeated social psychotraumatic factors;

2. • depressive disorder and prolonged treatment with anticholinergic antidepressants;

3. • cerebral hypoxia, metabolic disfunction;

4. • ischemic cerebral vasculary alterations.

A correlation was made between the observed risk factors with the rapidity in the evolution of the disease in identical treatment conditions (donepezil, rivastigmine).

The evolution from MCI to AD of the patients in the lot showed three ways :

1. • rapid, under 1 year (6 patients, 20%);

2. • medium, over 2 years (15 patients, 50%);

3. • slow, over 3 years (9 patients, 30%);

For the entire lot the weight of risk factors was :

1. • psychotraumatic (50%);

2. • depression (67%);

3. • prolonged antidepressant treatment (57%);

4. • cerebral hipoxia and metabolic dysfunction (33%);

5. • vascular (63%).

The rhythm for settlement of cognitive deterioration is proportional with the number of risk factors.

The social impact at family level was significantly important in the forms with rapid evolution.

The rapid evolution automatically associates depression, prolonged antidepressant treatment, hipoxia and vascular component and requires profilactic strategies.

To investigate the behavioral and cognitive effects of memantine in moderate to severe patients with Alzheimer disease receiving donepezil.

Study was a 24 weeks prospective, randomized, parallel group. 43 patients were enrolled in the study, 21 continued treatment with donepezil and 22 were randomized to donepezil and memantine treatment. Patients were at least 50 years old, receiving ongoing therapy with donepezil for at least 6 months (10 mg / day). Average age for both groups was 72.5 years. There were no significant imbalances between the treatment groups in demographic and baseline clinical characteristics. Cognitive, ADL, and global measures were collected at baseline and at the end of weeks 4, 8, 12, 18 and 24. Behavioral measures were obtained at baseline, at the end of week 12 and at week 24. Mean baseline MMSE scores were 15.2 for donepezil group and 14.9 for donepezil – memantine group. Mean baseline NPI scores were of 15.8 for the donepezil group and 16.4 for the donepezil – memantine group.

Patients treated with donepezil – memantine had significantly lower NPI total scores than patients treated only with donepezil. Analyses of the 12 NPI domains revealed significant effects in favor of memantine on agitation / aggression, eating / appetite, and irritability / lability. Memantine - treated patients showed significantly less deterioration in their functionality. The Severe Impairment Battery showed significant differences favoring memantine – donepezil group.

Treatment with memantine was well tolerated and reduced agitation / aggression, irritability, and appetite eating disturbances.

Diagnosis of Creutzfeld-Jacob disease (CJD) is based on typical clinical features and can be supported by detection of 14-3-3 protein in the cerebrospinal fluid (CSF).

Present study suggests the importance of investigating the ratio between CSF total tau-protein and CSF phosphorylated tau-protein in differentiating CJD from other dementias.

Thirty-one patients with Alzheimer disease (AD) of Frontotemporal dementia (FTD) and four patients with definitive diagnosis of Creutzfeldt-Jacob disease were included into the study. All study subjects underwent MRI scan of the brain and extended neuropsychiatric examination at baseline to classify the patients as having AD or FTD. Results were compared with an age-matched cognitively normal control group. Tau-protein was analyzed using a commercially available ELISA and 14-3-3 protein was assessed by Western blotting. Three markers were put into comparison: total tau-protein (cutoff value of 355 pg/ml), phosphorylated tau-protein (cutoff value of 55 pg/ml), and beta amyloid (cutoff value of 458 pg/ml). The receiver operating characteristic (ROC) curve has been designed to achieve the best possible sensitivity and specificity for each marker.

High ratio between CSF total tau-protein and CSF phosphorylated tau-protein has been found in all patients diagnosed by CJD, even in those with negative 14-3-3 protein blots results. Contrary, marker s analysis in patients with AD revealed the highest ratio between CSF beta amyloid and CSF phosphorylated tau-protein levels.

CSF tau-protein and phosphorylated tau-protein are valuable diagnostic biomarkers for CJD, especially in patients with negative 14-3-3 protein findings.

The new standard computerized reading span test (RST), which is a complex verbal working memory test, was tested.

Sixty native Dutch speakers, divided over four different groups (average age of 20, 26, 51, 75), entered the study. The selection of the participants was based on strict (clinical) criteria. A comparison was made between the 4 different age groups with respect to their verbal working memory capacity. The new standard computerized RST (Van den Noort et al., 2006a; 2008) was used.

In this study, in line with previous aging studies, a significant decrease in verbal working memory capacity over time and a significant slowing down in mental processing were found. In addition, it was found that older adults made significantly more intrusion errors than young adults thereby confirming the inhibition theory (Hasher & Zacks, 1988). The analysis of the memory-pattern showed a clear recency-effect for the young-, but not for the old adults. Interestingly, the results of this study show that there are larger age-related effects in verbal working memory span than was expected on the basis of aging theories so far (Van den Noort et al., 2006b).

The new standard computerized RST (Van den Noort et al., 2006a; 2008) is a suitable complex verbal working memory test that could be used for clinical applications, for instance, for the early detection of dementia. This is important since most psychological tests so far are not sensitive enough to detect this early deterioration.

Alzheimer Dementia (AD) is known as the most common cause of degenerative dementias that decrease patient life expectancy, quality of life and increase caregivers burden. Objective: To determine the evolution of cognitive and non-cognitive symptoms under donepezil treatment and to evaluate the impact of these symptoms evolution over the caregivers.

This prospective, open-label, trial included a group of 56 patients, 34 male and 22 female, mean age 72.4, diagnosed with AD according to DSM-IV-TR criteria. Patients received either donepezil (n= 30) or 1400 UI/day mean dose of vitamin E (n=26). We evaluated these patients monthly during 1 year using Mini-Mental State Examination (MMSE), AD Assessment Scale (ADAS), Hamilton Depression Rating Scale (HAMD)-17 items, Brief Psychiatric Rating Scale (BPRS)- 18 items, Global Assessment of Functioning Scale (GAF), Burden Interview (BI).

Patients presented significant better evolution under donepezil on cognitive symptoms as scores evolution on ADAS-Cognitive behavior subscale (+1.5+/-0.2 vs. +10.4+/-0.8, p<0.0001) and MMSE (-0.8+/-0.2 vs. –7.7+/-0.4, p<0.0001) reflected. The non-cognitive symptoms evolution was also better under donepezil treatment, as the ADAS-Noncognitive behavior subscale (+2.6+/-0.4 vs. +8.2+/-0.7, p<0.0001), HAMD (increases of 4.5 vs. 8.2, p<0.001) and BPRS (increases of 6.7 vs.14.2, p<0.0001) reflected. The evolution of GAF was better in the donepezil group (-10.5 vs. –27.5, p<0.0001) and the burden of caregivers was significant less in the same group (+10.2 vs. +30.8 on BI, p<0.0001).

Donepezil is efficient in controlling both cognitive and non-cognitive symptoms in mild to moderate AD and therefore it decreases also the caregivers burden.

Serotonin syndrome is a disorder caused by drug induced excess of intra-synaptic 5-hydroxytryptamine (5-HT). Combination of drugs with different mechanisms of action is the most common cause of the reaction.

To report a case of serotonin syndrome in order to underline the interactions between antidepressant and pain relief medication.

Case study and description of a patient treated in out-patient clinic.

A 48 year old gentleman was referred to a community mental health team for review of his depressive disorder and medication. The patient had a 15 year history of recurrent depressive disorder and a 10 year history of chronic back pain and migraine. The patient had been on medication for both conditions requiring frequent changes in drugs and doses. A recent episode of depression was managed by changing from sertraline to venlafaxine. His pain relief medication included sumatriptan and tramadol. He soon experienced agitation, confusion, restlessness, dry mouth, and sweatiness. The symptoms worsened for 10 days until the patient stopped venlafaxine and returned to sertraline.

In patients with chronic pain and depression a detailed drug history and awareness from clinicians to the risk of serotonin syndrome are vital due to potentially fatal complications.

Selective serotonin reuptake inhibitors (SSRIs) are thought to exert their therapeutic action through increased serotonergic neurotransmission and hippocampal neurogenesis. Both of these processes may also contribute to the disinhibiting effects of SSRIs currently considered to contribute to potential risk of suicide or self-harm.

This study examined the acute (3 hours) and chronic (28 days) effects of citalopram administration on response inhibition and contextual processing (a hippocampal related function). Twenty healthy male volunteers were randomised to either placebo or 20 mg of oral citalopram for 28 days in a double blind design. Response inhibition was measured with the degraded symbol continuous performance test (DS-CPT) and contextual processing with a visual delayed non-matched to sample task (DNMS).

Citalopram treatment did not produce measurable changes to reaction time, hit rate and false alarms in the DS-CPT at any time point. The citalopram treated group underperformed in the DNMTS after acute treatment and this decrement appeared to persist at 28 days.

Our results suggest that SSRI treatment may lead to small but measurable decrements in contextual processing, which require further confirmation, and evaluation in clinical populations.

The association between stressfull lifeevents and onset of major depression has been verified in various studies, but more dubious are results concerning the association between life events and treatment outcome.

This study is part of a multicenter investigation evaluating genetic and psychosocial factors influence on outcome after pharmacological treatment of depression.

All cases of admittance or outpatient contact to a psychiatric department in Denmark are covered by the Danish Psychiatric Central Research Register. In this study we obtain personal data on all patients in a defined region of Denmark (Zealand) recently discharged with an ICD-10 diagnosis of a single depressive episode. These patients are invited to an interview including structural interviews and questionnaires to evaluate the presence of previous or recent life events (IRLE), personality traits (EPQ) or disorders (SCID), a family history of affective disorder, and the outcome of pharmacological treatment of their depression (TRAQ). The clinical diagnosis of depression is confirmed by the SCAN semistructural interview. The study is scheduled to include approximately 400 patients.

Data collection continues until january 2008 and statistical evaluation will be completed subsequently. Results are ready for presentation in April 2008.

Compared with a prospective randomized study the drawback of the present study may be less validity of response to antidepressive treatment, on the other hand the present design enables an investigation of a large and representative sample of patients to reveal the influence of life events on the outcome of pharmacological treatment of depression.

The genetic contribution to individual differences in drug response is probably polygenetic with a number of susceptibility genes and gene interactions. The non-genetic factors are likewise comprehensive, interacting and might even be under genetic influence themselves. Thus, antidepressant response is a complex and multifactorial phenomenon.

This study sought to examine the effects of various genetic variations on the outcome of antidepressant treatment taking into account the possible interactions with environment and personality.

Patients discharged from a psychiatric clinic in a region of Denmark with the diagnosis of single depressive episode are identified via the Danish Psychiatric Central Research Register and invited to participate in interviews regarding present psychiatric illness, treatment response, recent life events, and personality disorder. Further, blood test for genetic analyses are taken and the participants complete questionnaires regarding present symptoms, personality traits, coping, and side effects.

The study will include approximately 400 patients.

Data collection will proceed until January 2008, and the presentation will therefore include new and unpublished results.

Associations between genetic polymorphisms (including the genes encoding the serotonin transporter, catecol-O-methyl-transferase, 5-HT2 receptors, dopamin beta-hydroxylase, cytochrome P450 and brain derived growth factor) and outcome of antidepressant treatment will be presented.

The systematic recruitment of a relatively large, unselected and ethnic as well as phenotypic homogeneous sample of patients and the inclusion of genetic as well as non-genetic predictors of treatment response will make it possible throw new light on the role of genetic variation in the treatment of depression.

To characterize the safety and tolerability of desvenlafaxine succinate (DVS) in patients with major depressive disorder (MDD).

Pooled data from 7 double-blind, placebo-controlled studies were analyzed. Adult outpatients with DSM-IV MDD received DVS or placebo for 8 weeks. Four studies employed flexible dosing of DVS (100-200mg/d [1 study]; 200-400mg/d [3 studies]); 3 studies evaluated fixed doses (100/200/400mg/d [1 study]; 200/400mg/d [2 studies]). Vital signs and treatment-emergent adverse events (TEAEs) were evaluated. In the fixed-dose subset of studies, dose-related effects were analyzed.

The overall safety population consisted of 2014 patients (DVS: n=1211; placebo: n=803); 60% were women. Adverse events were responsible for discontinuations in 4% of placebo-treated patients and 15% of DVS-treated patients. Discontinuation rates increased with dose (10% with 100mg/d to 17% with 400mg/d) in the subset of fixed-dose studies. TEAEs were consistent with the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Nausea was generally mild to moderate with a median duration less than or = to 6 days; the incidence decreased to placebo-like rates after week 1. With all doses of DVS, small but statistically significant changes in mean blood pressure were observed. Mean changes in pulse rate and the proportion of potentially clinically important increases in sustained elevations in supine diastolic blood pressure were higher for patients receiving 200/400mg/d than among placebo-treated subjects; values for these parameters with the 100mg/d dose did not differ from placebo.

DVS treatment exhibited a safety and tolerability profile that was generally consistent with the SNRI class.

The aim of this study was to verify the effects of the selective serotonin reuptake inhibitor escitalopram on the recognition of facial emotional expressions.

Twelve healthy males completed two experimental sessions each, separated by at least 2 weeks, in a randomized, balanced order, double-blind design. An oral dose of escitalopram (10 mg) or placebo was given 3 hours before the task. Face recognition task: Subjects were presented with pictures of faces from the Pictures of Facial Affect Series (Ekman and Friesen, 1976). Faces with six basic emotions (anger, disgust, fear, happiness, sadness and surprise) had been morphed between neutral (0%) and each standard emotion (100%), in 10% steps. Accuracy was analyzed through MANOVA with repeated measures. Values of p < 0.05 were considered significant.

Volunteers recognized more accurately negative emotions in female faces than in male faces, whereas happiness was identified more easily in male faces. In general, the acute administration of a single dose of escitalopram increased the accuracy of the recognition of angry and sad faces. When the gender of the faces was analyzed, escitalopram facilitated the recognition of sad expressions and impaired the recognition of happy faces in male, but not in female faces. A global order effect has also been found; the administration of escitalopram in the second experimental session facilitated the recognition of emotional expressions.

These results indicate that serotonin modulates the recognition of emotional faces. Previous experience and gender of the emotional face interact with this modulation.

To compare the quality of life using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) in patients with MDD or GAD, before and after treatment and to compare remission based on symptoms versus functioning.

Q-LES-Q and symptom-specific MADRS and HAMA data from 8 published randomised, 8-week, double-blind, placebo-controlled clinical trials with escitalopram were used. The short form of the patient-rated Q-LES-Q was used to assess patients’ perceived quality of life and satisfaction at baseline and at last assessment. ANCOVA was used, adjusting for study, centre, baseline value, and treatment. MADRS and HAMA total scores were equated to Q-LES-Q using the method of equipercentile linking.

MDD or GAD patients report a substantial degree of impairment in their quality of life (64% and 76% of community norm, respectively). Treatment with escitalopram resulted in statistically and clinically significant improvement in patient quality of life. The improvement was greater in remitters (MADRS<=12 or HAMA<=7) than in non-remitters and greater in patients treated with escitalopram than in patients treated with placebo. There was a strong correlation between each symptom scale (MADRS, HAMA) and the Q-LES-Q. The present analyses suggest that scores as low as 3-8 on the MADRS and 5-10 on the HAMA (complete remission) correspond to a Q-LES-Q score of 58 (+/- 10%), found in community comparison subjects.

Treatment with escitalopram results in a statistically significant improvement of quality of life in patients with MDD or GAD.

Evidence in the literature supports the introduction of interventions to enhance adherence to antidepressant therapy, especially in patients with major depression.

The objectives of this study are; (1) to examine patient and population-based research on patient's adherence to antidepressants and (2) to develop and psychometrically assess a four-item instrument to measure adherence to antidepressants.

Although causes for non-adherence are multifatorial, drug omissions could occur in one or more, of main four mechanisms; forgetting, carelessness, stopping the drug when feeling worse, or stopping the drug when feeling better. To our knowledge, no reliable valid instruments were developed to measure adherence to antidepressants. Authors modified an instrument that was developed by (Morisky 1986), to measure adherence to antihypertensive drugs. The modified instrument was distributed to experts in depression (n=12), to rate the instruments’ relevancy, as a measure of patients’ adherence to antidepressants, and was administered to patients (n=63), who are on antidepressants.

The modified instrument has an improved reliability (Chronbachs’ Alpha = 0.66), there is 90 %, overall agreement among experts, that the instrument relevant to measure adherence in outpatients with depression, supporting a strong evidence for content validity, and there is also strong evidence for convergent and criterion related validities.

The developed instrument is short, both reliable and valid, and could be completed in approximately 3 minutes. Although it was developed for with outpatients, it could be applied in different sittings, with wide range of psychiatric population who suffer from depression.

SEROQUEL® (quetiapine) is an atypical antipsychotic in the dibenzothiazepine class. Clinical studies have demonstrated consistent efficacy in the treatment of schizophrenia, bipolar mania, and bipolar depression. Further clinical results suggest robust efficacy in the long-term treatment of bipolar disorder and major depressive disorder. This broad spectrum of clinical effect has not been fully predicted based on quetiapine's preclinical pharmacology. However, norquetiapine, a recently discovered major active human metabolite of quetiapine, has unexpected properties that may explain the observed clinical antidepressant and mood-stabilizing effects.

Radioligand binding and functional assays using rat and human tissue were used to characterize receptor interactions. Positron emission tomography (PET) studies performed on cynomolgus monkeys and man explored the relationship between clinically relevant plasma exposures and occupancy at serotonin 5HT2A and dopamine D2 receptors and the norepinephrine transporter (NET).

Norquetiapine had high affinity for and potently inhibited the NET, a property shared by tricyclic antidepressants and SNRIs but not other atypical antipsychotics at clinically relevant doses. In addition, norquetiapine had moderate-to-high affinity for D2, 5HT1A, 5HT2A, and 5HT2C receptors and shared some commonality with SSRIs. PET studies confirmed the properties of norquetiapine including occupancy of D2 and 5HT2A receptors as well as the NET at clinically relevant plasma exposures.

A unique combination of direct and indirect effects at noradrenergic, serotonergic, and dopaminergic receptors by quetiapine and norquetiapine provides a putative mechanism of action for the broad spectrum of clinical efficacy observed with SEROQUEL® in psychiatric disorders.

Two-month head-to-head clinical trials of escitalopram and venlafaxine demonstrated similar efficacy and better tolerability for escitalopram. However, as routine practice may differ from controlled trial, it is necessary to investigate the translation of clinical trial findings into real life. This work aims at comparing treatment early discontinuation (ED) at 1 and 2 months and its economic consequences at 6 months, under venlafaxine and escitalopram.

Using US denominator-based claims database PharMetrics (includes data from 86 managed care health plans covering 45 million patients), we included adult patients diagnosed with depression who started venlafaxine or escitalopram between January 1st and December 31st 2004. ED was compared at 1 and 2 months using Cox proportional hazard models and healthcare costs at 6 months, using log-linear regression. Propensity scoring was used to account for baseline differences.

13,227 patients started escitalopram; 5,922 patients started venlafaxine. ED at 2 months was 47% for venlafaxine, 45% for escitalopram. At 1 month, venlafaxine patients had 50% more risk of ED than escitalopram patients (Hazard Ratio=0.493 [95%CI 0.432-0.564]); while this difference decreased at 2 months, (Hazard Ratio=0.955 [95%CI 0.912-0.999]). Continuing treatment at 2 months doubled the chance of still being on treatment at 6 months. Moreover 1) ED at 2 months incurred more costs over 6 months (+US$173); 2) 6-month healthcare costs were higher with venlafaxine (+US$626, p<0.001).

Early discontinuation rate was higher with venlafaxine than escitalopram, possibly due to intolerance to venlafaxine. ED was shown to affect later continuation and incurred costs.