Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer's dementia.

BACKGROUND: The progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1-42 (Aß42), amyloid-beta1-40 (Aß40) levels, the ratio of Aß42/Aß40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. METHODS: We used 115 complete datasets from MCI patients of the "Dementia Competence Network", a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%. RESULTS: Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aß40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80-0.83, and the four-parameter combination from AUC 0.81-0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone. CONCLUSION: A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials.

Ghrelin Serum Concentrations Are Associated with Treatment Response During Lithium Augmentation of Antidepressants.

Background: Lithium augmentation of antidepressants is an effective strategy in treatment-resistant depression. The proteohormone ghrelin is thought to be involved in the pathophysiology of depression. The purpose of this study was to investigate the association of treatment response with the course of ghrelin levels during lithium augmentation. Method: Ghrelin serum concentrations and severity of depression were measured in 85 acute depressive patients before and after 4 weeks of lithium augmentation. Results: In a linear mixed model analysis, we found a significant effect of response*time interaction (F1.81=9.48; P=.0028): under treatment, ghrelin levels increased in nonresponders and slightly decreased in responders to lithium augmentation. The covariate female gender had a significant positive effect (F1.83=4.69; P=.033), whereas time, response, appetite, and body mass index (kg/m2) did not show any significant effect on ghrelin levels (P>.05). Conclusion: This is the first study showing that the course of ghrelin levels separates responders and nonresponders to lithium augmentation. Present results support the hypothesis that ghrelin serum concentrations might be involved in response to pharmacological treatment of depression.

The Latent Dementia Phenotype δ is Associated with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease and Predicts Conversion to Dementia in Subjects with Mild Cognitive Impairment.

BACKGROUND: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer's disease (AD) research and clinical trials. OBJECTIVE: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). METHODS: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. RESULTS: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aß42/tau ratio indicative of AD (n = 340, AUC = 0.78, p <  0.001), and predicted incident dementia within 1-3 years of follow-up (n = 525, AUC = 0.84, p <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. CONCLUSION: These findings support the interpretation of δ as a construct capturing the disease-related "essence" of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research.

Subjective cognitive decline is related to CSF biomarkers of AD in patients with MCI.

OBJECTIVE: To test whether, in individuals with mild cognitive impairment (MCI), different measures of subjective cognitive decline (SCD) in the memory domain predict abnormal CSF biomarkers of Alzheimer disease (AD). METHODS: We analyzed the multicenter baseline (cross-sectional) data of 245 patients with MCI. SCD was measured quantitatively with the Subjective Memory Decline Scale (SMDS) and qualitatively by assessing particular concerns associated with self-experienced worsening of memory. Logistic regression models were used to examine associations between SCD and abnormal CSF biomarkers, taking into account objective memory impairment, depressive symptoms, and education as covariates. RESULTS: Abnormal CSF ß-amyloid 1-42 (Aß42) and more depressive symptoms were associated with higher SMDS scores and with the report of memory concerns. Risk of abnormal CSF Aß42 increased by an estimated 57% for a 1-SD increase in SMDS scores and was doubled in patients who had SMDS scores >4 or who reported memory concerns, respectively. In addition, both SCD measures predicted risk of having a biomarker signature indicative of prodromal AD defined as presence of low CSF Aß42 together with either high CSF tau or CSF phosphorylated tau 181 levels. CONCLUSIONS: In MCI, specific aspects of SCD severity and quality are related to CSF biomarkers indicative of AD. This extends findings in pre-MCI samples and calls for an improved operational assessment of SCD in MCI. This might be useful for sample enrichment strategies for increased likelihood of AD pathology.

Memory concerns, memory performance and risk of dementia in patients with mild cognitive impairment.

BACKGROUND: Concerns about worsening memory ("memory concerns"; MC) and impairment in memory performance are both predictors of Alzheimer's dementia (AD). The relationship of both in dementia prediction at the pre-dementia disease stage, however, is not well explored. Refined understanding of the contribution of both MC and memory performance in dementia prediction is crucial for defining at-risk populations. We examined the risk of incident AD by MC and memory performance in patients with mild cognitive impairment (MCI). METHODS: We analyzed data of 417 MCI patients from a longitudinal multicenter observational study. Patients were classified based on presence (n = 305) vs. absence (n = 112) of MC. Risk of incident AD was estimated with Cox Proportional-Hazards regression models. RESULTS: Risk of incident AD was increased by MC (HR = 2.55, 95%CI: 1.33-4.89), lower memory performance (HR = 0.63, 95%CI: 0.56-0.71) and ApoE4-genotype (HR = 1.89, 95%CI: 1.18-3.02). An interaction effect between MC and memory performance was observed. The predictive power of MC was greatest for patients with very mild memory impairment and decreased with increasing memory impairment. CONCLUSIONS: Our data suggest that the power of MC as a predictor of future dementia at the MCI stage varies with the patients' level of cognitive impairment. While MC are predictive at early stage MCI, their predictive value at more advanced stages of MCI is reduced. This suggests that loss of insight related to AD may occur at the late stage of MCI.

Functional disability and death wishes in older Europeans: results from the EURODEP concerted action.

PURPOSE: Physical illness has been shown to be a risk factor for suicidal behaviour in older adults. The association between functional disability and suicidal behaviour in older adults is less clear. The aim of this study was to examine the relationship between functional disability and death wishes in late life. METHODS: Data from 11 population studies on depression in persons aged 65 and above were pooled, yielding a total of 15,890 respondents. Level of functional disability was trichotomised (no, intermediate, high). A person was considered to have death wishes if the death wish/suicidal ideation item of the EURO-D scale was endorsed. Odds ratios for death wishes associated with functional disability were calculated in a multilevel logistic regression model. RESULTS: In total, 5 % of the men and 7 % of the women reported death wishes. Both intermediate (OR 1.89, 95 % CI 1.42; 2.52) and high functional disability (OR 3.22, 95 % CI 2.34; 4.42) were associated with death wishes. No sex differences could be shown. Results remained after adding depressive symptoms to the model. CONCLUSIONS: Functional disability was independently associated with death wishes in older adults. Results can help inform clinicians who care for older persons with functional impairment.

Paranoid symptoms and hallucinations among the older people in Western Europe.

OBJECTIVE: It is not clear whether the prevalence of psychosis increases with age. We studied the age-specific prevalence of psychotic symptoms in older people in Western Europe. METHODS: Older people without dementia (age 65-104 years, N = 8762) from the western part of Europe in the EURODEP concerted action took part in psychiatric examinations. RESULTS: In total, 2.4% of the men and 2.9% of the women had psychotic symptoms. Using a multilevel logistic regression model that included gender and age as a continuous variable, we found that a 5-year increase in age increased the prevalence of psychotic symptoms (odds ratio 1.2 95% confidence interval 1.06-1.3, p = 0.001). A second multilevel regression model showed that wishing to be dead, depressed mood, functional disability, not being married and cognitive impairment measured with Mini mental state examination were all associated with psychotic symptoms whereas gender was not. CONCLUSION: The prevalence of psychotic symptoms in non-demented older people increases with age, and these symptoms are associated with other psychopathology, social isolation and problems with daily living.

Complex mental and physical activity in older women and cognitive performance: a 6-month randomized controlled trial.

BACKGROUND: Several reports suggest beneficial impacts of either physical or mental activity on cognitive function in old age. However, the differential effects of complex mental and physical activities on cognitive performance in humans remain to be clarified. METHODS: This randomized controlled trial evaluates a cognitive and a physical standardized 6-month activity intervention (3 x 1.5 h/wk) conducted in Berlin (Germany). Two hundred fifty nine healthy women aged 70-93 years were randomized to a computer course (n = 92), an exercise course (n = 91), or a control group (n = 76), of whom 230 completed the 6-month assessment. Group differences in change over a period of 6 months in episodic memory (story recall, possible range, 0-21; word recall, possible range, 0-16), executive control (working memory, ie, time quotient of Trail Making Tests B/A), and verbal fluency were evaluated by analyses of covariance (intention to treat) adjusting for baseline, fluid intelligence, and educational level. RESULTS: In contrast to the control group, both the exercise group, DeltaM (SD) = 2.09 (2.66), p < .001, and the computer group, DeltaM (SD) =1.89 (2.88), p < .001, showed improved delayed story recall. They maintained performance in delayed word recall and working memory (time measure) as opposed to the control group that showed a decline, DeltaM (SD) = -0.91 (2.15), p = .001, and DeltaM (SD) = 0.24 (0.68), p = .04, respectively. CONCLUSIONS: In healthy older women, participation in new stimulating activities contributes to cognitive fitness and might delay cognitive decline. Exercise and computer classes seem to generate equivalent beneficial effects.

Depression and parkinsonism in older Europeans: results from the EURODEP concerted action.

OBJECTIVE: The prevalence rate of depression among patients with Parkinson's disease (PD) has been estimated at 25%, although prevalence figures range between 7-76%. Relatively few studies on PD and depression are based on random samples in the general population. Some depressive symptoms can also be understood as symptoms of parkinsonism, and the current study aims to describe which 'overlap' symptoms can be identified in a community sample. METHODS: Data are employed from the EURODEP collaboration. Nine study centres, from eight western European countries, provided data on depression (most GMS-AGECAT), depressive symptoms (EURO-D items and anxiety), parkinsonism (self-report of PD or clinical signs of PD), functional disability and dementia diagnosis. RESULTS: Data were complete for 16 313 respondents, aged 65 and older; 306 (1.9%) reported or had signs of parkinsonism. The rate of depression was about twice as high among respondents with parkinsonism (unadjusted Odds Ratio 2.44, 95% Confidence Interval 1.88-3.17), also among those without functional disability. 'Overlap' symptoms between parkinsonism and depression, were represented by motivation and concentration problems, appetite problems and especially the symptom of fatigue (energy loss). However, principal component analysis showed that these 'overlap' symptoms loaded on different factors of the EURO-D scale. CONCLUSIONS: As among clinical patients with PD, depression is highly common in community dwelling older people with parkinsonism, even among those without functional disability. Although fatigue did not strongly relate to motivational symptoms, both types of 'overlap' symptoms possibly trigger a final common pathway towards a full depressive syndrome.

Altered function of ventral striatum during reward-based decision making in old age.

Normal aging is associated with a decline in different cognitive domains and local structural atrophy as well as decreases in dopamine concentration and receptor density. To date, it is largely unknown how these reductions in dopaminergic neurotransmission affect human brain regions responsible for reward-based decision making in older adults. Using a learning criterion in a probabilistic object reversal task, we found a learning stage by age interaction in the dorsolateral prefrontal cortex (dlPFC) during decision making. While young adults recruited the dlPFC in an early stage of learning reward associations, older adults recruited the dlPFC when reward associations had already been learned. Furthermore, we found a reduced change in ventral striatal BOLD signal in older as compared to younger adults in response to high probability rewards. Our data are in line with behavioral evidence that older adults show altered stimulus-reward learning and support the view of an altered fronto-striatal interaction during reward-based decision making in old age, which contributes to prolonged learning of reward associations.

Pineal calcification in Alzheimer's disease: an in vivo study using computed tomography.

Melatonin has been postulated to have diverse properties, acting as an antioxidant, a neuroprotector, or a stabilizer within the circadian timing system, and is thus thought to be involved in the aging process and Alzheimer's disease (AD). We used computed tomography to determine the degree of pineal calcification (DOC), an intra-individual melatonin deficit marker, as well as the size of uncalcified pineal tissue, in 279 consecutive memory clinic outpatients (AD: 155; other dementia: 25; mild cognitive impairment: 33; depression: 66) and 37 age-matched controls. The size of uncalcified pineal tissue in patients with AD (mean 0.15 cm(2) [S.D. 0.24]) was significantly smaller than in patients with other types of dementia (0.26 [0.34]; P=0.038), with depression (0.28 [0.34]; P=0.005), or in controls (0.25 [0.31]; P=0.027). Additionally, the DOC in patients with AD (mean 76.2% [S.D. 26.6]) was significantly higher than in patients with other types of dementia (63.7 [34.7]; P=0.042), with depression (60.5 [33.8]; P=0.001), or in controls (64.5 [30.6]; P=0.021). These two findings may reflect two different aspects of melatonin in AD. On the one hand, the absolute amount of melatonin excretion capability, as indicated by uncalcified pineal volume, refers to the antioxidant properties of melatonin. On the other hand, the relative reduction in melatonin production capability in the individual, as indicated by DOC, refers to the circadian properties of melatonin.

Role of ventral striatum in reward-based decision making.

So far, the specific role of the ventral striatum in reward-based decision making remains elusive. Here, we examined the role of the ventral striatum in reward-based decision making using functional MRI and a probabilistic object reversal task. During decision making, activity in the ventral striatum increased monotonically as a function of association learning and was greatest when the individuals expected to be rewarded for the decision with high certainty. Conversely, during the reward phase, activity in the ventral striatum showed an inverted U-shaped modulation by learning and was greatest when uncertainty about the outcome was maximal. Our data indicate that, during reward-based decision making, the ventral striatal signal dynamically changes over time dependent on the phase of the reward process and on the learning status and thereby acts as a motivational engine for the continuation of behavior.

Interictal slow-wave focus in left medial temporal lobe during bilateral electroconvulsive therapy.

The interictal state between two electroconvulsive therapy (ECT) sessions is clinically characterised by possible cognitive adverse effects like mild amnestic syndrome. ECT-induced amnestic deficits can persist for several weeks after ECT. Electrophysiologically, slowing of brain electrical activity in the interictal state has often been reported. Especially, for bilateral ECT a correlation between enhanced left frontotemporal theta activity and retrograde amnesia has been demonstrated. This study focuses on the topographic distribution of cortical slow-wave oscillations during the interictal state of a bilateral ECT cycle. Twelve patients with major depression have been investigated with 32-channel resting EEG 24 h after the 6th ECT session. As controls, 8 major depressive patients were investigated prior to antidepressive treatment. The generating sources of slow-wave activity are estimated within the theta frequency band with low-resolution brain electromagnetic tomography. Source analysis revealed a distinct pattern of theta activity in the depth of the left temporal lobe (fusiform and parahippocampal gyri, Brodmann areas 37 and 36, respectively; p< 0.05) during the interictal state. This finding suggests a dysfunction of the left medial temporal lobe memory system during the interictal state of a bilateral ECT cycle. It will further be discussed whether it is possible to obtain information about activity of deep brain structures like the hippocampal formation from scalp-recorded signals.

Electrophysiological and neuropsychological analysis of a delirious state: the role of the anterior cingulate gyrus.

Functional neuroimaging studies in humans have provided evidence that a frontal network including the anterior cingulate cortex (ACC) plays an important role in attention and awareness. Disturbed attention and awareness are core symptoms of delirium, but imaging studies of attentional dysfunctions in delirium are lacking. However, an increase of slow electroencephalographic (EEG) activity (delta, theta) is a consistent biological finding in delirium. The question whether this slow activity is related to a disturbance in the frontal attentional network has not yet been addressed. The delirium after electroconvulsive therapy (ECT) has been investigated using 32-channel resting EEG before and shortly after ECT in 12 patients with major depressive disorder. During delirium compared with baseline studies, substantial increases of delta and theta power and a decrease of alpha power were observed. The decrease of theta activity at the Fz electrode position in the following 24 h was significantly related to the recovery of awareness and performance of free recall. Source analysis with Low Resolution Electromagnetic Tomography (LORETA) indicated that the main generators of the theta excess during delirium were significantly localized in the anterior cingulate cortex, and additionally in right fronto-temporal brain areas. The results support the concept that a disturbance of attention and awareness during delirium is related to a dysfunction of an attentional network involving the ACC. However, the localization of the theta excess may reflect some motor dysfunctions as well. This dysfunction of the ACC was shown for the first time in patients during a delirious state and may represent an important pathophysiological aspect of delirium.

Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE).

OBJECTIVE: Longitudinal studies of neuropsychological changes in the preclinical phase of Alzheimer disease (AD) have yielded mixed results. Although some studies report tests of episodic memory, others report tests of attention and executive functions as reliable predictors of subsequent AD. Following theoretical models of neuropsychological processes before AD onset, the authors examined the predictive value of attention and executive function in the preclinical phase of AD in old age. METHODS: Authors studied the cognitive performance of 187 initially normal participants of the Berlin Aging Study, a community-based representative sample of Berlin citizens age 70 to 103, over a period of 4 years. Tests of attention and executive function (Digit Letter Test, Trailmaking Part B Test, Digit Symbol Substitution Test, and Identical Pictures Test) and of learning and recall functions (Activity Recall, Memory for Text, and Paired-Associate Learning) were administered at baseline. Diagnosis of AD was made according to NINCDS-ADRDA criteria (probable AD). Receiver operating characteristics curve analyses and Cox regression analyses were used to assess the diagnostic accuracy and predictive value of the neuropsychological tests at baseline for incident AD after 4 years. RESULTS: After 4 years, 15 participants had developed AD. Tests of attention and executive function discriminated best between nonconverters and incident AD cases. A similar pattern was found in survival analyses; attention and executive function tests, together with tests of learning and recall, significantly predicted incident AD over and above age, gender, and education. CONCLUSION: These results support theoretical models of attention and executive function in the preclinical phase of AD in old age.

National context of healthcare, economy and religion, and the association between disability and depressive symptoms in older Europeans: results from the EURODEP concerted action.

Associations between disability and depression have been shown to be consistent across cultures among middle-aged adults. In later life the association between disability and depression is much more substantial and may be amenable to influences by health care facilities as well as economic and sociocultural factors. Fourteen community-based studies on depression in later life in 11 western European countries contribute to a total study sample of 22,570 respondents aged 65 years or older. Measures are harmonised for depressive symptoms (EURO-D scale) and disability. Using multilevel modelling to control for the stratified data structure we examined whether the association between disability and depressive symptoms is modified by national health care and mental health care availability, national economic circumstances, demographic characteristics and religious tradition. The association between depressive symptoms and disability is attenuated by health care expenditure and availability of mental health care and also by gross domestic product; it was more pronounced in countries with high levels of orthodox religious beliefs. Higher levels of depressive symptoms are found in countries with a larger gross domestic product (per capita) and higher health care expenses but are interpreted with care because of measurement differences between the centres. The findings from this contextual perspective indicate that general and mental health care should be geared to one another wherever possible.

Brain mechanisms of visual encoding and working memory in psychometrically identified schizotypal individuals and after acute administration of haloperidol.

A probabilistic association task that manipulated the necessity to temporarily store information was combined with the recording of event-related potentials. In Experiment 1, scores obtained from a positive schizotypy scale were used to categorize participants as either low or high schizotypal individuals. Low, but not high, schizotypal individuals displayed evidence for selective associative learning in the working memory dependent ("trace") version of the task. The amplitudes of the occipito-temporal N150 were attenuated in high schizotypal individuals. In Experiment 2, the intravenous administration of a single dose of haloperidol (0.04 mg/kg), but not of a placebo, strengthened the selectivity of associative learning in the trace version of the task. The amplitudes of the occipito-temporal N150 were augmented by haloperidol. Psychometrically identified schizotypal individuals and normal individuals under mild stress demonstrated defective prioritization of information in working memory and deficient visual encoding. These neurocognitive effects of schizotypy and stress seem to be mediated by the D2 family of dopamine receptors.

Moderate psychosocial stress appears not to impair recall of words learned 4 weeks prior to stress exposure.

Recent studies in humans have reported that recall of previously learned material is especially sensitive to the disruptive effects of pharmacologically induced cortisol elevations. Whether similar effects occur after exposure to psychosocial stress remains to be shown. Moreover it is unknown whether stress before or after the initial learning interacts with the later effects of repeated stress on delayed recall (e.g. state-dependent learning). Forty subjects participated in the present experiment. They learned a word list either one hour before or 10 min after exposure to a psychosocial laboratory stressor. Delayed recall was tested 4 weeks later, again either before or after stress. Salivary cortisol levels increased significantly in response to both stress exposures. Stress had no effects on the initial learning and also did not impair delayed recall. Moreover there was no evidence for state-dependent learning. The current data seem to be in conflict with previous studies demonstrating that delayed recall is especially sensitive to elevated cortisol levels. Several reasons for these discrepancies are discussed. Among them is the small sample size, the moderate cortisol increase in response to the second stress exposure but also the long recall delay, which might lead to memory traces less susceptible to stress.

Effects of supraphysiological doses of L-thyroxine on cognitive function in healthy individuals.

Cognitive disturbance is commonly associated with disorders of the thyroid gland, particularly hypothyroidism, and usually subsides following thyroid hormone replacement therapy. In contrast, the effects of thyroid hormones on cognitive functions in healthy individuals have rarely been studied. The goal of this open-label study was to investigate the short-term effects (duration of administration 45 days on average) of supraphysiological doses of L-thyroxine (L-T(4)) on cognitive performance in young, euthyroid, healthy subjects. Eleven subjects performed a comprehensive neuropsychological test battery, once without and once during administration of supraphysiological doses of L-T(4). There were no significant differences in any of the cognitive test results between the two test sessions. The results of this study do not support our working hypothesis that thyroid hormone can change cognitive performance in young, euthyroid, healthy individuals.

Initial lithium and valproate combination therapy in acute mania.

Early onset of treatment efficacy is especially important for severe mania syndromes. Lithium has usually a delayed onset of response, which is disadvantageous for inpatient treatment of severe mania. Valproate is effective in treating acute mania and has sedative properties. It has, however, a response rate of approximately only two thirds. Therefore, the initial combination of valproate and lithium was evaluated in a prospective case series of 12 patients, and a retrospective analysis was carried out for 5 patients in comparison with a pretreatment period when lithium therapy was applied without valproate. Outcome criterion for analysis was the latency of response and remission, as well as the amount of neuroleptics used for additional sedation. Patients had a mania syndrome-severity score comparable with the mean mania score of the bipolar manic patients treated in the same unit. All patients under the combination treatment responded. The response occurred within a shorter time compared with the lithium pretreatment episode, which is statistically marginally significant, and the use of neuroleptic medication could be markedly reduced from 18,601.6 mg chlorpromazine equivalents to 3,927.6 mg (p < 0.025). The initial valproate-lithium combination therapy seems to be a safe and effective way to treat severe mania syndromes in the clinic.