Subjective Cognitive Decline as a predictor of Frailty in older adults: Hellenic Longitudinal Investigation of Aging and Diet study (HELIAD).

BACKGROUND: Subjective cognitive decline (SCD) is a self-evaluation of cognitive impairment, in the absence of observed objective cognitive deficits on a neuropsychological assessment. Frailty refers to a multidimensional syndrome where the individual has poor health including falls, disabilities, hospitalization, and vulnerability. Both terms are associated with cognitive decline and increased incidence of dementia. The present longitudinal study explored whether the detection of SCD can predict the development of frailty over time. METHODS: The Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) is an epidemiological, population-based study. From the original testing sample of 1,984 older Greek individuals (≥65 years old), 1,121 remained in the longitudinal analysis. Participants diagnosed with frailty, Mild Cognitive Impairment (MCI), dementia, severe depression, and anxiety, in the baseline assessment were excluded from the analysis (n=146), resulting in a total sample of 975 participants. The average follow-up interval was 3.1 years (SD=0.84 years). SCD was assessed in the baseline assessment with a series of eighteen questions. The questions regarding SCD were categorized according to cognitive domains. Frailty was assessed according to a phenotypic-physiologic (Fried's definition) and a multidomain approach (Frailty Index). Univariate and multivariate Cox regression analyses were used for exploring the role of SCD in developing frailty. RESULTS: The proportion of individuals with frailty according to Fried's definition was greater compared to the Frailty Index. At follow-up according to Fried's definition, a greater proportion of cases with frailty was found in those who reported SCD complaints regarding orientation (OD) (HR=3.12 95% CI:1.45-6.73 p<0.004) or in those who reported at least three SCD complaints regarding their memory performance (SMC3) (HR=1.92 95% CI:1.05-3.52 p<0.035) at the baseline assessment. Subjective complaints regarding orientation were predictive of a greater hazard of frailty as defined by the Fried scale (HR=3.12 95% CI:1.45-6.73 p<0.004) and the Frailty Index (HR=3.59 95% CI:1.77-7.25 p<0.001). CONCLUSION: Our findings demonstrate that healthy older adults who report SCD complaints regarding orientation or state that they have at least three memory complaints have a higher risk of developing frailty. Additionally, the number of participants with a clinical diagnosis of MCI or dementia, compared to individuals with normal aging, at follow-up was found to be significantly greater in cases with frailty according to both frailty definitions applied (p<0.001). Consequently, it is advisable to use screening questionnaires for SCD covering multiple cognitive domains in clinical practice for identifying and managing frailty, thus, implementing effective interventions to promote healthy aging.

Objective and Subjective Measurements of Motor Function: Results from the HELIAD Study.

BACKGROUND: Slow gait speed has recently emerged as a potential prodromal feature of cognitive decline and dementia. Besides objective measurements, subjective motor function (SMF) difficulties might be present prior to the manifestation of gait disorders. OBJECTIVES: To examine the association of walking time and the presence of SMF with future cognitive decline in cognitively normal individuals. DESIGN: Longitudinal study. SETTINGS: Athens and Larissa, Greece. PARTICIPANTS: 931 cognitively normal individuals over the age of 64 with longitudinal follow-up from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). MEASUREMENTS: We used a simple chronometer for recording objective walking time (OWT) and SMF was assessed using a self-reported physical functioning questionnaire. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline OWT and SMF difficulties and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. RESULTS: Each additional second of OWT was associated with 1.1% of a standard deviation more decline per year in the composite z-score, 1.6% in the memory z-score, 1.1% in the executive z-score and 1.8% in the attention-speed z-score. The presence of SMF difficulties was not associated with differential rates of decline in any cognitive domain. CONCLUSION: Gait speed can be indicative of future cognitive decline adding credence to the notion that gait speed might serve as a simple and easily accessible clinical tool to identify a larger pool of at risk individuals and improve the detection of prodromal dementia.

Sex Differences in Frailty Incidence in Greek Community-Dwelling Older People: The HELIAD Study.

BACKGROUND: Previous frailty studies found higher prevalence of frailty in female than in male participants. This was mainly attributed to the fact that compared to men, women show increased longevity. Recent studies have reported that the observed difference between sexes applies irrespectively of the age of older people. OBJECTIVES: To provide data on sex differences in incident frailty by applying both phenotypic and multi-domain frailty measures in the same population of Greek community-dwelling older people. DESIGN: Longitudinal study. SETTING: Data were drawn from the Hellenic longitudinal Investigation of Aging and Diet (HELIAD), a population-based, multidisciplinary study designed to estimate the prevalence and incidence of dementia in the Greek population. PARTICIPANTS: 1104 participants aged 65 year and above were included in this longitudinal study. This incidence cohort was re-evaluated after a mean follow-up period of 3.04±0.90 years. MEASUREMENTS: Frailty was operationalized using 5 different definitions in the same population: the Fried Frailty Phenotype (FFP) definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI) and the Groningen Frailty Index (GFI). Frailty incidence was calculated a) for the whole sample, b) separately for men and women and c) after both age and sex stratification. RESULTS: Age and sex stratification revealed that irrespective of age and frailty measurement, women showed higher incidence rates of frailty than men. Specifically, frailty seems to be a condition concerning women >65 years old, but when it comes to men, it is more frequent in those aged more than 75 years old. Finally, in relation to overall frailty incidence and comparing our results to previous studies, we detected a lower frailty incidence in the Greek population. CONCLUSIONS: Differences between the two sexes indicate that when exploring the factors that are related to frailty, studies should provide data disaggregated for men and women.

Adherence to the Mediterranean diet and incident frailty: Results from a longitudinal study.

OBJECTIVES: The aim of the current prospective study was to examine the relationship between adherence to the Mediterranean diet and incident frailty. STUDY DESIGN: 1075 Greek community-dwelling older adults from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present longitudinal analysis. MAIN OUTCOME MEASURES: Adherence to the Mediterranean diet was evaluated through the MedDietScore, calculated from the information participants provided on a validated food frequency questionnaire. Frailty was assessed using two multidomain tools: the Frailty Index (FI) and the Tilburg Frailty Indicator (TFI). Analysis of the incidence of frailty as a function of the baseline MedDietScore was performed using Cox proportional hazards models. Additionally, Generalized Estimating Equations (GEE) models were used to explore whether the baseline MedDietScore was associated with the change in the total number of frailty criteria met by participants over time. In testing for a dose-response association between Mediterranean diet and frailty, the MedDietScore was treated either as a continuous variable or as tertiles of low, medium and high adherence to MeDi. RESULTS: 176 and 131 participants developed incident frailty, as measured with the FI and TFI respectively. Each unit of MedDietScore was associated with a 5% (ΗR 0.95, 95% CI 0.91-0.99, p = 0.012) and 10% (ΗR 0.90, 95% CI 0.86-0.95, p ≤ 0.001) decrease in the risk of incident frailty when measured with the FI and TFI respectively. Compared with participants reporting low adherence to the Mediterranean diet (lowest tertile), those with high adherence (highest tertile) had a 41% (ΗR 0.59, 95% CI 0.38-0.91, p = 0.017) and a 57% (ΗR 0.43, 95% CI 0.27-0.70, p ≤ 0.001) lower risk of incident frailty as measured with the FI and TFI respectively. After excluding from the analyses participants diagnosed with dementia at baseline or follow-up, the same results were obtained: each unit of MedDietScore was associated with a 5% (HR 0.95 CI 0.91-0.99, p = 0.023) and a 10% (HR 0.90 CI 0.86-0.94, p ≤ 0.001) decrease in the risk of incident frailty as measured with the FI and TFI respectively. CONCLUSIONS: The present longitudinal study showed that non-frail community-dwelling older adults with high adherence to the Mediterranean dietary pattern had a significantly lower incidence of frailty.

Plasma GSH levels and Alzheimer's disease. A prospective approach.: Results from the HELIAD study.

BACKGROUND: Potential links between oxidative stress and the pathophysiology of Alzheimer's disease (AD) have been reported in the existing literature. Biological markers of oxidative stress, such as the reduced form of glutathione (GSH), may have a potential role as predictive biomarkers for AD development. The aim of the present study was to explore the longitudinal associations between plasma GSH and the risk of developing AD or cognitive decline, in a sample of community-dwelling, non-demented older adults. METHODS: Participants from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present prospective study. The sample used in the analyses consisted of 391 non-demented individuals over the age of 64 (mean age = 73.85 years; SD = 5.06), with available baseline GSH measurements and longitudinal follow-up. Plasma GSH was treated both as a continuous variable and as tertiles in our analyses. Cox proportional hazards models were used to evaluate the hazard ratio (HR) for AD incidence as a function of baseline plasma GSH. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline plasma GSH and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Supplementary exploratory models were also adjusted for mild cognitive impairment (MCI) at baseline, risk for malnutrition, physical activity and adherence to the Mediterranean dietary pattern. RESULTS: A total of 24 incident AD cases occurred during a mean (SD) of 2.99 (0.92) years of follow-up. Individuals in the highest GSH tertile group (highest baseline plasma GSH values) had a 70.1% lower risk for development of AD, compared to those in the lowest one [HR = 0.299 (0.093-0.959); p = 0.042], and also demonstrated a slower rate of decline of their executive functioning over time (5.2% of a standard deviation less decline in the executive composite score for each additional year of follow-up; p = 0.028). The test for trend was also significant suggesting a potential dose-response relationship. CONCLUSION: In the present study, higher baseline plasma GSH levels were associated with a decreased risk of developing AD and with a better preservation of executive functioning longitudinally.

Assessing functional status using the IADL-extended scale: results from the HELIAD study.

OBJECTIVES: Instrumental activities of daily living (IADL) have been operationalized as exhibiting a greater level of complexity than basic ADL. In the same way, incorporating more advanced ADLs may increase the sensitivity of functional measures to identify cognitive changes that may precede IADL impairment. Towards this direction, the IADL-extended scale (IADL-x) consists of four IADL tasks and five advanced ADLs (leisure time activities). DESIGN: Retrospective, cross-sectional study. SETTING: Athens and Larissa, Greece. PARTICIPANTS: 1,864 community-dwelling men and women aged over 64. MEASUREMENTS: We employed both the IADL-x and IADL scales to assess functional status among all the participants. Diagnoses were assigned dividing the population of our study into three groups: cognitively normal (CN), mild cognitive impairment (MCI) and dementia patients. Neuropsychological evaluation was stratified in five cognitive domains: memory, language, attention-speed, executive functioning and visuospatial perception. Z scores for each cognitive domain as well as a composite z score were constructed. Models were controlled for age, sex, education and depression. RESULTS: In both IADL-x and IADL scales dementia patients reported the most functional difficulties and CN participants the fewest, with MCI placed in between. When we restricted the analyses to the CN population, lower IADL-x score was associated with worse cognitive performance. This association was not observed when using the original IADL scale. CONCLUSION: There is strong evidence that the endorsement of more advanced IADLs in functional scales may be useful in detecting cognitive differences within the normal spectrum.

Prevalence and Risk Factors of Frailty in a Community-Dwelling Population: The HELIAD Study.

Objective: To estimate the prevalence of frailty using five different instruments in a cohort of older adults and explore the association between frailty and various risk factors. Method: 1,867 participants aged 65 years and above were included in the current retrospective cross-sectional study. Frailty was operationalized according to the Fried definition, the FRAIL Scale, the Frailty Index (FI), the Tilburg Frailty Indicator (TFI), and the Groningen Frailty Index (GFI). We explored the role of various frailty risk factors using logistic regression analyses. Results: The prevalence of frailty varied depending on the definition used (Fried definition = 4.1%, FRAIL Scale = 1.5%, FI = 19.7%, TFI = 24.5%, and GFI = 30.2%). The only risk factors consistently associated with frailty irrespectively of definition were education and age. Conclusion: The frailty prevalence reported in our study is similar or lower to that reported in other population studies. Qualitative differences between frailty definitions were observed.

Understanding of Faux Pas in patients with schizophrenia.

Theory of Mind (ToM) refers to our ability to attribute mental states such as beliefs, intentions and desires to other, allowing us to explain, manipulate and predict others' behavior. ToM abilities of patients with schizophrenia were repeatedly found to be deficient. Our purpose in undertaking the present study was to explore ToM deficits in patients with schizophrenia, using a task of an affective aspect of ToM abilities, namely, "Faux Pas" Test (FPT). The FPT requires a "cognitive" ToM ability (i.e., knowing that the person who insults the other has not realized that she/he should not do that) and a more "affective" component (i.e., empathizing for the person who received the insulting utterance). We assessed 40 inpatients with schizophrenia (32 men) and 30 healthy participants (24 men), matching on age, level of education and sex ratio. All patients met DSM-IV criteria for schizophrenia. Four written scenarios containing a faux pas (unintentionally insulting or hurtful statements given a particular context) were presented to each examinee. The participants read each scenario and responded to a series of 4 questions: "Did anyone say something she/he should not have said?" (faux pas detection); "Why shouldn't she/he have said it?" (appreciation of potential negative impact on others); "Why do you think she/he said it?" (appreciation of speaker's lack of consideration); "How do you think the other person might have felt?" (awareness of other's emotional reaction). Patients with schizophrenia performed more poorly than healthy participants across all conditions: detection of FP [U=366.5, p=0.001], reasons should not have made FP [U=215.5, p<0.001], reasons for making FP [t(65)=4.294, p<0.001], and empathy [U=372, p=0.001]. Only the third condition (reasons for making FP) was significantly correlated with the age at first diagnosis (r=0.462, =0.004) and with ratings of positive symptoms (r=-0.391, p=0.017) and with symptoms of general psychopathology (r=-0.339, p=0.040). The present study further supports previous findings of patients with schizophrenia difficulties in theory of mind, as it was measured through a faux pas which also assess, apart from the understanding of a person' s mental state, the understanding of a person's emotional state, after having received an unintentional insult. The inability of patients with schizophrenia to empathize and therefore detect a faux pas may cause serious problems in their everyday communication with others. Appropriate cognitive interventions may help patients to avoid unintentionally hurting other people's emotions, thus improving their interpersonal relationships.

History of induced abortions and frailty in older Greek women: results from the HELIAD study.

PURPOSE: Women are almost twice as likely as men to develop frailty and early-traumatic experiences related to reproduction may have a role to play. The purpose of this study was to investigate the association between a history of induced abortions and risk of frailty. METHODS: 1062 women aged ≥ 65 years from the HELIAD study were included in the present cross-sectional study. Frailty was assessed by frailty index and Fried definitions. The history of abortion and of other reproductive experiences (age onset of menstruation, age of menopause, number of offspring, and number of miscarriages) was obtained by all participants. Logistic and linear regression analyses were performed to examine whether the number of abortions was related to frailty. RESULTS: When frailty was defined with frailty index, women with 1 or 2 abortions had 1.7 higher risk of frailty compared to women with no history of abortions, while those with more than 3 abortions had more than a twofold higher risk of frailty. Two supplementary analyses excluding women with surgical operations' history and women with dementia revealed similar results. When frailty was defined with Fried definition, the analysis was marginally significant when abortion was inserted as a categorical variable. Women with more than 3 abortions showed 2.4 higher risk of frailty compared to women with no history of abortion. CONCLUSION: The number of induced abortions was associated with moderate higher odds of frailty, when frailty was defined according to frailty index. A similar trend was revealed in the model with Fried definition after trichotomization of abortions.

Dataset on the associations between sleep quality/duration and cognitive performance in cognitively healthy older adults.

In the present data, we provide the details of the cross-sectional study examining the associations between sleep quality/sleep duration and cognitive performance. Data are from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). A total of 1484 older adults (65 y.o. or older) took part in the study. Sleep measurements were drawn from the sleep scale of the Medical Outcomes Study (MOS). Cognition was used as a z-score drawn by different tests. The domains examined were: executive function, visuo-spatial ability, language, attention- speed of processing, as well as the composite z-score of all the cognitive domains (including memory). Linear regression models were conducted to investigate the associations between sleep quality and cognition, and sleep duration and cognition as well. We also conducted linear regression analyses for the associations between sleep quality/duration and cognitive domains/composite cognitive score based on the status of the Apolipoprotein E-ε4 (ApoE-ε4) genotype. Analyses were performed excluding both the demented and the Mild Cognitive Impairment (MCI) participants. Adjustments conducted for multiple covariates. For further analyses and enhanced discussion, see original article: "Sleep quality and duration in relation to memory in the elderly: initial results from the Hellenic Longitudinal Investigation of Aging and Diet" by Tsapanou et al. [1].

Controlled shifting of attention in schizophrenia and bipolar disorder through a dichotic listening paradigm.

The dichotic listening (DL) task was developed originally to examine bottom-up or "automatic" information processing. More recently, however, it has been used as a tool in the study of top-down or "controlled" information processing. This has been done by including forced-choice conditions, wherein the examinee is required to focus attention on one or the other ear. It has been widely utilized with patients with schizophrenia, who exhibit rather severe deficits in managing their attention, but not with other patient groups, such as patients with bipolar disorder. In the present study, we examined potential performance similarities in the DL listening task. In total, the sample consisted of 38 patients with schizophrenia, 20 patients with psychotic bipolar disorder and 35 healthy individuals, who performed a DL task with verbal stimuli once at the beginning of their hospitalization and again on the last day before discharge. Our findings indicated that both patient groups showed similarly diminished performance when compared to healthy participants at both times of administration. Symptom improvement between the two evaluations did not significantly influence performance in the DL task. In conclusion, impaired automated and controlled information processing appears to be a common deficit in both schizophrenia and bipolar disorder.

Phonological fluency strategy of switching differentiates relapsing-remitting and secondary progressive multiple sclerosis patients.

The strategies used to perform a verbal fluency task appear to be reflective of cognitive abilities necessary for successful daily functioning. In the present study, we explored potential differences in verbal fluency strategies (switching and clustering) used to maximize word production by patients with relapsing-remitting multiple sclerosis (RRMS) versus patients with secondary progressive multiple sclerosis (SPMS). We further assessed impairment rates and potential differences in the sensitivity and specificity of phonological versus semantic verbal fluency tasks in discriminating between those with a diagnosis of MS and healthy adults. We found that the overall rate of impaired verbal fluency in our MS sample was consistent with that in other studies. However, we found no differences between types of MS (SPMS, RRMS), on semantic or phonological fluency word production, or the strategies used to maximize semantic fluency. In contrast, we found that the number of switches differed significantly in the phonological fluency task between the SPMS and RRMS subtypes. The clinical utility of semantic versus phonological fluency in discriminating MS patients from healthy controls did not indicate any significant differences. Further, the strategies used to maximize performance did not differentiate MS subgroups or MS patients from healthy controls.

Insights into theory of mind in schizophrenia: the impact of cognitive impairment.

The ability to mentalize and attribute beliefs, intentions and desires to others has been found by the vast majority of studies to be impaired in patients with schizophrenia. However, it is not yet clear if this deficit in Theory of Mind (ToM) is independent of their also well established deficits in basic cognitive functioning. In the present study, we sought to clarify the above relationship by exploring patients' ToM impairment after controlling for their putative cognitive deficits. We examined 36 patients with schizophrenia and 30 healthy matched controls on first and second order tasks of ToM and on commonly used neuropsychological tests. Patients performed poorly on ToM tasks even after controlling for their cognitive deficits, particularly on second order ToM. The present findings contribute to the understanding of the mechanism of ToM, suggesting that ToM deficits are core characteristics in schizophrenia and relatively independent of patients' cognitive impairment.

Transient epileptic amnesia in a memory clinic setting: a report of three cases.

Transient epileptic amnesia (TEA) is a recently described, typically misdiagnosed at presentation, distinctive syndrome, characterized by recurrent, brief attacks of memory loss in middle-aged or elderly people, accompanied by significant interictal memory difficulties. We describe the clinical, neuroimaging, electrophysiological, and neuropsychological characteristics of three patients fulfilling the proposed criteria for TEA, initially referred to our memory clinic for evaluation and treatment of probable dementia. Neuropsychological performance on admission and 6 months after treatment demonstrated a broad range of performance on measures of executive function, lower than expected visuospatial perception, and poor autobiographical memory. TEA should be included in the differential diagnosis of dementia to avoid misdiagnosis and needless medication. It is a benign and treatable condition, yet the associated decline in autobiographical and remote memory despite antiepileptic therapy poses challenges for further research.

Adaptation of Addenbrooke's Cognitive Examination-Revised for the Greek population.

BACKGROUND/PURPOSE: Addenbrooke's Cognitive Examination-Revised [1] is a highly sensitive and specific bedside test for the diagnosis of dementia. The aim of this study was to validate a Greek version of this simple, bedside instrument and to investigate its psychometric properties. METHOD: We translated and administered the Greek version of the ACE-R to 95 individuals comprising two groups: a dementia group (n=35) and an age-matched and education-matched healthy control group (n=60). RESULTS: Our results suggest high internal consistency and very good sensitivity, specificity and negative predictive value, but only adequate positive predictive value for the ACE-R, with excellent diagnostic accuracy. In our sample, the ratio of verbal fluency plus language scores to orientation plus memory (VLOM) subscore failed to discriminate patients in the target dementia group. CONCLUSION: The present findings support the usefulness of the ACE-R as a brief dementia screening tool in clinical practice. Further neuropsychologic evaluation is required for the differential diagnosis of dementia.

Do age and education contribute to performance on the clock drawing test? Normative data for the Greek population.

Our purpose in undertaking the present study was to develop norms for the Greek population for the Clock Drawing Test (CDT), using a systematic scoring procedure, and to explore the influence of demographic factors on the performance of healthy individuals. We administered the CDT to 223 healthy adults and scored it according to the method of Freedman et al. (1994). In 136 of the participants, we also measured global cognitive status with the Mini-Mental State Examination. We found that both age and level of education contributed to CDT performance. Interestingly, CDT performance was relatively consistent across the ages between 14-59 years, showing a marked decline after 60 and another decline after 70. Therefore, we concluded that CDT performance is relatively resistant to the effects of age for those below 60 years old. We present preliminary normative data for the Greek population stratified by age and level of education. Further research should include more extensive sampling of elderly participants (>60 years old) with varying levels of education, in order to establish more reliable norms for the elderly.

Avoidance learning in schizophrenia: a dissociation between the effects of aversive and non-aversive stimuli.

Patients with schizophrenia did not take significantly more trials than normal controls to learn to use a visual warning signal to avoid a non-aversive stimulus on a simple computer-administered avoidance learning task. When the stimulus to be avoided was aversive (i.e., a loud buzzer), however, the schizophrenic group could be divided into two subgroups based upon their performance; almost one half of the schizophrenic group failed to learn how to avoid this task successfully. The other half, like the normal controls and the closed head injury group in our previous studies, benefited from the aversiveness of the stimulus to be avoided, and learned to avoid more quickly than in the non-aversive condition. A post-hoc analysis of the differences between these two subgroups of the patients suggested that the discrepancy in learning was related to the age of onset of illness.

Sex differences in seasonal variations in P300.

Previous reports of seasonal variations in P300 were based on cross-sectional observations of subjects tested at different times of the year. In this study, we tested three groups of subjects in each of two seasons: winter and spring, spring and summer, and summer and winter. We found winter or spring maxima in auditory and visual P300 and visual slow wave. This pattern of results, with the amplitude of P300 being inversely related to the amount of sunlight in a season, supports the hypothesis that the allocation of processing resources varies across the seasons. Our results also suggest a trend for an increased sensitivity of women, as compared with men, to seasonal influences on P300. Although our findings do not provide strong evidence that P300 varies systematically as a function of season, seasonal factors appear to affect cognitive processing (as indexed by P300) differentially in men and women.

The dopamine D3 receptor (DRD3) Ser9Gly polymorphism and schizophrenia: a haplotype relative risk study and association with clozapine response.

Several lines of evidence suggest that the dopamine D3 receptor is involved in the pathophysiology of schizophrenia. The D3 receptor gene (DRD3) contains a polymorphism resulting in a serine-glycine substitution in the N-terminus of the receptor. Shaikh and colleagues have reported a significant association between the DRD3 Ser9 allele and the Ser9/Ser9 genotype with schizophrenia in 133 Caucasians. In a meta-analysis of previous studies, Ser9 and the Ser9/Ser9 genotype were found to be significantly associated with schizophrenia, although these investigators could not confirm reports of excess homozygosity at this locus in schizophrenia. These authors also report that, in an unblinded study, the Ser9/Ser9 genotype was more frequent in patients who did not respond to clozapine. These data represent the most comprehensive examination of DRD3 Ser9Gly in schizophrenia to date. We have therefore determined DRD3 Ser9Gly genotypes in 58 patients with schizophrenia and in their parents. Moreover, we have genotyped 68 schizophrenics participating in double-blind clozapine trials. We do not find that Ser9 is preferentially transmitted in schizophrenia, cannot confirm excess DRD3 homozygosity in schizophrenia, and do not replicate the association between DRD3 and clozapine response. These data suggest that allelic variation in DRD3 may not play a role in the pathophysiology of schizophrenia or in clozapine response.