Vesna Medved

Genome-wide expression analysis of peripheral blood identifies candidate biomarkers for schizophrenia

The aim of this study was to analyze gene expression in blood of patients with newly-diagnosed schizophrenia during their first psychotic episode and subsequent remission. Whole blood samples were obtained from 32 untreated patients presenting with their first psychotic episode suggestive of schizophrenia and 32 age- and gender-matched controls. Using Affymetrix micoarrays, we identified significantly altered expression of 180 gene probes in psychotic patients compared to controls. A subset of four significantly changed genes was further confirmed with QRT-PCR. The following genes were significantly altered in patients: glucose transporter, SLC2A3 (p<0.001) and actin assembly factor DAAM2 (p<0.001) were increased, whereas translation, zinc metallopeptidase, neurolysin 1 and myosin C were significantly decreased (p<0.05). Expression of these candidate markers was also analyzed in a longitudinal study (12-24 months) in 12 patients who achieved full remission. Interestingly, expression of DAAM2 returned to control levels in patients who were in remission after their first psychotic episode, suggesting that its expression correlates with diseases progression and/or response to treatment. In summary, we identified changes of gene expression from peripheral blood which might help discriminate patients with schizophrenia from controls. While these results are promising, especially for DAAM2 whose polymorphic variants have been found significantly associated with schizophrenia, it will be important to analyze larger cohorts of patients in order to firmly establish changes in gene expression as blood markers of schizophrenia.

The influence of 5-HT2C and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >or=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >or=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >or=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.

Association study of olanzapine-induced weight gain and therapeutic response with SERT gene polymorphisms in female schizophrenic patients

We investigated the relationships between L/S promoter (SERTPR) and l/s intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with olanzapine-induced weight gain and treatment response in 94 female schizophrenic patients treated with olanzapine for up to 3 months. Body mass index (BMI) was calculated for each patient prior to olanzapine administration and 3 months afterwards. To assess and evaluate improvement of clinical psychotic symptoms and therapeutic response to the antipsychotic, all patients were rated using the Positive and Negative Syndrome ScaLe (PANSS). Overall, the presence of S SERTPR allelic variant and SS genotype was associated with significantly higher weight gain in subjects who were non-obese at the time of admission. The presence of L SERTPR variant was associated with significantly better treatment response measured with total PANSS and general PANSS subscale, while the presence of l SERTin2 variant determined better treatment response only in several items. No evidence of linkage disequilibrium between the two loci was found in the sample. These findings identify genetic factors associated with oLanzapine-induced weight gain and treatment response in femaLe schizophrenic patients.

Suicide ideators and attempters with schizophrenia – The role of 5-HTTLPR, rs25531, and 5-HTT VNTR Intron 2 variants

AIM To examine the role of 5-HTTLPR, rs25531 and 5-HTT VNTR Intron 2 variants in subjects with psychotic disorders manifesting suicide ideation and behaviour. METHODS The study included 519 subsequently hospitalized subjects who were genotyped for 5-HTTLPR, rs25531 and 5-HTT VNTR In2 variants. Clinical assessments included structured psychiatric interview, sociodemographic characteristics, suicide ideation and behaviour (SIBQ), severity of psychopathology (PANSS) and depression (CDSS). RESULTS Three subgroups were identified: suicide attempters (N = 161), suicide ideators (N = 174) and subjects who never reported suicide ideation or behaviour (comparative group, N = 184). MAJOR FINDINGS 1) Suicide attempters scored highest on the CDSS, while no differences between the three clinical subgroups were detected in the PANSS scores; 2) Suicide attempters were more frequently the carriers of L(A) allele, while subjects in the comparative group were more frequently the carriers of low expression 5-HTTLPR/5-HTT rs25531 haplotype SL(G); 3) No difference was found between the three clinical groups in the 5-HTT VNTR In2 variants; 4) Subjects with 5-HTTLPR/5-HTT rs25531 intermediate expression haplotype (L(A)L(G,)SL(A)) scored higher on the PANSS general psychopathology subscale; 5) There was no association between suicide attempt or ideation and 5-HTTLPR/In2 or 5-HTTLPR/rs25531/In2 haplotype distribution. CONCLUSION The suicide ideators, attempters and controls did not differ significantly in 5-HTTLPR or 5-HTT VNTR In 2 variants, but 5-HTTLPR/5-HTT rs25531 haplotype might be a useful genetic marker in distinguishing these three clinical groups.

Association between psychopathology and suicidal behavior in schizophrenia. A cross-sectional study of 509 participants.

BACKGROUND Suicide in schizophrenia is a serious problem--ideation rates go up to 40%, and approximately one half of patients attempt suicide at least once. The distinction between attempters and ideators is vital in everyday clinical practice. AIM To explore the association between psychopathology and suicidal behavior in a comparative study of three groups of patients with schizophrenia: suicide ideators, suicide attempters, and subjects without suicide ideation and behavior. METHOD The study included 509 patients: suicide attempters (n = 159), ideators (n = 180), and a comparative group (n = 170). The clinical assessment consisted of a structured psychiatric interview and an evaluation of sociodemographics, suicidality (SIBQ), psychopathology (PANSS), and depression (CDSS). RESULTS Suicide attempters were more depressed than ideators, and both groups had higher CDSS scores than the comparative group. The overall contribution of positive, negative, and general PANSS symptoms was not statistically significant enough to differentiate ideators from attempters. A principal component analysis of the PANSS items revealed five components: disinhibition, withdrawal, anxiety and guilt, reality distortion, and disorganization. Two logistic regression analyses showed that suicide ideation or attempt was significantly related to depression, anxiety, guilt, gender, age, and number of previous hospitalizations. Compared to suicide ideators, attempters were more depressed, had a higher number of previous hospitalizations, and lower education. CONCLUSION The results indicate that clinicians should look for depression, anxiety, and guilt feelings, while positive and negative symptoms seem to be less relevant for suicide assessment in schizophrenia.

Clinical significance of a CYP2D6 poor metabolizer--a patient with schizophrenia on risperidone treatment.

A case of a 46-year-old woman with schizophrenia who was treated with risperidone and followed up for 1 year is reported. She was genotyped as a CYP2D6 poor metabolizer (PM): CYP2D6-4*/*6, which was confirmed by a dextromethorphan (DM) test (metabolic ratio = 5.8). Genotypes of ABCB1 (MDR1) were 2677TT and 3435TT. Because risperidone is CYP2D6 and P-glycoprotein substrate, the patient might have been expected to accumulate risperidone and suffer from significant side effects. However, the patient tolerated the drug extremely well. Plasma concentration of risperidone was 73.2 nmol/L and of 9-OH-risperidone was below the limit of quantitation (6.1 nmol/L). Target range of risperidone plus 9-hydroxyrisperidone is 50-150 nmol/L. During the follow-up, patient was continuously taking 3 mg/day of risperidone. Plasma levels of risperidone and 9-OH-risperidone were 70.2 and 18.1 nmol/L, respectively. We repeated a DM test, metabolic ratio was 3.6, thus confirming that the patient remained a PM. Psychopathology was assessed with Positive and Negative Syndrome Scale, and stable remission of illness was achieved over the stated period. No adverse effects were observed or reported by the patient. We conclude that PM phenotype for CYP2D6 does not necessarily have clinical significance in regard to risperidone treatment. DM and risperidone are both CYP2D6 and P-glycoprotein substrates and significant interactions might occur with both drugs, in parallel with the possible impact of ABCB1 and CYP2D6 polymorphic gene variants.

Psychiatric symptoms in idiopathic intracranial hypertension

IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH) is a medical condition defined by intracranial hypertension without hydrocephalus or brain lesion, usually presented with neurological symptoms. We describe a case of a woman, age 26 years, mother of a 1-year-old child, living with the child’s father, employed and recently promoted, who was diagnosed as IIH after experiencing unspecific neurological and prominent psychiatric symptoms ranging from affective to dissociative spectrum disorders. The patient gave informed consent to the publication of this letter. The first symptoms occurred 1 year before hospital admission, soon after childbirth. She displayed anxiety, depressed mood, loss of energy, decreased pleasure in activities, mood swings with aggressive behavior towards her mother and intensive fear that something bad would happen to the child. She also complained about mild headaches, occasional vomiting and transient visual obscurations. On the day of hospital admission she suddenly began to show inadequate behavior, a trance-like state, with agitation, narrowed awareness, derealization, depersonalization, perseverations, occasional mutism and disorganization behavior characterized by repetitive movements of standing up and sitting, unresponsive to verbal commands. The next day she displayed adequate behavior and was partially amnestic for yesterday’s events describing them as blurred. She complained about vomiting and intensive headaches, resistant to analgesics. Psychiatric evaluation revealed features of borderline and histrionic personality disorder: tendency to overdramatization, theatricality and exaggerated expressions of emotions, affect of predominantly angry nature and impulsivity. Standard laboratory tests, including drug screenings and electroencephalogram were normal. An ophthalmologist diagnosed bilateral chronic papilledema. Multislice computed tomography showed widened cerebrospinal fluid space around the ophthalmic nerves and partial empty sella. After reviewing these findings, the neurologist diagnosed IIH. After acetazolamide was introduced she displayed no more neurological or psychiatric symptoms from that time or during the 1-year follow up period. There are few reports of IIH presenting with psychiatric symptoms: affective, psychotic and dissociative. The underlying mechanisms are unclear. Poor psychosocial functioning in patients with headache, whether of general origin or related to IIH, might suggest that IIH rather facilitate the expression of predisposed psychiatric states than cause them directly. Apart from biological factors, based on this case, we could hypothesize that psychological factors might be important in evaluating IIH. Borderline/histrionic personality traits of our patient and stressful events (e.g. job promotion) are associated with increased susceptibility to affective and dissociative disorders. We believe that underlying IIH might have helped the expression of those symptoms.