Erol Ozan

The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels

OBJECTIVE To determine the effect of BDNF gene val66met polymorphism on serum BDNF levels in drug-free patients with major depressive disorder (MDD) and healthy subjects, that differ by gender. METHODS Sixty-six drug-free patients (19 males+47 females) with non-psychotic MDD and fifty-six healthy controls (18 males+38 females) were recruited. Three-way ANOVA was employed to analyze the effect of mental health status, met-carriage and gender on Hamilton Depression Rating Scale (HDRS) scores and serum BDNF levels, by using the MIXED Procedure (SAS). RESULTS Patients had a lower serum BDNF level than healthy subjects (22.47 vs. 27.49; p<0.0001). Met-carrier patients had a higher HDRS score than Val homozygotes (25.99 vs. 22.99, p<0.02). Serum BDNF level for met-carrier subjects (patients+controls) was lower than Val homozygote subjects (23.08 vs. 26.87; p<0.002). However, there were no effects of two-way interactions of met-carriage and mental health status on HDRS scores and serum BDNF levels. There was no gender effect on HDRS scores in the patients. Overall, male subjects (patients+controls) had a higher serum BDNF level than female subjects (26.87 vs. 23.08; p<0.002). However, there were no effects of two-way interactions of gender with mental health status and met-carriage on serum BDNF levels. CONCLUSIONS We replicated the previous findings of lower serum BDNF levels during depression and in females. In addition, we found that met-carriage had an effect in reducing serum BDNF levels, regardless of gender and depression. Further animal and human studies with a larger sample size should investigate whether BDNF val66met polymorphism could alter brain and serum BDNF levels.

Brain-derived neurotrophic factor, stress and depression: a minireview.

Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family, and is widely expressed in the adult mammalian brain. Besides its well known neuroprotective activity after traumatic brain injury the evidences regarding its activity dependent release by the pathophysiology of major depression are rapidly replicating. Considering the data that stress plays an important role by the development of depression which is characterized with prominent hippocampal cell death, as well as the well known neuroprotective effects of BDNF, we aimed to investigate the link between the BDNF, stress and depression. Thus we prepared a minireview in order to evaluate the neuroprotective role of BDNF by psychiatric disorders which are characterized with prominent neuronal cell death.

Association of the brain-derived neurotrophic factor Val66Met polymorphism with hippocampus volumes in drug-free depressed patients.

Abstract Objectives. Val66Met BDNF gene polymorphism is shown to affect the function of mature BDNF and mature BDNF plays an important role in the hippocampal neurogenesis and neuronal survival. Methods. A relationship of Val66Met BDNF gene polymorphism and hippocampal volumes in 33 MDD patients and 40 healthy controls is investigated. Region of interest analysis was conducted on the images acquired via MRI. Results. Depressed patients had smaller left hippocampal volumes compared to healthy controls. The diagnosis of MDD was not significantly related to hippocampal volumes among Met carriers; however, among Val homozygotes depressed patients had significantly smaller left hippocampal volumes compared to controls. Although both right and left hippocampal volumes showed nearly significant correlation with the duration of illness, this correlation reached (negative) significant levels only in the right hippocampal volume of the Val homozygotes. Conclusions. Val homozygote genotype may serve as a vulnerability factor in MDD regarding hippocampal volume loss. This finding can be considered as a supportive evidence for the neurotrophic factor hypothesis of depression.

Smaller Hippocampus Volume Is Associated with Short Variant of 5-HTTLPR Polymorphism in Medication-Free Major Depressive Disorder Patients

Aim: Serotonin is known for its importance in the pathophysiology of major depressive disorder. Although the hippocampus is one of the key regions in which neurogenesis occurs, and serotonin plays an important role in neurogenesis, results of studies that investigate effect of the 5-HTTLPR polymorphism on hippocampal volumes in major depressive disorder are inconclusive. Method: We looked for a relationship between the 5-HTTLPR polymorphism and hippocampal volumes in 44 depressed patients (mean age ± SD 33.6 ± 9.5 years) and 43 healthy controls (30.4 ± 6.7 years). Region of interest analysis was conducted on the images acquired via MRI. Results: Although hippocampal volumes were similar in healthy and patient groups, there was a significant interaction between genotype and diagnosis on hippocampus volumes. Post-hoc ANCOVA showed that hippocampal volumes of S/S homozygous depressed patients were smaller compared to healthy controls in both hemispheres. Conclusion: The 5-HTTLPR polymorphism has an effect on hippocampal volumes of depressed patients, which is apparent only in S/S genotype. It seems that decreased neurogenesis by effects of reduced serotoninergic transmission may be responsible for smaller hippocampal volumes observed in S/S homozygous depressed patients.

Handedness, eyedness, and hand–eye crossed dominance in patients with schizophrenia: Sex-related lateralisation abnormalities

Schizophrenia is referred to as cerebral lateralisation abnormality. In this study the possible relationships among handedness, eye dominance, and crossed and non-congruent hand–eye dominance in patients with schizophrenia are investigated. A total of 88 patients with schizophrenia and 118 controls were included in the study. The patient group included 60 men and 28 women who ranged in age from 17 to 63 years. Diagnoses were made on the basis of information provided from clinical interviews and Structured Clinical Interview for DSM-IV. Handedness was ascertained by using the Edinburgh Handedness Inventory. Eye dominance was measured only by the near–far alignment test. Patients with schizophrenia had a significantly increased frequency of mixed-handedness and decreased frequency of both right- and left-handedness in comparison with controls. Also, the male patients with schizophrenia had significantly increased frequencies of left eye dominance, crossed hand–eye dominance, and non-congruent hand–eye dominance compared to controls, but not the female patients. Cerebral lateralisation abnormalities in schizophrenia may be associated with sex-related hormonal factors.

No pituitary gland volume change in medication-free depressed patients

Increased serum cortisol levels and a hyperactive hypothalamo-pituitary-adrenal (HPA) axis have been proposed to play an important role in the pathophysiology of Major Depressive Disorder (MDD). However, there are inconsistent results regarding pituitary gland volume (PGV), which is one of the key elements of the HPA axis evaluated by MRI in depressed patients. In this study, we analyzed the PGV of medication-free moderately depressed MDD patients (N=34) and age and sex matched healthy controls (N=39). PGV did not differ between MDD patients and healthy controls [mean volume+/-S.D.; 0.76+/-0.17 cm3 and 0.75+/-0.14 cm3; ANCOVA, F1,69=1.25 p>0.05; respectively]. Our results confirm that volumetric PGV changes are not crucial for depression pathophysiology among unmedicated, moderately depressed adults.

Altered hippocampal formation shape in first-episode depressed patients at 5-year follow-up.

It is generally accepted that patients with major depressive disorder have smaller hippocampus size compared to healthy people. However, it is still not known if this situation exists before the onset of the disease or is a result of the toxic mechanism created by the depression itself. The findings of the long-term follow-up studies of first-episode depressed patients might contribute to solve the ongoing problem. In this study, the hippocampus of 18 first-episode patients who were followed-up for 5 years, were compared with those of healthy controls. There were no volumetric differences among groups neither at the baseline nor after 5 years of follow-up. However, shape analyses, using high dimensional mapping methods, revealed regional structural changes in the head and tail of the hippocampal formation in CA1 and subiculum regions in patients at the follow-up. Furthermore, a significant negative correlation was found with the number of days in depression without antidepressant treatment in the CA1 region in the head and tail of the hippocampal formation bilaterally. The findings of this study support the hypothesis that pathophysiological processes of depression induce structural alterations in depressed patients.

The relationship between the anterior corpus callosum size and prefrontal cortex volume in drug-free depressed patients

INTRODUCTION An evolving literature suggests a volume reduction and a loss of functional integrity of prefrontal cortex in depressed patients. Interhemispheric prefrontal functional integrity is mediated via the anterior portion of the corpus callosum. Until recently interhemispheric fibers connecting prefrontal cortex have not been well defined. In this study, we compared the corpus callosum area of depressed patients with controls using a novel schema proposed by Hofer and Frahm (2006) which defined a specific anterior callosal area for prefrontal interhemispheric fibers. We further investigated the correlation between callosal area and prefrontal cortical volume. METHODS Thirty-six patients with major depressive disorder and thirty-three healthy controls were recruited. All subjects were psychotropic medication-free and right-handed. The imaging was performed on a 1.5T MR unit (Magnetom Vision Siemens). The images obtained from 3D MP-RAGE sequence were used for analyses. Medical Image Processing, Analyzing and Visualization (MIPAV) software was used for callosal and prefrontal measurements. RESULTS Depressed patients had reduced prefrontal cortical volume and a loss of the normal callosal/gray matter correlation, but normal white matter volume and normal callosal areas. LIMITATIONS It is not known if the observed changes were preexisting or acquired. CONCLUSION Our results indicate that the normal structural relationship between anterior callosal area and prefrontal cortical volume is disrupted in major depressive disorder and that the disruption is due to reduced cortical volume rather than to changes in interhemispheric connections.

The Neuroprotective Effect of Olanzapine

Case Report Mr. W is a 50-year-old Caucasian male who underwent a left frontotemporal craniotomy for a cerebral aneurysm originating from the P2 segment of the left posterior cerebral artery. Several months after the surgery, he developed major depression for which he was treated with escitalopram. As there was minimal improvement of his symptoms he was referred to the Johns Hopkins Brain Injury Clinic. His family history was significant for bipolar disorder in one brother and major depression in another brother. Prior to the brain surgery, Mr. W had never been diagnosed with psychiatric or medical problems. On cognitive testing, he scored 25 on the Mini-Mental State Examination, losing three points on recall, one on repetition of a sentence, and one on copying the intersecting pentagons. We increased the dose of escitalopram from 10 to 20 mg and recommended weekly psychotherapy. His mood stabilized temporarily, but he returned almost 2 years later with several days’ history of elated mood, increased energy, poor sleep, and racing thoughts. On the Young Mania Rating Scale, he scored 16. The dose of escitalopram was reduced to 10 mg and he was started on divalproex sodium, 500 mg/day, which was quickly increased to 1000 mg/day. Once again on this regimen, his mood symptoms stabilized. He remained euthymic for the next several months. During a follow-up evaluation almost a year later, he was started on donepezil, 5 mg, for inattention and short-term memory problems. Three weeks later, he presented with hypomanic symptoms which had begun after the initiation of donepezil. He scored 15 on the Young Mania Rating Scale. Donepezil was stopped with complete resolution of hypomanic symptoms and decreased his score on the Young Mania Rating Scale to 2.

Challenges in Diagnosing and Adequately Treating Malignant Catatonia and Its Fatal Consequences

To the Editor: Catatonia may often present with puzzling symptoms and etiologies that can delay adequate and timely treatment, increasing the risk of mortality. When accompanied with hyperthermia and autonomic instability, it is called malignant catatonia (MC). When preceded by antipsychotic use, catatonia is usually termed and treated as neuroleptic malignant syndrome (NMS), which is regarded as a variant of MC. The case below inspired us to highlight the challenges in diagnosing and adequately treating MC and its fatal consequences. An 82-year-old man with Bipolar-I disorder (BD) consulted in the Neurology-ICU for failure to respond to an adequate trial of bromocriptine (7.5 mg/day for 20 days) administered as a hospital practice, depending on the provisional diagnosis of olanzapineinduced NMS. Reportedly, he was taken to ER and then transferred to the Neurology-ICU with acute-onset insomnia, fever (38.5°C), excessive sweating, hypertension (140/90 mmHg), tachycardia (105 bpm), diffuse rigidity, elevated serum-CPK, and delirium state marked by fluctuating consciousness and lying naked on the floor with extreme resistance to being moved. Head injury, metabolic disorders, seizures, infections, and intoxication were all excluded with comprehensive history and labs. His BD was in remission for 6 months with valproate sodium 1,000 mg/day and olanzapine 5 mg/day. However, he had discontinued both medications 1 week before admission. Clinical history and bedside examination that revealed diffuse rigidity and immobility associated with disturbances in thought, mood, and vigilance suggested catatonia, and accompanying hyperthermia and autonomic instability suggested MC. The retarded/ stuporous variant of catatonia was predominant throughout the entire hospital stay, although he sometimes displayed several signs of the excited form, as reported. We reformulated the phenomena by considering the following diagnostic elements: First, discontinuation of olanzapine 1 week before admission would significantly reduce the possibility of NMS, which should have been considered at intake. Second, he failed to respond to an adequate trial of bromocriptine, a specific treatment for NMS. Therefore, on the 21st day of MC, we initiated lorazepam 5 mg/day and increased it to 12.5 within a few days. We preferred lorazepam because of its ease of administration, wide margin of safety, fast response, the absence of cardiovascular challenge even at high doses, unlike ECT, the fact that there is no need for anesthesia, and that it is less stigmatizing than ECT. We maintained an adequate trial of lorazepam for 28 days, with little improvement in catatonia. We decided to administer ECT for its efficacy in relieving MC where benzodiazepines have failed (a response rate of 89% to ECT, 40% to benzodiazepines), but we could not. The patient died of aspiration pneumonia developed during stuporous exhaustion. We took several lessons from this case. Hierarchy of treatment selection in catatonia should consider all variants and etiologies. Although benzodiazepines and ECT can treat both malignant and non-malignant catatonia, bromocriptine is peculiar to NMS, that is, neuroleptic-induced MC. To satisfy all needs with one deed, ECT can be the first-choice treatment in life-threatening catatonic states due to restriction of oral intake, having breached the malignancy threshold, and long duration of catatonia that predicts poor response to benzodiazepines, and that it can quickly relieve catatonia, accompanying delirium, and the underlying psychiatric disorder.