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    Clinical potential of cariprazine in the treatment of acute mania
    (2013) Altınbaş, Kürşat; Gülöksüz, Sinan; Oral, E. Timuçin
    Cariprazine (RGH-188, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]- ethyl}-N,N-dimethylcarbamoyl-cyclohexyl-Amine hydrochloride), is a novel antipsychotic with dopamine D2 and D3 receptors antagonist-partial agonist properties. Cariprazine has also moderate affinity for serotonin 5-hydroxytryptophan (5-HT) 1A receptors, high affinity for 5-HT1B receptors with pure antagonism and low affinity for 5-HT2A receptors. Randomized, double blind, placebo controlled, flexible-dose (3-12 mg/day) studies have demonstrated cariprazine is effective in both schizophrenia and acute manic episodes associated with bipolar disorder. The incidence of serious adverse events in cariprazine arm was no different than in placebo arm in these studies. The most common adverse events were extrapyramidal symptoms, headache, akathisia, constipation, nausea, and dyspepsia which can be explained with cariprazine's partial dopamine agonism. Although cariprazine treatment was associated with a higher incidence of treatmentemergent adverse events, particularly akathisia and tremor, common side effects of marketed second generation antipsychotics such as weight gain, metabolic disturbances, prolactin increase or QTc prolongation were not associated with cariprazine, probably due to its moderate to low binding affinity for histamine H1 and 5-HT2C receptors. Animal studies show that cariprazine may have additional therapeutic benefit on impaired cognitive functioning with D3 receptor activity, however clinical data is still scarce. The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date. © Medicinska naklada - Zagreb, Croatia.
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    Cytokine levels in euthymic bipolar patients
    (2010) Gülöksüz, Sinan; Aktaş, Çetin E.; Çetin, Turan; Deniz, Günnur; Oral, E. Timuçin; Nutt, David J.
    Background: The pathophysiology of bipolar disorder is not thoroughly understood. Several studies have investigated the possible role of cytokines in psychiatric disorders, based on their role in neuro-immune modulation; however, findings in studies on bipolar disorder remain limited and contradictory, and most studies have focused on either manic or depressive episodes. These studies suggest that both manic and depressive episodes could be pro-inflammatory states. The present study aimed to determine whether there are enduring differences in cytokine levels-unrelated to the effects of medication-between euthymic bipolar patients and healthy controls. Methods: The study included 31 euthymic bipolar patients-16 medication-free (MF) and 15 on lithium monotherapy (LM) and 16 healthy volunteers in whom serum cytokine levels were measured. The 3 groups were homogenous in terms of age, gender, and ethnicity. IFN-?, TNF-?, IL-2, IL-4, IL-5, and IL-10 levels were measured in all groups using flow cytometry. Results: There were no differences in cytokine levels between MF euthymic bipolar patients and healthy controls. TNF-? and IL-4 levels in LM euthymic bipolar patients were higher than in both the MF euthymic bipolar patients and controls. Limitations: The small and strictly selected study sample could limit the generalizability of the findings. Conclusions: Cytokine production in MF euthymic bipolar patients was similar to that in healthy controls. The present study shows that the pro-inflammatory state resolves in euthymia and that lithium had an influence on the cytokine profile, which could create a confounding factor while investigating disease- related immunopathology of bipolar disorder. © 2010 Elsevier B.V. All rights reserved.
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    Evidence for an association between tumor necrosis factor-alpha levels and lithium response
    (2012) Gülöksüz, Sinan; Altınbaş, Kürşat; Aktaş, Çetin E.; Kenis, Gunter; Bilgiç Gazioğlu, Sema; Deniz, Günnur; Os, J. Van
    Background: The role of inflammation in bipolar disorder has recently emerged as a potential pathophysiological mechanism. Tumor necrosis factor-alpha (TNF-?) modulation may represent a pathogenic molecular target and a biomarker for staging bipolar disorder. In this context, the possible association between lithium response and TNF-? level was examined. Methods: Sixty euthymic bipolar patients receiving lithium therapy were recruited for assessment of TNF-? level. The ALDA lithium response scale (LRS) was used to evaluate longitudinal lithium response in bipolar patients, using cut-offs of poor response, partial response and good response. TNF-? level was assessed using enzyme-linked immunosorbent assay. Results: There was a significant increase in TNF-? level in patients with poor lithium response compared to those with good response, also after controlling for a range of potential confounders (adjusted effect size: 0.47, p=0.011). Partial response showed a directionally similar, but attenuated and statistically inconclusive association (adjusted effect size: 0.16, p=0.326). Limitations: Assessment of response was retrospective and natural course cannot be separated easily from treatment response in an observational design. Selection of additional inflammatory markers could provide for a better understanding of underlying immune changes. Conclusions: This study strengthens the hypothesis that TNF-? level may mark or mediate lithium response, and that continuous immune imbalance in poor lithium responders may occasion treatment resistance. Further investigation of immune alterations in treatment-resistant bipolar patients may be productive. © 2012 Elsevier B.V.
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    If Kraepelin was still alive would dichotomy still survive?
    (Kare Publishing, 2011) Alt?nbaş, Kürşat; Tunç, Serhat; Yazar, Menekşe S?la; Özçetinkaya, Serap; Gülöksüz, Sinan; Oral, Esat Timuçin
    Emil Kraepelin's dichotomy, which has been providing a basis for psychiatric classification, has been valid for many years. However, dimensional approaches based on the recent evidences from genetic, biological and clinical researches are in agreement, putting forth the need of this dichotomous view's revision for consideration. In particular, failure of describing many of the psychiatric cases in nature with descriptive paradigm used for psychiatric classification in clinical practice hinders clinicians' effort for developing a common language and leads to the questioning of psychiatric diagnoses' stability. In fact, it has been stated that the descriptive validity was low in the patient group with both psychotic and affective symptoms. It has also been informed that bipolar disorder and schizophrenia were presented with common symptom clusters in the studies evaluating the patterns of clinical symptom clustering with factor analysis. Moreover, some of the candidate genes developing susceptibility for each disorder have been shown to be common in the recent genetic studies, suggesting there is an overlap between these disorders. It appears that dimensional approach suggested by geneticists is consistent with the data from clinical researches. In the light of these clinical and genetic evidences, famous German scientist Emil Kraepelin's ground-breaking dichotomous approach in psychiatry should be revised after a century. Who knows if Kraepelin was still alive, maybe he would change his dichotomous view after a while.
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    Kraepelin bugün yaşasaydı dikotomi varlığını sürdürüyor olur muydu?
    (2011) Altınbaş, Kürşat; Tunç, Serhat; Yazar, Menekşe Sıla; Özçetinkaya, Serap; Gülöksüz, Sinan; Oral, Esat Timuçin
    Emil Kraepelin’in psikiyatrik sınıflandırma sistemlerinin temelini oluşturan dikotomisi, uzun yıllardır geçerliliğinisürdürmektedir. Öte yandan, genetik, biyolojik ve klinik araştırmalardan elde edilen güncel kanıtlara dayanarakönerilen boyutsal modellemelerin benzerlik göstermesi bu dikotomik görüşün gözden geçirilme gerekliliğiniortaya koymaktadır. Özellikle klinik pratikte, psikiyatrik tanı sistemlerinde kullanılan tanımlayıcı (descriptive)paradigma ile doğada görülen azımsanmayacak sayıdaki psikiyatrik olgunun yeterince iyi tanımlanamaması,klinisyenlerin ortak dil geliştirme gayretlerini engellemekte ve psikiyatrik tanıların stabilitesinin sorgulanmasınaneden olmaktadır. Nitekim, psikotik ve duygudurum belirtilerinin bir arada görüldüğü hasta grubunda tanısalgeçerliliğin oldukça düşük olduğu bildirilmektedir. Bununla birlikte, klinik belirtilerin kümelenme şekillerinifaktör analizi ile değerlendiren çalışmalarda, bipolar bozukluk ve şizofreninin belirli oranlarda ortak belirtikümelerini gösterdiği bildirilmektedir. Ayrıca güncel genetik araştırmalarda her iki hastalığa özgü yatkınlıkoluşturan aday genler olduğu gösterilmekle birlikte, bazı ortak aday genlerin paylaşıldığı ve bir çakışmanın(overlap) olduğu öne sürülmektedir. Genetikçilerin önerdiği boyutsal yaklaşım, klinik araştırmalardan eldeedilen bilgilerle uyumlu gözükmektedir. Tüm bu klinik ve genetik kanıtlar ışığında, ünlü Alman bilim adamı EmilKraepelin’in psikiyatride çığır açan dikotomik yaklaşımının bir asır sonra gözden geçirilmesi gerekmektedir. Kimbilir Kraepelin günümüzde yaşasaydı, belki de kendi modelini bir süre sonra değiştirecekti.
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    Minor hemoglobins HbA2 and HbF associate with disease severity in bipolar disorder with a likely protective role of HbA2 against post-partum episodes
    (Elsevier B.V., 2013) İnce, Bahri; Gülöksüz, Sinan; Altınbaş, Kürşat; Oral, E. Timuçin; Alpkan, Latif Ruhşat; Altınöz, Meriç A.
    Background: There exist studies indicating that bipolar disorder (BD) associates with changes in brain blood flow. Human brain with its high demand to oxygen constitutes 2% of the total body weight, while it receives 20% of cardiac output. and 3 globin chains of hemoglobin were recently found in neural tissues, yet no study has questioned blood hemoglobins in BR Methods: A total of 120 euthymic BD patients (40 males and 80 females) were analyzed via high performance liquid chromatography (HPLC) to measure minor hemoglobin levels, which were statistically compared with disease characteristics. Results: Minor hemoglobins HbA2 and HbF associated positively with episode density as a measure of disease severity in BR An increased level of HbA2 meant significantly less postpartum episodes in child bearing women. HbF levels were higher in patients with a positive family history of any psychotic disorder. Sum of HbA2 and HbF correlated with episode density with a stronger significance (p <0001) supporting intermittent hypoxia hypothesis in BR Limitations: The study was conducted only on euthymic patients to avoid likely bigger exogenous effects such as electro-convulsive therapy and diverse drug regimes, yet larger comparative studies are needed to support our current findings. Conclusions: Higher HbA2 and HbF in more severe bipolar disorder may be compensations against intermittent hypoxias in BR HbA2 increases following myocardial angina and in mountain dwellers, which may indicate protective roles in extreme conditions. HbF increase may act more as a maladaptation or emerge via haplotypal associations of BD genes and gamma-globin locus at II p155. © 2013 Elsevier B.V. All rights reserved.
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    Yaratıcılık ve İki Uçlu Bozukluk
    (2014) Maçkalı, Zeynep; Gülöksüz, Sinan; Oral, Timuçin
    Yaratıcılık ve psikopatoloji arasındaki ilişki antik dönemlerden bu yana ilgi çekici bir konudur. Yaratıcı kişilerin özelliklerinin betimlendiği in- celemelerin ardından yirminci yüzyılın son çeyreğine denk gelen dö- nemden itibaren araştırmacılar duygudurum bozuklukları ve yaratıcılık arasındaki ilişkiyi inceleyen çalışmalar yapmaya başlamışlardır. Başlan- gıçta çalışmalar sanatçıların biyografik metinlerine dayandırılmış ve elde edilen bulgular yaratıcılık ve psikopatoloji arasında ilişki olabileceğini işaret etmiştir. Geriye dönük incelemelerin kısıtlılıkları araştırmacıları bu alanda sistematik çalışmalar geliştirmeye yöneltmiştir. Sanatsal yara- tıcılığa odaklanan sistematik çalışmalarda gerek duygudurum bozukluk- larının yaygınlığı, gerekse yaratıcılık süreci incelenmiştir. Bir grup çalış- macı ise bu ilişkiyi afektif mizaçlar bağlamında ele almışlardır. Doksanlı yılların sonuna doğru yaratıcılığın kapsamı genişletilmiş ve gündelik yaratıcılık kavramı ortaya atılmıştır. Bu tanımlamanın ortaya çıkması, araştırmacıları sıradan (sanatçı olmayan) bireylerde yaratıcı sürecin bile- şenlerini incelemeye yönlendirmiştir. Bu derlemede ise öncelikle yaratı- cılık ve yaratıcı sürecin tanımlamalarından bahsedilmiş, ayrıca iki uçlu bozukluk açısından yaratıcı süreç irdelenmiştir. Daha sonra yaratıcılık ve iki uçlu bozukluk arasındaki ilişki mevcut çalışmalar (biyografik, sis- tematik, psikobiyografik ve afektif mizaçlar) ışığında değerlendirilmiştir. Ayrıca yaratıcılık ve psikopatoloji arasındaki bağlantıyı açıklamak üzere geliştirilen yeni bir model olarak Paylaşılmış Yatkınlık Modeli de tanı- tılmıştır. Son olarak, araştırmaların yöntemsel kısıtlılıkları, bu kısıtlılık- ları gidermeye yönelik önerilere yer verilmiştir.