Changes in brain metabolites measured with magnetic resonance spectroscopy in antidepressant responders with comorbid major depression and posttraumatic stress disorder [Promjene razina moždanih metabolita mjerenih magnetskom rezonantnom spektroskopijom u ispitanika s komorbiditetom depresije i posttraumatskog stresnog poremećaja koji su odgovorili na antidepresivno liječenje]

In a present pilot study, performed on 11 subjects, we studied proton magnetic resonance spectroscopy (1H-MRS) changes in early to intermediate (3-6 weeks) responders to antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs). All subjects had diagnosis of major recurrent depression comorbid to posttraumatic stress disorder (PTSD). Magnetic spectroscopy was done in the region of dorsolateral prefrontal cortex on a 3T MRI-unit. Participants were selected out of the larger sample due to an early response to antidepressant treatment within 3–6 weeks, measured with Beck Depression Inventory (BDI). We measured levels of neuronal marker N-acetyl-aspartate (NAA), choline (CHO) and creatine (Cr). There was no difference in NAA/Cr ratios between the first and the second spectroscopic scans (p=0.751). However, CHO/Cr ratios showed increasing trend with mean value at the first scan of 1.09 (SD=0.22) while mean value at second scan was 1.25 (SD=0.24), displaying statically significant difference (p=0.015). In conclusion, significant increase in choline to creatine ratio from the first to the second spectroscopic scan during the antidepressant treatment, compared to almost identical values of NAA to creatine ratio, suggests increased turnover of cell membranes as a mechanism of the early response to the antidepressant drug therapy

Neuroimaging research in posttraumatic stress disorder – focus on amygdala, hippocampus and prefrontal cortex

Neuroimaging research reflects the complexity of post-traumatic stress disorder and shares some common difficulties of post-traumatic stress disorder research, such as the different classifications of the disorder over time, changes in diagnostic criteria, and extensive comorbidities, as well as precisely delineated and prevailing genetic and environmental determinants in the development of the disorder and its clinical manifestations. Synthesis of neuroimaging findings in an effort to clarify causes, clinical manifestations, and consequences of the disorder is complicated by a variety of applied technical approaches in different brain regions, differences in symptom dimensions in a study population, and typically small sample sizes, with the interplay of all of these consequently bringing about divergent results. Furthermore, combinations of the aforementioned issues serve to weaken any comprehensive meta-analytic approach. In this review, we focus on recent neuroimaging studies and those performed on larger samples, with particular emphasis on research concerning the amygdala, hippocampus, and prefrontal cortex, as these are the brain regions postulated by the core research to play a prominent role in the pathophysiology of post-traumatic stress disorder. Additionally, we review the guidelines for future research and list a number of new intersectional and cross-sectional approaches in the area of neuroimaging. We conclude that future neuroimaging research in post-traumatic stress disorder will certainly benefit from a higher integration with genetic research, better profiling of control groups, and a greater involvement of the neuroimaging genetics approach and from larger collaborative studies

Changes in Brain Metabolites Measured with Magnetic Resonance Spectroscopy in Antidepressant Responders with Comorbid Major Depression and Posttraumatic Stress Disorder

In a present pilot study, performed on 11 subjects, we studied proton magnetic resonance spectroscopy (1H-MRS) changes in early to intermediate (3-6 weeks) responders to antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs). All subjects had diagnosis of major recurrent depression comorbid to posttraumatic stress disorder (PTSD). Magnetic spectroscopy was done in the region of dorsolateral prefrontal cortex on a 3T MRI-unit. Participants were selected out of the larger sample due to an early response to antidepressant treatment within 3–6 weeks, measured with Beck Depression Inventory (BDI). We measured levels of neuronal marker N-acetyl-aspartate (NAA), choline (CHO) and creatine (Cr). There was no difference in NAA/Cr ratios between the first and the second spectroscopic scans (p=0.751). However, CHO/Cr ratios showed increasing trend with mean value at the first scan of 1.09 (SD=0.22) while mean value at second scan was 1.25 (SD=0.24), displaying statically significant difference (p=0.015). In conclusion, significant increase in choline to creatine ratio from the first to the second spectroscopic scan during the antidepressant treatment, compared to almost identical values of NAA to creatine ratio, suggests increased turnover of cell membranes as a mechanism of the early response to the antidepressant drug therapy

Comparison of Hippocampal Volumes in Schizophrenia, Schizoaffective and Bipolar Disorder

The reduction of hippocampal volume was frequently reported in schizophrenia, but not in bipolar disorder. This volume reduction is associated with clinical features of schizophrenia, in particular with working and verbal memory impairments. Schizoaffective disorder, as a specific disorder sharing clinical features of both schizophrenia and bipolar disorder is rarely analyzed as a separate disorder in neurobiological studies. The aim of this study was to compare hippocampal volumes in separate groups of patients with schizophrenia, schizoaffective and bipolar disorder. Hippocampal volumes were estimated using high resolution magnetic resonance imaging in 60 subjects, 15 subjects in each patient and one healthy volunteer (control) group. There were no significant differences in hippocampal volume between bipolar disorder and control group. Hippocampal volume was statistically significantly reduced in the group of patients with schizophrenia and schizoaffective disorder, compared to either bipolar disorder or control group, thus supporting the hypothesis that hippocampal volume reduction could be considered as a possible neurobiological basis for clinical aspects of schizophrenia and schizoaffective disorder associated with working and verbal memory impairment

Correlation of therapeutic response with changes in 1H-MRS findings in treatment of depression

Depresija je najčešći psihijatrijski poremećaj sa životnom prevalencijom od preko 10% i povezan je s visokom stopom suicida. Metoda prvog izbora farmakološkog liječenja unutar skupine antidepresiva su selektivni inhibitori ponovne pohrane serotonina (SIPPS), a terapijski odgovor se najčešće opaža tek nakon 4-6 tjedana. Nisu ustanovljeni pouzdani biološki markeri ranog prepoznavanja ili korelacije s kliničkim terapijskim odgovorom. Najčešće korištene ocjenske ljestvice u kliničkoj praksi su Montgomery-Åsbergova ljestvica (MADRS) i Hamiltonova ocjenska ljestvica za depresiju (HAM-D). Konzervativnim pristupom se pozitivnim terapijskim odgovorom smatra smanjenje ukupnog zbroja na MADRS od najmanje 50%. Spektroskopija protonskom magnetskom rezonacijom (1H-MRS) je ne-ionizirajuća radiološka metoda koja omogućuje višekratne procjene u kraćem vremenskom razdoblju i jedina je metoda koja omogućuje in vivo prepoznavanje razina metabolita u mozgu. Cilj je istraživanja bio prepoznati korelate kliničkog terapijskog odgovora kod depresije s parametrima mjerenim putem spektroskopije magnetskom rezonancijom, a posebno razine kolina (Cho) u amigdali (AMYG). Istraživanje je uključivalo i druge neurometabolite: N-acetil-aspartat (NAA), kompleks glutamin/glutamat/GABA koji se na 1H-MRS očituje kao Glx vrh, mioinozitol (MI) i kreatin (Cr) koji se zbog svoje relativne stabilne razine smatra referentnim parametrom za određivanje razine pojedinog metabolita. Uz AMYG, druga područja mozga od interesa (ROI) uključivala su dorzolateralni prefrontalni korteks (DLPFC), bazalne ganglije (BG), prednji cingularni korteks (ACC) i hipokampus (HIPPO). Istraživanje je provedeno na skupini od 59 ispitanika (36 žena i 23 muškarca) koji su u početku istraživanja udovoljavali kliničkim kriterijima depresivnog poremećaja prema DSM-IV, prosječne dobi od 29,4 godine (SD = 7,4), u rasponu od 18,4 godine do 42,5 godina. Mjerenja razina neurometabolita putem 1H-MRS na 3T učinjena su na početku istraživanja, prije započinjanja antidepresivne terapije, i nakon 8 tjedana liječenja. U početnim razinama Cho u AMYG nisu ustanovljene značajne razlike između skupine ispitanika s pozitivnim terapijskim odgovorom i skupine kod koje nije postignut očekivani terapijski odgovor. Analizom mješovitim linearnim modelom (LMM) ustanovljena je negativna korelacija razine Cho sa stupnjem depresivne simptomatike nakon 8 tjedana antidepresivne terapije SIPPS. LMM analiza upućuje na značajnu povezanost poboljšanja simptomatike mjerene promjenom ukupnog zbroja na MADRS s efektima Cho (1.48, p = 0.036), vremena liječenja (-11.53, p < 0.001) i promjene Cho izražene interakcijom Cho i vremena istraživanja (-1.95, p = 0.044). Razina Cho na kraju istraživanja bila je značajno viša kod ispitanika kod kojih je postignut pozitivni terapijski odgovor. Rezultati istraživanja upućuju da je razina Cho mjerena 1H-MRS objektivni korelat kliničke procjene terapijskog odgovora mjerenog putem MADRS, uz značajan inter-individualni varijabilitet u razinama Cho. Razlike po spolu nisu opažene. Prediktivna valjanost Cho nije potvrđena. Ponovljenim rezultatima na većim skupinama ispitanika, uz češća objektivna vrednovanja putem 1H-MRS i dužim longitudinalnim praćenjem, bilo bi moguće pouzdanije utvrditi korelacijski potencijal Cho mjerenog 1H-MRS kao objektivnog parametra u praćenju terapijskog odgovora.Depression is the most common psychiatric disorder with a lifetime prevalence of over 10% and is a disorder associated with a high suicide rate. The method of first choice of pharmacological treatment within the group of antidepressants is selective serotonin reuptake inhibitors (SSRI). The therapeutic response is usually observed only after 4-6 weeks. No reliable biological markers for early recognition or correlation with clinical therapeutic response have been established. The most commonly used rating scales in clinical practice are the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D). Conservatively, a positive therapeutic response is considered a reduction of the total sum on the MADRS of at least 50%. Proton magnetic resonance spectroscopy (1H-MRS) is a non-ionizing radiological method that enables multiple assessments in a shorter period of time and is the only method that allows in vivo recognition of metabolite levels in the brain. The aim of the research was to identify the correlations of clinical therapeutic response in depression with parameters measured by magnetic resonance spectroscopy, and especially choline (Cho) levels in the amygdala (AMYG). The research also included other neurometabolites: N-acetyl-aspartate (NAA), the glutamine/glutamate/GABA complex which appears on 1H-MRS as a Glx peak, myoinositol (MI) and creatine (Cr), which is considered a reference for determining the level of an individual metabolite due to its relatively stable level parameter. In addition to the amygdala, other brain regions of interest (ROIs) included the dorsolateral prefrontal cortex (DLPFC), basal ganglia (BG), anterior cingulate cortex (ACC), and hippocampus (HIPPO). The research was conducted on a group of 59 subjects (36 women and 23 men) who, at the beginning of the study, met the clinical criteria for a depressive disorder according to DSM-IV, with an average age of 29.4 years (SD = 7.4), in the range of 18.4 years to 42.5 years. Neurometabolite levels were measured by 1H-MRS at 3T at the beginning of the study, before starting antidepressant therapy, and after 8 weeks of treatment. No significant differences were found in the initial levels of Cho in AMYG between the group of subjects with a positive therapeutic response and the group in which the expected therapeutic response was not achieved. A linear mixed models (LMM) analysis revealed a negative correlation of Cho level with the degree of depressive symptoms after 8 weeks of SSRI antidepressant therapy. LMM analysis indicates a significant association of improvement in symptoms measured by the change in the total score on the MADRS with the effects of Cho (1.48, p = 0.036), treatment time (-11.53, p < 0.001) and the change in Cho expressed by the interaction of Cho and research time (-1.95, p = 0.044). The level of Cho at the end of the study was significantly higher in subjects who achieved a positive therapeutic response. Research results suggest that Cho level measured by 1H-MRS is an objective correlate of clinical assessment of therapeutic response measured by MADRS, with significant inter-individual variability in Cho levels. No gender differences were observed. The predictive validity of Cho has not been confirmed. Repeated results on larger groups of subjects, with more frequent objective evaluations by 1H-MRS and longer longitudinal follow-up, would make it possible to more reliably determine the correlation potential of Cho measured by 1H-MRS as an objective parameter in monitoring the therapeutic response

Comparison of hippocampal volumes in schizophrenia, schizoaffective and bipolar disorder [Usporedba volumena hipokampusa u shizofreniji, shizoafektivnom i bipolarnom poremećaju]

The reduction of hippocampal volume was frequently reported in schizophrenia, but not in bipolar disorder. This volume reduction is associated with clinical features of schizophrenia, in particular with working and verbal memory impairments. Schizoaffective disorder, as a specific disorder sharing clinical features of both schizophrenia and bipolar disorder is rarely analyzed as a separate disorder in neurobiological studies. The aim of this study was to compare hippocampal volumes in separate groups of patients with schizophrenia, schizoaffective and bipolar disorder. Hippocampal volumes were estimated using high resolution magnetic resonance imaging in 60 subjects, 15 subjects in each patient and one healthy volunteer (control) group. There were no significant differences in hippocampal volume between bipolar disorder and control group. Hippocampal volume was statistically significantly reduced in the group of patients with schizophrenia and schizoaffective disorder, compared to either bipolar disorder or control group, thus supporting the hypothesis that hippocampal volume reduction could be considered as a possible neurobiological basis for clinical aspects of schizophrenia and schizoaffective disorder associated with working and verbal memory impairment

1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer’s disease [1-H MRS promjene u dorzolateralnom prefrontalnom korteksu nakon primjene donepezila u pacijenata s blagim i umjerenim oblicima Alzhemierove bolesti]

Magnetic resonance spectroscopy (MRS) noninvasively provides information on the concentration of some cerebral metabolites in vivo. Among those measurable by proton magnetic resonance spectroscopy (1H-MRS), N-acetyl-aspartate (NAA) is decreased, and myo-inositol (mI) and choline (Cho) levels are increased in patients with Alzheimer’s disease (AD). Donepezil, an acetylcholinesteraze inhibitor, has proven effect on cognitive symptoms in patients with AD. In previous studies, treatment response was associated with an increase of NAA and NAA/Cr in the parietal lobe and hippocampi. Correlation of longitudinal changes of 1H-MRS detectable metabolites in dorsolateral prefrontal cortex (DLPFC) with clinically observable changes is a poorly researched topic. The objective of this non-interventional study is to assess whether changes in 1H-MRS measurable metabolites correlate with clinical outcome after donepezil treatment. Twelve patients with mild to moderate AD were evaluated during 26 weeks of donepezil treatment. 1H-MRS parameters in DLPFC were assessed before and after 26 weeks of donepezil treatment. Cognition was assessed with Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog). A significant increase in NAA/Cr ratio and significantly lower decrease in mI/Cr ratio were found in AD patients with positive treatment response. The results of this study indicate possible modest donepezil effect on prevention of neuronal functional deterioration in DLPFC which correlates with clinical outcome and point the use of 1HMRS as technique of help in assessment of drug effect

The effect of atypical antipsychotics on brain N-acetylaspartate levels in antipsychotic-naïve first-episode patients with schizophrenia: a preliminary study

PURPOSE: To investigate the correlates of a clinical therapeutic response by using the parameters measured by proton magnetic resonance spectroscopy after the administration of atypical antipsychotics. ----- PATIENTS AND METHODS: Twenty-five antipsychotic-naïve first-episode patients with schizophrenia were monitored for 12 months. The patients were evaluated using (1)H magnetic resonance spectroscopy in the dorsolateral prefrontal cortex and Positive and Negative Syndrome Scale, Clinical Global Impression Scale of Severity, Tower of London - Drexel University, Letter-Number Span Test, Trail Making Test A, and Personal and Social Performance Scale. They were administered atypical antipsychotics, starting with quetiapine. In the absence of a therapeutic response, another antipsychotic was introduced. ----- RESULTS: After 12 study months, the N-acetylaspartate/creatine (NAA/Cr) level did not significantly change at the whole-group level. Additional analysis revealed a significant rise in the NAA/Cr level in the study group that stayed on the same antipsychotic throughout the study course (P=0.008) and a significant drop in NAA/Cr in the study group that switched antipsychotics (P=0.005). On the whole-group level, no significant correlations between NAA/Cr values and other scores were found at either baseline or after 12 study months. ----- CONCLUSION: One-year treatment with atypical antipsychotics administered to antipsychotic-naïve patients didn't result in a significant rise in the NAA/Cr ratio. However, a significant rise was witnessed in the study group in which a satisfactory therapeutic response had been achieved with a single antipsychotic administration

No change in N-acetyl aspartate in first episode of moderate depression after antidepressant treatment: (1)H magnetic spectroscopy study of left amygdala and left dorsolateral prefrontal cortex

BACKGROUND: The role of brain metabolites as biological correlates of the intensity, symptoms, and course of major depression has not been determined. It has also been inconclusive whether the change in brain metabolites, measured with proton magnetic spectroscopy, could be correlated with the treatment outcome. ----- METHODS: Proton magnetic spectroscopy was performed in 29 participants with a first episode of moderate depression occurring in the left dorsolateral prefrontal cortex and left amygdala at baseline and after 8 weeks of antidepressant treatment with escitalopram. The Montgomery-Asberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory were used to assess the intensity of depression at baseline and at the endpoint of the study. At endpoint, the participants were identified as responders (n=17) or nonresponders (n=12) to the antidepressant therapy. ----- RESULTS: There was no significant change in the N-acetyl aspartate/creatine ratio (NAA/Cr) after treatment with antidepressant medication. The baseline and endpoint NAA/Cr ratios were not significantly different between the responder and nonresponder groups. The correlation between NAA/Cr and changes in the scores of clinical scales were not significant in either group. ----- CONCLUSION: This study could not confirm any significant changes in NAA after antidepressant treatment in the first episode of moderate depression, or in regard to therapy response in the left dorsolateral prefrontal cortex or left amygdala. Further research is necessary to conclude whether NAA alterations in the first episode of depression could possibly be different from chronic or late-onset depression, and whether NAA alterations in stress-induced (reactive) depression are different from endogenous depression. The potential role of NAA as a biomarker of a treatment effect has yet to be established

Correlation of Cognitive Functions with some Aspects of Illness, Treatment and Social Functioning in Recurrently Hospitalized Schizophrenic Patients

Cognitive deficits are found to be contributors to poorer psychosocial functioning, rehabilitation outcome and lack of treatment success in schizophrenia. Aim of the study was to examine correlation of cognitive functions with some aspects of illness, treatment and social functioning in a group of recurrently hospitalized schizophrenic patients (N=60). Deficient results on psychomotor processing speed, verbal fluency and verbal learning correlated with the longer duration of illness, higher number of hospitalizations and shorter duration of regular antipsychotic treatment. Deficient results on verbal fluency correlated with the younger age of onset, poor functional autonomy and organizational skills, whereas deficient results on psychomotor processing and verbal learning correlated with poor organizational skills alone. Score on verbal fluency was predictive of social skills impairment, whereas score on psychomotor processing was predictive of functional autonomy and organizational skills impairment. Functioning of different cognitive domains could be predictive of functioning in different social domains. Interplay of specific cognitive deficit and social functioning could be responsible for recurrent hospitalizations and unfavorable treatment choices