Comparing achievements of medical graduates in an alternative unique pre-medical track vs regular medical track.

Objectives: To evaluate the association between the achievements of medical students and whether they were admitted via the pre-medical track or the regular direct track. Methods: We performed a comparative retrospective data study using data from a three-year experimental cohort in a six-year medical school. We analyzed the academic achievements of all students admitted at one Israeli medical school between 2013-2015, either directly to the six-year program or via a pre-medical track. We compared averages of both yearly final grades and final medical examinations grades between the two groups. Descriptive statistics were calculated and differences between groups were evaluated using multivariate analysis. Results: Of the 324 students included in the study, 65 (20.1%) were enrolled in all three cohorts of the pre-medical track. Age and Gender distribution were nearly similar for both tracks. For the first two cohorts, the average final grades of year one of pre-medical students were significantly higher than those of regular direct track (F=(3,167) 6.10, p=0.001), but the opposite was true for the third cohort (F=(3,110)2.38, p=0.073). No further statistically significant differences were found neither between the groups in their final exams grades nor between choosing a MD/PhD optional track and admission pathway. Conclusions: Our results suggest promising achievements with the pre-medical admission pathway. This should encourage further discussion about the significant potential human resources lost by current admission processes and may question the effectiveness of six-year programs in medical schools.

Severe Mental Illness and Acute Stress: A Study of Service Utilization in a Conflict Zone.

Patients suffering from severe mental illness (SMI) are considered especially vulnerable to stress. In this study, their use of acute stress services in a military context affecting civilian populations was assessed, using naturally occurring data. The proportion of patients with a previously known SMI, defined as any chronic psychotic disorder or bipolar disorder, among all civilians examined at a center for treatment of stress during a military conflict versus at the ER in usual times, was compared, using the Chi square statistical test. Among 354 subjects examined at the center for treatment of stress, 12 had a SMI diagnosis. Among 404 subjects examined at the ER in usual times, 16 had a SMI diagnosis. Patients with SMI were under-represented, but not in a statistically significant manner, at the center for treatment of stress (χ2 = 0.31, p = ns). Although these results may imply that patients with SMI are not more vulnerable to external stress than the general population, we believe that they may have difficulties in seeking immediate help in such traumatogenic contexts. In order to reduce the occurrence of PTSD and gain efficacy in the treatment of the primary disorder, psychiatric services should perhaps make a reaching out effort to identify and examine these patients in the community. .

The Patient-Psychiatrist Relationship on the Axis of the Other and the Same.

The patient-psychiatrist relationship is a cornerstone of psychiatric professionalism and ethics. We discuss this topic along the axis of the Other and the Same, concepts defined by continental philosophy. The self of Anglo-American philosophy is typically described in individualistic terms. Individualism, autonomy and ideal self are valorized within the current model of care. These characteristics belong to the Lacanian Imaginary Order, which is the core of narcissism. Patients may yearn for another model of interaction. For Levinas, ethics should not involve a search for perfectionism and accomplishment but responsibility toward others. Ethics is, according to him, rooted in the calling into question of one's Sameness by the other's Otherness. The question of hospitality and of the welcoming of Otherness is central to his thought. Derrida further asks whether hospitality is not an interruption of the self. Hospitality may thus become a fundamental way of re-thinking clinical practices. A relationship to the Other as an-other is characterized as of Euclidian-type, establishing borders between the self and the Other, whereas a relationship to the Other as same is characterized as of fractal-type, emphasizing similarities between self and other as same and obliterating boundaries. Winnicott's object-relating versus use of object and Buber's I-you and I-it relations are also examined along the axis of Sameness and Otherness. Since psychiatric clinical practice requires to our view adequate and adaptive to and fro movements along this axis, the two forms of relating to the Other are discussed both theoretically and through a clinical case presentation.

Antidepressant-induced differential ubiquitination of ß-arrestins 1 and 2 in mononuclear leucocytes of patients with depression.

ß-Arrestins 1 and 2, cytosolic proteins known to mediate receptor desensitization, endocytosis and G protein-independent signalling, are post-translationally modified by ubiquitination regulating their ability to serve as adaptors and scaffolds. ß-Arrestins were suggested to play a role in the pathophysiology of depression and in antidepressant mechanism of action. To determine whether a depressive episode or antidepressant treatment induce significant selective differences in ß-arrestin 1 and 2 levels or their ubiquitination patterns in leucocytes of patients with depression, 46 outpatients diagnosed with a depressive episode were examined before and after 4-wk antidepressant treatment compared with age- and gender-matched control subjects. ß-Arrestin levels were measured by immunoblotting using anti-arrestin antibodies. Ubiquitination of ß-arrestins was measured using anti-ubiquitin antibodies followed by an immunoprecipitation step and immunoblotting using anti-arrestin antibodies. Antidepressants induced selective alterations in leucocyte ß-arrestin 1 and 2 levels and ubiquitination. The levels of ß-arrestin 1 and 2 and their ubiquitinated forms in leucocytes of yet untreated patients with depression were significantly decreased in a symptom severity correlated manner compared to control subjects. Antidepressants normalized ß-arrestin 1 and 2 levels and uncovered novel differences between the two isoforms: (a) while antidepressants normalized ubiquitination of ß-arrestin 1, ubiquination of ß-arrestin 2 was unaffected; (b) while under antidepressants ubiquitination extent of ß-arrestin 1 positively correlated with its level, an inverse picture of negative correlation was found between ubiquitination extent of ß-arrestin 2 and its level. We conclude that antidepressants may serve as a tool to detect functional differences between the two ß-arrestin isoforms and that through these differential effects antidepressants can induce specific alterations in alternative cellular signalling.

Non-Linear Dynamic Analysis of Inter-Word Time Intervals in Psychotic Speech.

UNLABELLED: "Language is a form and not a substance" - Ferdinand de Saussure Objective: Analyses of speech processes in schizophrenia are invariably focused on words as vocal signals. The results of such analyses are, however, strongly related to content, and may be language- and culture-dependent. Little attention has been paid to a pure measure of the form of speech, unrelated to its content: inter-words time intervals. METHOD: 15 patients with schizophrenia and 15 healthy volunteers are recorded spontaneously speaking for 10-15 min. Recordings are analyzed for inter-words time intervals using the following non-linear dynamical methods: unstable periodic orbits, correlation dimension, bi-spectral analysis, and symbolic dynamics. RESULTS: The series of inter-word time intervals in normal speech have the characteristics of a low-dimensional chaotic attractor with a correlation dimension of [Formula: see text]. Deconstruction of the attractor appears in psychosis with re-establishment after anti-psychotic treatment. Shannon entropy, a measure of the complexity in the time series, calculated from symbolic dynamics, is higher for psychotic speech, which is also characterized by higher levels of phase coupling: higher bicoherence, obtained using bi-spectral analysis. CONCLUSION: Non-linear dynamical methods applied to ITIs thus enable a content-independent, pure measure of the form of normal thought, its distortion in psychosis, and its restoration under treatment.

Antidepressants elevate GDNF expression and release from C6 glioma cells in a ß-arrestin1-dependent, CREB interactive pathway.

Glial cell line-derived neurotrophic factor (GDNF), essential for neuronal survival, plasticity and development, has been implicated in the mechanism of action of antidepressant drugs (ADs). ß-arrestin1, a member of the arrestin protein family, was found to play a role in AD mechanism of action. The present study aimed at evaluating whether the effect of ADs on GDNF in C6 rat glioma cells is exerted through a ß-arrestin1-dependent, CREB-interactive pathway. For chronic treatment, C6 rat glioma cells were treated for 3 d with different classes of ADs: imipramine - a non-selective monoamine reuptake inhibitor, citalopram - a serotonin selective reuptake inhibitor (SSRI) or desipramine - a norepinephrine selective reuptake inhibitor (NSRI) and compared to mood stabilizers (lithium and valproic acid) or to the antipsychotic haloperidol. Only ADs significantly elevated ß-arrestin1 levels in the cytosol, while reducing phospho-ß-arrestin1 levels in the cell nuclear fraction. ADs significantly increased both GDNF expression and release from the cells, but were unable to induce such effects in ß-arrestin1 knock-down cells. Chronic AD treatment significantly increased CREB phosphorylation without altering the level of total CREB in the nuclear fraction of the cells. Moreover, treatment with ADs significantly increased ß-arrestin1/CREB interaction. These findings support the involvement of ß-arrestin1 in the mechanism of action of ADs. We suggest that following AD treatment, ß-arrestin1 generates a transcription complex involving CREB essential for GDNF expression and release, thus enhancing GDNF's neuroprotective action that promotes cellular survival and plasticity when the survival and function of neurons is compromised as occurs in major depression.

Antidepressants increase ß-arrestin 2 ubiquitinylation and degradation by the proteasomal pathway in C6 rat glioma cells.

beta-Arrestins, regulators of G protein-coupled receptor-G protein coupling and receptor desensitization and internalization, function also as scaffolding proteins mediating cellular signaling events. beta-Arrestin1 was previously implicated by us in the pathophysiology of depression and in the mechanism of action of antidepressants (ADs). The ubiquitously expressed beta-arrestins1 and 2 are structurally highly homologous. There has been extensive investigation of these two proteins to determine whether they serve different roles in receptor signaling. In this study, we show that treatment of C(6) rat glioma cells with ADs of various types for 3 days resulted in decreased beta-arrestin2 levels. In contrast, beta-arrestin2 mRNA expression was found to be up-regulated by ADs. To unravel the mechanism for these opposite effects several possible beta-arrestin2 post-transcriptional events and modifications were examined. C(6) rat glioma cells transfected with beta-arrestin1-targeted short hairpin RNA showed similar effects of ADs on beta-arrestin2 levels. AD-induced decreases in beta-arrestin2 protein levels were not due to cytosolic membrane translocation. Immunoprecipitation experiments showed that ADs were able to increase coimmunoprecipitation of ubiquitin with beta-arrestin2. AD-induced increases in beta-arrestin2 ubiquitinylation led to its degradation by the proteasomal pathway, as the proteasome inhibitor N-[(phenylmethoxy)carbonyl]-l-leucyl-N-[(1S)-1-formyl-3-methylbutyl]-l-leucinamide (MG-132) prevented antidepressant-induced decreases in beta-arrestin2 protein levels.

Normalization of GRK2 protein and mRNA measures in patients with depression predict response to antidepressants.

G-protein-coupled receptor kinases (GRKs) interfere in receptor-G-protein coupling leading to desensitization of G-protein-mediated receptor signalling. G-protein-coupled receptor signalling and its desensitization were previously implicated in the pathophysiology, diagnosis and treatment of mood disorders. The present study aimed to evaluate alterations in GRK2 protein and mRNA levels in mononuclear leukocytes (MNL) of untreated patients with major depression and the effects and time-course of antidepressant treatments on these alterations. Repeated GRK2 protein and mRNA measurements were carried in MNL of 24 patients with major depression. Each patient was examined while untreated and after 1, 2, 3 and 4 wk of antidepressant treatment; 24 healthy subjects were also studied. GRK2 protein and mRNA levels were evaluated through immunoblot analyses using monoclonal antibodies against GRK2 and reverse transcriptase-polymerase chain reaction, respectively. GRK2 protein and mRNA levels in MNL of untreated patients with major depression were significantly lower than the measures characterizing healthy subjects. The decreased GRK2 protein and mRNA levels were alleviated by antidepressant treatment. Normalization of GRK2 measures preceded, and, thus, could predict clinical improvement by 1-2 wk. These findings support the implication of GRK2 in the pathophysiology of major depression and in the mechanism underlying antidepressant-induced receptor down-regulation and therapeutic effects. GRK2 measurements in patients with depression may potentially serve for biochemical diagnostic purposes and for monitoring and predicting response to antidepressants.

Beta-arrestin signaling complex as a target for antidepressants and as a depression marker.

Beta-arrestins uncouple G protein-coupled receptors (GPCRs) from G proteins and promote their internalization, leading to desensitization and downregulation and serving as negative regulators of GPCR signaling. beta-Arrestins also function as scaffold proteins, interacting with several cytoplasmic proteins and linking GPCRs to intracellular signaling pathways such as the mitogen-activated protein kinase (MAPK) cascade. Recent work has also revealed that beta-arrestins translocate from the cytoplasm to the nucleus and associate with transcription factors such as histone acetyltransferase p300 and cyclic adenosine monophosphate (cAMP)-responsive element-binding protein. These substances also interact with regulators of transcription factors. We review findings on the effects of antidepressants on beta-arrestins and the plethora of antidepressant effects on signal transduction elements in which beta-arrestins serve as signaling scaffold proteins, focusing on the three major groups of MAPKs: extracellular signal-regulated kinases, c-Jun N-terminal kinases and p38 MAPKs, and on transcription factors and cofactors of which beta-arrestins mediate transcription regulation.

Antidepressants, beta-arrestins and GRKs: from regulation of signal desensitization to intracellular multifunctional adaptor functions.

G protein-coupled receptors (GPCR) have generated considerable interest in the pharmaceutical industry as drug targets. Theories concerning antidepressant targets of action suggested pre-synaptic monoamine reuptake mechanisms regulating GPCR activities including delayed receptor desensitization and down-regulation. GRKs and beta-arrestins translocate to the cell membrane and bind to agonist-occupied receptors. This uncouples these receptors from G proteins and promotes their internalization, leading to desensitization and down-regulation. Thus, GRKs and beta-arrestins serve as negative regulators of GPCR signaling. Recently, GPCR have been demonstrated to elicit signals through interaction with beta-arrestin as scaffolding proteins, independent of heterotrimeric G-protein coupling. beta-arrestins function as scaffold proteins that interact with several cytoplasmic proteins and link GPCR to intracellular signaling pathways such as MAPK cascades. Recent work has also revealed that beta-arrestins translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and CREB. They also interact with regulators of transcription factors. We review findings concerning effects of antidepressants on GRKs and beta-arrestins and the plethora of antidepressants effects on signal transduction elements in which GRKs and beta-arrestins serve as signaling scaffold proteins, and on transcription factors and cofactors in which beta-arrestins mediate regulation of transcription. The emergence of G-protein-independent signaling pathways, through beta-arrestins, changes the way in which GPCR signaling is evaluated, from a cell biological to a pharmaceutical perspective and raises the possibility for the development of pathway specific therapeutics e.g., antidepressant medications targeting GRKs and beta-arrestin regulatory and signaling proteins.

Regulators of G-protein-coupled receptor-G-protein coupling: antidepressants mechanism of action.

There is a significant gap between advances in medication for mental disorders and the present static situation of biological diagnosis and monitoring treatment. The system of neural transmission and signal transduction is a complicated, highly regulated cascade of biochemical events. Growing evidence suggests that receptor-G-protein coupling may be involved in both the pathogenesis and treatment of mood disorders. Our knowledge concerning the basic mechanisms underlying the phenomenon of desensitization, internalization, downregulation and resensitization of the G-protein-coupled receptor has been advanced during the last decade. The present review discusses the possible involvement of regulators of G-protein-coupled receptor-G-protein coupling: beta-arrestins, G-protein-coupled receptor kinases and phosducin-like proteins, as well as beta-arrestins alternative signaling events, in the pathophysiology, diagnosis and treatment monitoring of mood disorders and in the mechanism of action of antidepressant medications.

Phosducin-like protein levels in leukocytes of patients with major depression and in rat cortex: the effect of chronic treatment with antidepressants.

The importance of signal transduction processes beyond receptors involving receptor-G protein coupling, in both the pathophysiology and the treatment of mood disorders, is well documented. Thus, regulatory elements of G protein function may play a role in the molecular mechanisms underlying these alterations. Phosducin-like proteins, a family of regulators of G protein function expressed throughout brain and body, modulate G protein function by high affinity sequestration of G protein-betagamma subunits, thus impeding G protein-mediated signal transmission by both Galpha and Gbetagamma subunits. An important consequence of Gbetagamma neutralization is the prevention of G protein-coupled receptor kinase phosphorylation resulting in a temporary protection to agonist-bound receptor desensitization. Phosducin-like protein levels were measured in brain cortices of rats chronically treated with one of five classes of antidepressants: imipramine, venlafaxine, maprotiline, citalopram, and moclobemide. None of the antidepressant treatments had any significant effect on phosducin-like protein levels. Phosducin-like protein levels were evaluated in mononuclear leukocytes from a group of 15 patients diagnosed with major depressive episode, both before the initiation of antidepressant treatment and after 4 weeks of antidepressant medication. No protein changes were found in leukocytes of either untreated patients with major depressive disorder or after 4 weeks of the treatment in comparison with healthy volunteers.

The involvement of G proteins and regulators of receptor-G protein coupling in the pathophysiology, diagnosis and treatment of mood disorders.

Biochemical research in mood disorders has focused, along the cascade of events involved in signal transduction, from studies at the level of the monoamine neurotransmitter to the level of the neurotransmitter receptors, and lately to information transduction mechanisms beyond receptors, involving the coupling of receptors with signal transducers. We review findings concerning (a) the involvement of G proteins, in the pathophysiology, diagnosis and treatment of mood disorders; (b) the importance of regulation of receptor-G protein coupling, G protein-coupled receptor kinases (GRKs), beta-arrestins, to the pathophysiology of mood disorders and the mechanism of action of antidepressants. We relate to the special complexity of mental disorders with regards to etiology and pathophysiological diagnosis as well as to the strength and limitations of the 'pharmacological bridge' approach governing studies to unravel the etiology of mental disorders. There are presently no established and reliable, sensitive and specific objective biological diagnostic markers in psychiatry that can serve as 'gold standards'. The future achievement of an objective biochemical differential diagnostic system for major mental disorders that will also enable an objective biological treatment monitoring is expected to be revolutionary for psychiatry with a magnitude similar to the impact of the discovery of psychopharmacological treatments for mental disorders more than 50 years ago.

Beta-arrestin-1 levels: reduced in leukocytes of patients with depression and elevated by antidepressants in rat brain.

OBJECTIVE: Beta-arrestins play a pivotal role in G protein-coupled receptor desensitization. beta-Arrestins interfere in G protein receptor interaction, thus leading to desensitization of G protein-mediated receptor signaling. G protein receptor signaling and its desensitization were previously implicated in the pathophysiology of mood disorders and in the mechanism of action of antidepressant and mood-stabilizing treatments. The present study aims at quantitatively evaluating beta-arrestin-1 levels in leukocytes of patients with major depression and the effect of antidepressants on beta-arrestin-1 levels in rat brain. METHOD: Beta-arrestin-1 measurements were carried out in cortical, hippocampal, and striatal brain regions of rats chronically intragastrically treated with either imipramine, desipramine, or fluvoxamine. Similar measurements were conducted in mononuclear leukocytes of 36 untreated patients with major depression and 32 healthy volunteer subjects. Beta-arrestin-1 levels were evaluated through immunoblot analyses using monoclonal antibodies to beta-arrestin-1. RESULTS: Beta-arrestin-1 levels were significantly elevated by all three antidepressants in rat cortex and hippocampus, while in the striatum no alterations could be detected. This process became significant within 10 days and took 2-3 weeks to reach maximal increase. Mononuclear leukocytes of patients with depression showed significantly reduced immunoreactive quantities of beta-arrestin-1. The reduction in beta-arrestin-1 levels was significantly correlated with the severity of depressive symptoms. CONCLUSIONS: The findings in the rat study suggest beta-arrestin-1 elevation as a biochemical mechanism for antidepressant-induced receptor down-regulation. The findings in human subjects support the implication of beta-arrestin-1 in the pathophysiology of mood disorders. Beta-arrestin-1 measurements in patients with depression may potentially serve as a biochemical marker for depression.

Application of G-proteins in the molecular diagnosis of psychiatric disorders.

Mental disorders are highly prevalent and often difficult to diagnose. Although significant advances have been achieved in medication for mental disorders, the diagnosis and treatment monitoring of these disorders remain in a static situation. The absence of objective diagnostic 'gold standards', derives from the special complexity of diagnosis in psychiatry. Heterotrimeric G-proteins are crucial elements in post-receptor information transduction. These proteins have been implicated in the biochemical mechanism of action of drugs used to treat psychiatric disorders. G-protein measurements have unravelled a differential pattern characteristic of each of the major mental disorders. The accumulated data supports the potential use of G-protein measures as state-dependent markers for the biochemical diagnosis of mental disorders and as aid in the biochemical monitoring of the response to a specific treatment.

Toward molecular diagnostics of mood disorders in psychiatry.

Mental disorders are highly prevalent and often difficult to diagnose. There is a significant gap between advances in their pharmacotherapy and the present lack of objective biologic tests for diagnosis. The special complexity of diagnosis in psychiatry is related to the absence of objective diagnostic "gold standards", co-morbidity, heterogeneity and equifinality, quantitative trait loci, and locus heterogeneity. Here, we review recent findings relating to diagnostic, pathophysiological, and linkage markers for mood disorders at the biochemical level involving monoamine neurotransmitters, hormones, and signal-transducing G proteins. Identification of biological diagnostic markers could enable segregating mood disorders to several biologically different subtypes. New-era methods and strategies involving genomics, proteomics, multi-marker approach and single nucleotide polymorphisms have the potential to revolutionize future diagnosis in psychiatry.