Aleksander Araszkiewicz

The role of the neuroendocrine and immune systems in the pathogenesis of depression

Development of depression is associated with the bodys response to prolonged stress, which adversely affects the functioning of the nervous, endocrine and immune systems. Prolonged stress can lead to the development of a so-called allostatic load and reduction of concentration of brain-derived neurotrophic factor. These changes result in impairment of neurogenesis and synaptic remodeling process. This article illustrates the involvement of key mediators of allostasis such as the neuroendocrine and immune systems, in the pathogenesis of depression. The literature concerning the contribution of the neuroendocrine and immune systems to depression incidence was reviewed. Development of depression is associated with disturbance of the bodys allostasis and inflammatory activation of the immune system. It leads to a chronic increase in the concentration of cortisol and proinflammatory cytokines, which results in an allostatic load. This load leads to neurodegeneration, eventually causing irreversible cognitive impairment and permanent disability. Determination of the concentration of chemokines and their receptors is an important indicator of activation of the immune and neuroendocrine systems. The activity of these systems reflects the severity of the disease and provides important information for effective antidepressant treatment.

Comparison of chemokines (CCL-5 and SDF-1), chemokine receptors (CCR-5 and CXCR-4) and IL-6 levels in patients with different severities of depression

BACKGROUND Depression can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the bodys neurochemical and neuroendocrine functions play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. METHODS 160 men and women were enrolled in the study. 120 of them were diagnosed with various types of depression. The mean age was 45.2 ± 4.5 years (range: 19-47 years). The control group consisted of 40 healthy individuals. The average age in this group was 42.4 ± 4.1 years. Plasma levels of chemokines and their receptors (CCL-5 - RANTES and CXCR-5, SDF-1 and CXCR-4), as well as of IL-6, were assessed by ELISA. RESULTS There was an increase in SDF-1 and CCL-5 levels in women and men with different severities of depression, versus the control group. Also, an increase in the IL-6 levels, CXCR4 and CCR-5 receptors was observed in both women and men with all types of depression. Levels of SDF-1 and CCL-5 chemokines, as well as of CCR-5 and CXCR4 chemokine receptors, were higher in women than in men. CONCLUSIONS The results of this study indicate the need for assessment of CCL-5 and SDF-1 chemokines levels, as they are likely markers of developing depression. Early measurement of these chemokines levels may be helpful in choosing the best pharmacotherapy.

Melatonin and neurotrophins NT-3, BDNF, NGF in patients with varying levels of depression severity

BACKGROUND Disrupted circadian rhythm of melatonin secretion in depression shows a relationship with the exacerbation of inflammatory processes. Proinflammatory mechanisms of depression are sustained by oxidative stress. This contributes to melatonin deficiency and to the malfunction of the defense mechanisms in the brain. Disrupted melatonin secretion in depression may have an influence on the concentrations of neurotrophic factors (NF), such as neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Disturbance in neurotrophin release may affect synaptic plasticity and cause exacerbation of neurodegenerative processes in the central nervous system. The aim of this study was to assess the concentrations of melatonin and NF of the brain in patients with varying levels of depression severity. METHOD 160 males and females were enrolled in the study, 120 of whom were diagnosed with various types of depression. The control group comprised 40 healthy individuals. At 3:00a.m. all patients had salivary melatonin concentrations determined utilizing a competitive enzyme immunoassay technique (ELISA). In addition, at 7:00a.m. all patients had serum neurotrophin (NT-3, BDNF, NGF) concentrations determined by means of ELISA. RESULTS The highest melatonin secretion was observed at 3:00a.m. in severely depressed females. In the groups with mild and moderate depression, melatonin secretion at 3:00a.m. was comparable between males and females. In addition, a decrease in the concentrations of neurotrophins was revealed in patients at all levels of depression severity. CONCLUSION Melatonin may be a significant marker of depression severity. Melatonin and NF in depressed patients show neuroprotective effects.

The MCP-1, CCL-5 and SDF-1 chemokines as pro-inflammatory markers in generalized anxiety disorder and personality disorders

INTRODUCTION The co-occurrence of generalized anxiety disorder and personality disorders suggests the existence of association between the neurobiological predispositions leading to the development of these disorders and activation of cytokine system. Pro-inflammatory chemokines such as CCL-5/RANTES (regulated upon activation normal T cell expressed and secreted) and CXCL12/SDF-1 (stromal derived factor) play an important role in immune response. METHODS A total of 160 participants were enrolled in the study, 120 of whom comprised the study group (people with the dual diagnosis of personality disorder and generalized anxiety disorder). The mean age was 41.4 ± 3.5 years (range: 20-44 years). The control group consisted of 40 healthy individuals in the mean age of 40.8 ± 3.1 years (range: 20-43 years). A blood sample was collected from each participant and the plasma levels of the CCL-2/MCP-1 (monocyte chemoattractant protein-1), RANTES and SDF-1 chemokines were determined by ELISA. RESULTS Increased levels of MCP-1 and SDF-1 were found both in women and in men versus the control group for all types of personality disorders. The levels of CCL-5 in men were significantly increased versus the control group and significantly higher in women than in men. Neither women nor men with avoidant or obsessive-compulsive personality disorder showed any significant differences in MCP-1 or SFD-1 levels. In subjects with borderline personality disorder, the levels of the study chemokines were higher in women than in men. CONCLUSIONS Our study has shown the need for determination of proinflammatory interleukins which are considered as biomarkers of personality disorders and generalized anxiety disorders.

Fever development in neuroleptic malignant syndrome during treatment with olanzapine and clozapine

Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. Its development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is one of the main symptoms of this syndrome and its elevation is due to the activation of the immune system. Numerous studies report that treatment with clozapine (doses 37.5-600 mg) or olanzapine (doses 10-25 mg) or the use of these drugs in polytherapy cause pyrexia between 37.8-40.6 °C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF-α were increased. The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the drug taken by schizophrenic patients including changes in immunological system.

Olanzapine-induced neuroleptic malignant syndrome after 10 years of treatment

Neuroleptic malignant syndrome (NMS) is a dangerous, life-threatening condition that can be caused by antipsychotic drugs (Ananth et al., 2004; Yasugi et al., 2010). Food and Drug Administration (FDA) reports from 1999–2012 indicate that the frequency of NMS decreases when treatment with olanzapine is continued for a longer period (eHealthMe, 2013). According to an eHealthMe report compiled from the FDA reports, 11,204 patients taking olanzapine had suffered adverse effects, of which 417 patients had NMS during the first 6 months of treatment (eHealthMe, 2013). However, so far nobody has recorded a patient who has had NMS in the initial stages of typical neuroleptic treatment and another episode of NMS after 10 years of olanzapine treatment. To our knowledge, this report is the first to record the occurrence of NMS, 10 years after the implementation of olanzapine. A 63-year-old patient with a 20-year history of paranoid schizophrenia was admitted to the psychiatry ward due to non-compliance of antipsychotic treatment. The patient had previously had NMS 10 years ago during treatment with a typical neuroleptic. At the time of admission, the patient was commenced on olanzapine at a dose of 10 mg/day and the dose of the drug was titrated up to 15 mg/day on treatment day 7. On day 10, the signs and symptoms of NMS appeared. Muscular rigidity, hyperpyrexia (42°C), loss of consciousness, tachycardia, diaphoresis, and an increase in blood pressure were observed. Laboratory results showed leukocytosis (22,000/mm3), an increase in creatine phosphokinase (CPK) levels (962 U/l on day 10 and 1000 U/l on day 12). Other symptoms of inflammation were excluded. NMS was recognized and olanzapine treatment was discontinued. The symptoms of NMS described by us in this report confirm findings from previous case reports (Trollor et al., 2009). The patient subsequently received dantrolene 200 mg/day, bromergone 7.5 mg/day; lorazepam 6 mg/day, and relanium 100 mg/day and felt better. There was a reduction in fever (38°C), CPK (868 U/l and leukocytosis (15,000/mm3). During the following day of treatment, the patient became unconscious with general muscular rigidity and was intubated due to respiratory failure. Laboratory results showed an increased level of CPK (1100U/l) and leukocytosis (22,000/ mm3). The patient received a course of electroconvulsive therapy (ECT) under anaesthesia. Despite treatment, the condition of the patient became critical. Acute renal failure developed and the patient died. Acute renal failure and hyperpyrexia were the most likely cause of death. Earlier findings confirm the hypothesis as it has been shown that acute renal failure coexisting with hyperpyrexia in NMS increases the risk of death by about 50% (Casamassima et al., 2010). This report claims that even olanzapine treatment within the therapeutic range is burdened with the high risk of NMS, even after 10 years of treatment. Due to the risk of death caused by olanzapine after so many years of treatment, it is crucial to choose a sufficient but safe dose and to closely monitor for the signs and symptoms of the potentially fatal NMS.

Serum concentrations of chemokines (CCL-5 and CXCL-12), chemokine receptors (CCR-5 and CXCR-4), and IL-6 in patients with posttraumatic stress disorder and avoidant personality disorder

BACKGROUND Posttraumatic stress disorder (PTSD) can be perceived as a psychoneuroimmunological disorder in which cytokines affecting the neurochemical and neuroendocrine functions of the body play an important role. Among cytokines, chemokines participating in activation of the inflammatory response are considered to be crucial. METHOD 220 men and women were enrolled in the study. 180 of them constituted the study group. The studied groups consisted of: 60 patients with a diagnosed avoidant personality disorders (APD), 60 patients with a diagnosed APD and with PTSD and of 60 patients with PTSD but without a APD. There were 30 women and 30 men in each group of 60 subjects. The control group consisted of 40 healthy individuals. The plasma levels of chemokines and their receptors (CCL-5, CXCR-5, CXCL-12 and CXCR-4), as well as IL-6, were assessed by ELISA. RESULTS There was an increase in the CXCL-12 and CCL-5 levels in women and men with the PTSD versus the control group. Also, increased levels of IL-6 and the receptors CXCR-4, CCR-5 were observed in women and men with PTSD. The levels of CXCL-12 and CCL-5 chemokines, as well as CCR-5 and CXCR4 receptors were higher in women than in men. The results of this study indicate a need for assessment of the CCL-5 and CXCL-12 chemokine levels, as they are likely markers of PTSD. CONCLUSIONS Measurement of the concentrations of chemokines, chemokine receptors and IL-6 in women and men with PTSD along with concomittant APD may be useful for early detection of mental disorders.

A female patient with depression and conversion disorder following brain tumor surgery.

Australian & New Zealand Journal of Psychiatry, 47(12) from the fludrocortisone and the patient was discharged back to the community team with a stable mental state. His weight increased while in hospital from 63 kg to 69 kg. To our knowledge, this is the first published example of clozapine-induced hypotension leading to weight loss. Hypotension is not an uncommon side effect of this important psychiatric medication and we suggest that fludrocortisone may be an appropriate pharmacological agent for use in patients with persistent, troublesome orthostatic hypotension.

Bipolar disorder: Mixed episodes concomitant with gambling addiction.

Australian & New Zealand Journal of Psychiatry, 48(6) certainly be of significant interest given the importance of this concerning new finding. There are only three other cases of short-term de novo psychosis following withdrawal of antipsychotic agents (reserpine and metoclopramide) that have been described (Moncrieff, 2006). In our patient it could also be possible that long-term thioridazine treatment was masking and treating an underlying psychotic illness that only became noticeable following the withdrawal of thioridazine. Moncrieff ’s review of the literature (2006) on antipsychotic withdrawal suggested the possibility that chronic exposure to antipsychotic medication may alter neuronal receptor profiles, paradoxically creating a susceptibility to psychotic illness (supersensitivity psychosis). A mechanistic explanation remains elusive; however, the upregulation of dopamine receptor density and sensitivity to dopamine in mesolimbic pathways may play some role. Moncrieff (2006) proposed that supersensitivity psychosis would be most readily provoked by drugs with short half-lives and that the withdrawal psychosis could actually be a distinct entity from the underlying illness. This evidence for supersensitivity psychosis is stronger for clozapine (Moncrieff, 2006) but our case report and review of the literature also suggests that thioridazine is a medication that could induce a withdrawal psychosis. Of particular note is the suggestion that our patient may have developed a de novo treatment-resistant psychosis following years of thioridazine treatment. This presents the possibility that certain vulnerable populations such as intellectually impaired individuals may be at higher risk of enduring brain adaptations to longterm dopamine blockade, which could lead to an iatrogenic and longlasting psychotic syndrome. It may well be that this is an under-recognised clinical entity, particularly in the intellectually impaired population. Clinicians should therefore exercise caution in such populations before prescribing long-term antipsychotic medication. Intriguingly, our case report points to the possibility of iatrogenic and enduring psychosis triggered by longterm administration of antipsychotic medication. Funding

Electroconvulsive therapy in a patient with drug-resistant depression and thyroid hormone imbalance

Australian & New Zealand Journal of Psychiatry, 48(1) drug users. Many use marijuana and alcohol. Quite a few have used methamphetamine in the past, sometimes for prolonged periods. In the diagnostic phase I ask patients how they reacted to illegal amphetamines. Often the answers are: ‘It made my friends high, but it made me feel calm. I could get things done. It made me feel normal.’ Over time I have learned that these kinds of answers are highly predictive of a positive reaction to methylphenidate or dexamphetamine. Psychostimulants help patients organise their lives, allow them to work or study, and assist them to improve their relationships. Stimulants put them in control of their lives. The former ‘abuse’ of illegal drugs can easily be recast as a form of self medication. Doctors Dobry and Sher mention that a foreseeable problem with prescribing stimulants to former users of methamphetamine is that they can become addicted to the prescribed stimulants. This may be the case, but is, in my experience, unlikely. I have failed to find cases of methylphenidate or dexamphetamine addiction and could not find any colleagues who had diagnosed or treated such cases. So, if addiction occurs, the risk of addiction can’t be very high. Addiction to psychostimulants should not be confused with being dependent on them, in the sense that patients with ADHD can depend on psychostimulants to live their lives in an acceptable way, like other patients may not be able to get on with life without antidepressants. With the successful treatment of adult ADHD, stimulants generally also lower the urge to use alcohol or marijuana. One of the main features of adult ADHD is a lifelong feeling of stress and unrest. Alcohol, marijuana and sometimes methamphetamine are used to dampen these ongoing unpleasant feelings. In sum, patients with a history of methamphetamine addiction are, in my experience, more likely than others to suffer from ADHD, and are likely to react positively to treatment with stimulants.