1Nippon Rinsho 2001 Aug 59: 1494-8
PMID11519147
Title[Symptomatology and diagnosis of depression].
AbstractIt is characterized by mainly depressive mood and psychomotor retardation. Another symptoms are retardation of thought, diurnal change, anxiety, irritability, delusion of belittlement, etc. There are often somatic symptoms as loss of appetite, sleep disturbance, loss of body weight, constipation, etc. Depressive symptoms are often seen in schizophrenia, brain injury, endocrinosis illness and other somatic illness. Diagnosis of depression is carefully carried out by detailed interviews and symptoms. Recently diagnosis of depression is determined mechanically by DSM-IV or ICD-10. Neuro-endocrine tests as DST or Dex-CRH test, are useful strategies in examination of depression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
2Prog. Neurobiol. 2001 Dec 65: 427-51
PMID11689280
TitleAlterations induced by gestational stress in brain morphology and behaviour of the offspring.
AbstractRetrospective studies in humans suggest that chronic maternal stress during pregnancy, associated with raised plasma levels of CRH, ACTH and cortisol may increase the likelihood of preterm birth, developmental delays and behavioural abnormalities in the children. In adulthood, it may contribute to the significant association between the incidence of schizophrenia, increased left or mixed handedness, reduction in cerebral asymmetry and anomalies in brain morphology. Our studies and others have shown that prenatal stress in rats can mimic these developmental and behavioural alterations. These rats show a reduced propensity for social interaction, increased anxiety in intimidating or novel situations and a reduction in cerebral asymmetry and dopamine turnover, consistent with those in schizophrenic humans. Prenatally-stressed (PS) rats also show behaviour consistent with depression, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, a hedonic deficit and greater acquisition of learned helplessness under appropriate conditions. These behavioural abnormalities are associated with impaired regulation of the hypothalamic-pituitary-adrenal axis response to stress and increased CRH activity. PS males may show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in PS offspring could occur through sensitisation of the foetal brain by maternal stress hormones to the action of glucocorticoid and CRH and to neurotransmitters affected by them. This may have long-lasting consequences and could explain the precipitation of depressive symptoms or schizophrenia by psychosocial stress in later life. The character of the behavioural abnormalities probably depends on the timing of the maternal stress in relation to development of the particular neuronal systems.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
3Prog. Neurobiol. 2001 Dec 65: 427-51
PMID11689280
TitleAlterations induced by gestational stress in brain morphology and behaviour of the offspring.
AbstractRetrospective studies in humans suggest that chronic maternal stress during pregnancy, associated with raised plasma levels of CRH, ACTH and cortisol may increase the likelihood of preterm birth, developmental delays and behavioural abnormalities in the children. In adulthood, it may contribute to the significant association between the incidence of schizophrenia, increased left or mixed handedness, reduction in cerebral asymmetry and anomalies in brain morphology. Our studies and others have shown that prenatal stress in rats can mimic these developmental and behavioural alterations. These rats show a reduced propensity for social interaction, increased anxiety in intimidating or novel situations and a reduction in cerebral asymmetry and dopamine turnover, consistent with those in schizophrenic humans. Prenatally-stressed (PS) rats also show behaviour consistent with depression, including a phase-shift in their circadian rhythm for corticosterone, sleep abnormalities, a hedonic deficit and greater acquisition of learned helplessness under appropriate conditions. These behavioural abnormalities are associated with impaired regulation of the hypothalamic-pituitary-adrenal axis response to stress and increased CRH activity. PS males may show demasculinisation and feminisation of their sexual behaviour. The developmental and behavioural abnormalities in PS offspring could occur through sensitisation of the foetal brain by maternal stress hormones to the action of glucocorticoid and CRH and to neurotransmitters affected by them. This may have long-lasting consequences and could explain the precipitation of depressive symptoms or schizophrenia by psychosocial stress in later life. The character of the behavioural abnormalities probably depends on the timing of the maternal stress in relation to development of the particular neuronal systems.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
4Int. J. Obes. Relat. Metab. Disord. 2001 Jan 25: 24-32
PMID11244454
TitlePsychoneuroendocrine characteristics of common obesity clinical subtypes.
AbstractTo relate psychological profiles, cerebral asymmetry and the hypothalamus-pituitary-adrenal axis (HPA) reactivity to clinical characteristics of common obesity.
Sixty consecutive adult female overweight and obese patients attending the outpatient endocrine department were included in this study. Clinical evaluation specifically selected a priori the following indexes: obesity age of onset, parenthood obesity, carbohydrate craving, binge eating with purging, obesity degree (defined by the body mass index (BMI)--weight (kg)/height (m(2))), body fat distribution (defined by the abdominal--thigh ratio (A/T)) and initial weight loss after medical treatment. Psychological evaluation was performed with the Minnesota Multiphasic Personality Inventory (MMPI). In the last 30 patients, the Edinburgh Inventory of Manual Preference (EIMP) and the corticotrophin-releasing hormone (CRH) test were also performed.
Clinical characteristics defined a priori were independent variables as evaluated by contingency table analysis. Factorial analysis of variance (ANOVA) revealed a significantly different MMPI profile, according to parental obesity, with post-hoc significantly higher scores on the hypochondriasis (Hs), paranoia (Pa), psychasthenia (Pt) and schizophrenia (Sc) scales in patients with obese parents. Obese patients presented significantly higher dichotomized manual preference indexes in relation to overweight patients. Parental obesity, binge eating behaviour with purging, body fat distribution and the dichotomized manual preference index were independent significant factors for the ACTH response in the CRH test, together explaining 41% of the response variability. Age of onset of obesity and the dichotomized manual preference index were independent and significant factors for the cortisol response, together explaining 37% of its variability. A non-normal distribution was found for the ACTH response: high- and low-responders presented significantly different MMPI profiles, with high-responders presenting higher scores on all clinical scales except masculinity/femininity (Mf).
Overweight/obese subjects with parental obesity present a distinctive personality profile and a higher ACTH response in the CRH test. Cerebral asymmetry may be a relevant factor for obesity development and is associated with the HPA reactivity. HPA reactivity is a sensitive index integrating clinical, psychological and neural asymmetric factors. International Journal of Obesity (2001) 25, 24-32
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
5Psychiatry Res 2002 May 110: 1-7
PMID12007588
TitleCSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture.
AbstractHypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
6Psychiatry Res 2002 May 110: 1-7
PMID12007588
TitleCSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture.
AbstractHypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
7Psychiatry Res 2002 May 110: 1-7
PMID12007588
TitleCSF hypocretin-1 levels in schizophrenics and controls: relationship to sleep architecture.
AbstractHypocretins/orexins are newly identified peptides of hypothalamic origin. Hypocretin deficiency is involved in the sleep disorder narcolepsy, suggesting the importance of hypocretin neurotransmission for the regulation of sleep. Hypocretin is known to excite midbrain dopaminergic neurons and to induce hyperactivity and stereotypy in animals. Altered hypocretin neurotransmission might therefore be involved in schizophrenia, since an involvement of dopaminergic mechanisms and an association with sleep disturbance are well demonstrated in patients with schizophrenia. Hypocretin is also known to affect the hypothalamic-pituitary-adrenal axis by stimulating the release of corticotropin releasing hormone (CRH). In the current study, we measured CSF hypocretin levels in 12 controls and 13 patients with chronic schizophrenia associated with moderate sleep disturbance, such as longer sleep onset latency, decreased total sleep time and decreased sleep efficacy. No difference in CSF hypocretin levels between schizophrenia and control subjects was found. CSF hypocretin levels were positively correlated with CSF CRH levels in the patient, control and combined subject populations, but the correlation did not reach statistical significance in any population. The hypocretin levels in schizophrenic patients were, however, positively and significantly correlated with sleep latency, one of the most consistent sleep abnormalities seen in schizophrenia. This correlation was not significant in controls, and no other significant correlation between CSF hypocretin levels and any measure of sleep architecture in either patients or controls was observed. Further studies of whether CNS hypocretin neurotransmission is involved in sleep and neuroendocrine abnormalities seen in patients with schizophrenia and other psychiatric conditions are warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
8Biol. Psychiatry 2002 Apr 51: 583-90
PMID11950460
TitleReduced startle reactivity and plasticity in transgenic mice overexpressing corticotropin-releasing hormone.
AbstractCorticotropin-releasing hormone (CRH) hyperactivity in transgenic mice overexpressing CRH in the brain (CRH-OE(2122)) appears to be associated with chronic stress-like alterations, including increased CRH content in the hypothalamus, changes in hypothalamus-pituitary-adrenal axis regulation, and increased heart rate and body temperature. In the present study, we investigated if sensory information processing of startling auditory stimuli was affected in CRH-OE(2122) mice.
CRH-OE(2122) mice (on C57BL/6J background) were subjected to a number of procedures probing sensory information processing mechanisms, including the acoustic startle response, habituation, and prepulse inhibition of startle.
CRH-OE(2122) mice displayed reduced acoustic startle reactivity and increased motor activity during startle testing compared to wild-type mice. Furthermore, transgenic mice did not show habituation of the startle response after repeated exposure to the auditory stimulus, or habituation across procedures. CRH-OE(2122) mice exhibited robust impairments of prepulse inhibition in two different paradigms.
The results in CRH-OE(2122) mice indicate that chronic CRH hyperactivity is associated with reductions in startle reactivity, habituation, and prepulse inhibition. The latter two abnormalities are also observed in schizophrenia patients. We conclude that chronic CRH excess may reduce behavioral reactivity to environmental stimuli and impair information processing mechanisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
9J. Neural Transm. Suppl. 2003 -1 -1: 17-34
PMID12830927
TitleThe role of peptides in treatment of psychiatric disorders.
AbstractAbout 25 years ago the observation that neuropeptides serve as signalling molecules in the nervous system generated great expectations for drug industry. In this article the progress made since then in exploiting neuropeptide systems pharmacologically in psychiatry is highlighted. In affective disorders a number of neuropeptides seem to be causally involved in development and course of illness, especially corticotropin releasing hormone (CRH), vasopressin (AVP) and substance P, whose receptors are now targeted with small molecules designed to reduce depressive and anxiety symptoms. Although not exactly neuropeptides, also neurotrophins, may have a distinct role in antidepressant action and possibly also in causation of depression. schizophrenia-like symptoms are caused by neurotensin (NT), supporting the notion that drugs interfering with NT systems are potential antipsychotics. Finally, sleep disorders, currently treated with hypnotics, that have serious adverse effects can be targeted with neuropeptides. According to the work by Axel Steiger several neuropeptides even if peripherally administered produce improvements of quality of sleep. All these observations call for intensified application of novel research tools necessary to exploit the potential of neuropeptide systems as psychopharmaceutical targets.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
10Neuropsychopharmacology 2006 Apr 31: 853-65
PMID16205782
TitleAntipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases.
AbstractAntipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 microM), haloperidol (0.5-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (1.0-5.0 microM), promazine (5.0 and 10 microM), risperidone (5.0 and 10.0 microM), and raclopride (only at the highest used concentrations, ie 30 and 100 microM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by cAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 microM), haloperidol (1.0-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (3.0 and 5.0 microM), and raclopride (30 and 100 microM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 microM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3beta level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 microM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
11Aust N Z J Psychiatry 2008 Dec 42: 995-1002
PMID19016087
TitleStress and anxiety in schizophrenia and depression: glucocorticoids, corticotropin-releasing hormone and synapse regression.
AbstractStress during childhood and adolescence has implications for the extent of depression and psychotic disorders in maturity. Stressful events lead to the regression of synapses with the loss of synaptic spines and in some cases whole dendrites of pyramidal neurons in the prefrontal cortex, a process that leads to the malfunctioning of neural networks in the neocortex. Such stress often shows concomitant increases in the activity of the hypothalamic-pituitary-adrenal system, with a consequent elevated release of glucocorticoids such as cortisol as well as of corticotropin-releasing hormone (CRH) from neurons. It is very likely that it is these hormones, acting on neuronal and astrocyte glucocorticoid receptors (GRs) and CRH receptors, respectively, that are responsible for the regression of synapses. The mechanism of such regression involves the loss of synaptic spines, the stability of which is under the direct control of the activity of N-methyl-d-aspartate (NMDA) receptors on the spines. Glutamate activates NMDA receptors, which then, through parallel pathways, control the extent in the spine of the cytoskeletal protein F-actin and so spine stability and growth. Both GR and CRH receptors in the spines can modulate NMDA receptors, reducing their activation by glutamate and hence spine stability. In contrast, glucocorticoids, probably acting on nerve terminal and astrocyte GRs, can release glutamate, so promoting NMDA receptor activation. It is suggested that spine stability is under dual control by glucocorticoids and CRH, released during stress to change the stability of synaptic spines, leading to the malfunctioning of cortical neural networks that are involved in depression and psychoses.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
12Neuropharmacology 2008 Sep 55: 577-83
PMID18616955
TitleRole of metabotropic glutamate receptors in the control of neuroendocrine function.
AbstractGlutamate exerts its effects through binding and activation of two classes of specific receptors: ionotropic (iGluRs) and metabotropic (mGluRs). Group I mGluR includes mGluR1 and mGluR5 subtypes, group II includes mGluR2 and mGluR3 subtypes and group III includes the subtypes mGluR 4, 6, 7 and 8. Glutamate and its receptors are found in all key hypothalamic areas critically involved in reproduction and neuroendocrine function. To date, considerable data support an important role for iGluRs in the control of neuroendocrine function; however, the role of mGluRs as regulators of hypothalamic-pituitary function has not been clearly elucidated. mGluRs could be exerting a fine tune on the release of hypothalamic factors that regulate hormone release such as Substance P, GABA, alpha-MSH and CRH. Group II mGluR exert a direct inhibitory effect on anterior pituitary prolactin and GH secretion. Moreover, some group II mGluR agonists, like LY 354,740 and LY 379,268, can modulate PRL secretion from the anterior pituitary through their actions as dopamine receptor agonists. Evidence suggests a role for group III mGluR subtypes in stress-related behavioral disorders. Several reports indicate that selective ligands for mGluR subtypes have potential for the treatment of a wide variety of neurological and psychiatric disorders, including depression, anxiety disorders, schizophrenia, epilepsy and Alzheimer's disease among others. Since converging lines of evidence suggest a role for mGluRs subtypes in neuroendocrine regulation of hormone secretion, mGluRs neuroendocrine actions must be taken in consideration to insure proper treatment of these diseases. Moreover, discovery of selective agonists provides an opportunity to investigate the physiological role of mGluR subtypes and to directly test the neuroendocrine actions of mGluRs. Finally, mGluRs selective agonists may have an impact in the treatment of conditions involving chronic stress, such as depression and anxiety disorders, since they regulate neuroendocrine stress circuits involving the HPA axis and stress-sensitive hormones such as oxytocin and prolactin. This review aims to provide a survey of our current understanding of the effects of mGluR activation on neuroendocrine function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
13Eur. J. Pharmacol. 2008 Apr 583: 215-25
PMID18342852
TitleSynaptic physiology of central CRH system.
AbstractCorticotropin-Releasing Hormone (CRH) or Corticotropin-Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' [Guillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11-28]. However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee [Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M., 2003. International Union of Pharmacology. XXXVI. Corticotrophin-releasing factor and their ligands. Pharmacol. Rev. 55, 21-26] to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified [Orozco-Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P., Gallagher, J.P., 2006a. Regulation of Synaptic Transmission by CRF Receptors. Rev. Neurosci. 17, 279-307; Orozco-Cabal, L., Pollandt, S., Liu, J., Vergara, L., Shinnick-Gallagher, P., Gallagher, J.P., 2006b. A novel rat medial prefrontal cortical slice preparation to investigate synaptic transmission from amygdala to layer V prelimbic pyramidal neurons. J. Neurosci. Methods 151, 148-158] is especially noteworthy since this synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia [Fischbach, G.D., 2007. NRG1 and synaptic function in the CNS. Neuron 54, 497-497], and neurological disorders, e.g., Alzheimer's disease [Bell, K.F., Cuello, C.A., 2006. Altered synaptic function in Alzheimer's disease. Eur. J. Pharmacol. 545, 11-21]. We suggest that "The Stressed Synapse" has been overlooked [c.f., Kim, J.J., Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev., Neurosci. 3, 453-462; Radley, J.J., Morrison, J.H., 2005. Repeated stress and structural plasticity in the brain. Ageing Res. Rev. 4, 271-287] as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
14J. Psychopharmacol. (Oxford) 2010 May 24: 677-82
PMID18838498
TitleAssociation of HPA axis genes with suicidal behaviour in schizophrenia.
AbstractFamily, adoption and twin studies show that genetics influences suicidal behaviour, but do not indicate specific susceptibility variants. Stress response is thought to be mediated by the corticotrophin-releasing hormone (CRH), which is known to be a regulator of the hypothalamic-pituitary-adrenal pathway (HPA). Alterations in HPA system have been related to impulsivity, aggression and suicidal behaviour, common feature in schizophrenia. CRH is the hypothalamic factor that stimulates the pituitary gland. To search for markers conferring genetic susceptibility to suicide, we typed six HPA axis genes (CRH, CRHR1, CRHR2, CRHBP, MC2R, NC3R1) in a cohort of 231 subjects with schizophrenia in which 81 attempted suicide. The genotype analyses yielded significant association between CRH binding protein (CRHBP) and suicide attempt (P = 0.035). The genotype analysis for quantitative measures of suicidal behaviour showed no association. The interaction analysis showed a significant interaction between CRH receptor type 1 (CRHR1) and CRH binding protein (CRHBP) in influencing suicide attempt and the severity of suicidal behaviour. Current results show that genetic variation in HPA axis genes could be associated with suicidal behaviour in schizophrenia. This is to our knowledge the first study on suicidal behaviour investigating the interaction among the HPA axis genes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
15Nihon Shinkei Seishin Yakurigaku Zasshi 2012 Aug 32: 203-9
PMID23012888
Title[The hypothalamic-pituitary-adrenal axis and depressive disorder: recent progress].
AbstractDepression is a stress-induced disorder and there is compelling evidence for the involvement of hypothalamic-pituitary-adrenal (HPA) axis abnormalities in the disease. Chronic hyperactivity of the HPA axis and resultant excessive glucocorticoid (hypercortisolism) may be causal to depression. We demonstrated that the dexamethasone (DEX)/CRH test is a sensitive state-dependent marker to monitor HPA axis abnormalities. Restoration from HPA axis abnormalities occurs with clinical responses to treatment. Brain-derived neurotrophic factor (BDNF) has also been implicated in depression. We found that glucocorticoid (DEX) suppresses BDNF-induced dendrite outgrowth and synaptic formation via blocking the MAPK pathway in early-developing cultured hippocampal neurons. Furthermore, we demonstrated that glucocorticoid receptor (GR) and TrkB (a specific receptor of BDNF) interact and that DEX acutely suppresses BDNF-induced glutamate release by affecting the PLC-gamma pathway in cultured cortical neurons, indicating a mechanism underlying the effect of excessive glucocorticoid on BDNF function and resultant damage in cortical neurons. In a macroscopic view using magnetic resonance imaging (MRI), we found that individuals with hypercortisolism detected by the DEX/CRH test demonstrated volume loss in gray matter and reduced neural network assessed with diffusion tensor imaging in several brain regions. Finally, we observed that individuals with hypocortisolism detected by the DEX/CRH test tend to present more distress symptoms, maladaptive coping styles, and schizotypal personality traits than their counterparts, which points to the important role of hypocortisolism as well as hypercortisolism in depression spectrum disorders.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
16Genes Brain Behav. 2012 Nov 11: 949-57
PMID22998353
TitleGenetic load is associated with hypothalamic-pituitary-adrenal axis dysregulation inámacaques.
AbstractDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis pathway is associated with several neuropsychiatric disorders, including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia and alcohol abuse. Studies have demonstrated an association between HPA axis dysfunction and gene variants within the cortisol, serotonin and opioid signaling pathways. We characterized polymorphisms in genes linked to these three neurotransmitter pathways and tested their potential interactions with HPA axis activity, as measured by dexamethasone (DEX) suppression response. We determined the percent DEX suppression of adrenocorticotropic hormone (ACTH) and cortisol in 62 unrelated, male rhesus macaques. While DEX suppression of cortisol was robust amongst 87% of the subjects, ACTH suppression levels were broadly distributed from -21% to 66%. Thirty-seven monkeys from the high and low ends of the ACTH suppression distribution (18 'high' and 19 'low' animals) were genotyped at selected polymorphisms in five unlinked genes (rhCRH, rhTPH2, rhMAOA, rhSLC6A4 and rhOPRM). Associations were identified between three variants (rhCRH-2610C>T, rhTPH2 2051A>C and rh5-HTTLPR) and level of DEX suppression of ACTH. In addition, a significant additive effect of the 'risk' genotypes from these three loci was detected, with an increasing number of 'risk' genotypes associated with a blunted ACTH response (P?=?0.0009). These findings suggest that assessment of multiple risk alleles in serotonin and cortisol signaling pathway genes may better predict risk for HPA axis dysregulation and associated psychiatric disorders than the evaluation of single gene variants alone.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
17Int. J. Neuropsychopharmacol. 2012 Sep 15: 1051-61
PMID22008251
TitleQuetiapine affects neuropeptide Y and corticotropin-releasing hormone in cerebrospinal fluid from schizophrenia patients: relationship to depression and anxiety symptoms and to treatment response.
AbstractCumulative evidence indicates that neuropeptides play a role in the pathophysiology of schizophrenia. Early data showed increased neuropeptide Y (NPY) in cerebrospinal fluid (CSF) from schizophrenia patients and data from rodents show that antipsychotic drugs modulate NPY levels in and release from selected rat brain regions. In view of these findings we investigated whether the atypical antipsychotic quetiapine, originally used as an antipsychotic but subsequently shown to be efficient also in major depressive disorder and in both poles of bipolar disorder, would affect NPY-like immunoreactivity (-LI), and corticotropin-releasing hormone (CRH)-LI levels in CSF of schizophrenia patients. NPY-LI and CRH-LI in CSF were determined in 22 patients with schizophrenia. Lumbar puncture was performed at baseline and again after 4 wk of quetiapine treatment (600 mg/d). Patients were assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and at weekly intervals. Quetiapine treatment was associated with a significant increase in NPY-LI (p<0.001) and decrease in CRH-LI (p<0.01). Stepwise multiple regression analysis revealed that ?NPY-LI and ?CRH-LI levels predicted 63% (p<0.001) of the variability of the ?PANSS total score, ?NPY-LI 42% (p<0.05) of the ?PANSS anxiety items (G2) and ?CRH-LI 40% (p=0.05) of the ?PANSS depression items (G6). These results suggest that while quetiapine's effects on monoamines are probably related to its antipsychotic properties, the modulation of NPY and CRH accounts for its antidepressant and anxiolytic effects and can be markers of response.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
18Neuroscience 2013 Sep 249: 172-91
PMID23298853
TitleStress and neurodevelopmental processes in the emergence of psychosis.
AbstractThe notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
19Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94
PMID23085507
TitleImmune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma.
AbstractImpaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
20Handb Clin Neurol 2014 -1 124: 69-91
PMID25248580
TitleCorticotropin-releasing hormone and the hypothalamic-pituitary-adrenal axis in psychiatric disease.
AbstractSince the 1960s, both corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal (HPA) axis have been studied in detail across a range of psychiatric illnesses, leading to important contributions to our knowledge in this area. This research arose from the conceptualization of depression, in particular, as a stress-related disorder. However, stress is now regarded as an integral component of psychiatric illnesses in general, whether as an environmental trigger or in the initial pathogenesis, and there is evidence of altered HPA axis function across a range of mental disorders. The chapter will cover the extensive literature on HPA axis abnormalities in these disorders with a particular emphasis on the CRH system as it is very evident that this 41-amino acid-containing peptide is not only a major physiologic regulator of HPA axis activity but also important in the pathogenesis of mental disorders. In particular, we discuss the abundant reports pertaining to major depressive disorder, where hyperactivity of the HPA axis, of mild to moderate severity, has been demonstrated in 30-50% of cases. Also under consideration is the less extensively studied, but equally intriguing question of HPA axis integrity in bipolar affective disorder. In addition there will be a concise summary of recent findings in schizophrenia and anxiety disorders, with an emphasis on post-traumatic stress disorder (PTSD) in the latter case. Interestingly, in diametric opposition to the theory of HPA hyperactivity in depression, PTSD has features consistent with hypofunctioning of this system. Advances in animal and human studies have made it possible to synthesize these findings, and while much still remains unknown, we are gradually building up a clearer picture of this very important axis in health, at times of stress, and in chronic enduring mental illness.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
21Transl Psychiatry 2015 -1 5: e636
PMID26371764
TitleVariable telomere length across post-mortem human brain regions and specific reduction in the hippocampus of major depressive disorder.
AbstractStress can be a predisposing factor to psychiatric disorders and has been associated with decreased neurogenesis and reduced hippocampal volume especially in depression. Similarly, in white blood cells chronic psychological stress has been associated with telomere shortening and with mood disorders and schizophrenia (SZ). However, in previous post-mortem brain studies from occipital cortex and cerebellum, no difference in telomere length was observed in depression. We hypothesized that in psychiatric disorders, stress-driven accelerated cellular aging can be observed in brain regions particularly sensitive to stress. Telomere length was measured by quantitative-PCR in five brain regions (dorsolateral prefrontal cortex, hippocampus (HIPP), amygdala, nucleus accumbens and substantia nigra (SN)) in major depressive disorder (MDD), bipolar disorder, SZ and normal control subjects (N = 40, 10 subjects per group). We observed significant differences in telomere length across brain regions suggesting variable levels of cell aging, with SN and HIPP having the longest telomeres and the dorsolateral prefrontal cortex the shortest. A significant decrease (P < 0.02) in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response (FKBP5, CRH) showed altered levels of mRNA. Our results suggest the presence of hippocampal stress-mediated accelerated cellular aging in depression. Further studies are needed to investigate the cellular specificity of these findings.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
22Endocr Regul 2015 Apr 49: 58-67
PMID25960006
TitleImpact of repeated asenapine treatment on FosB/?FosB expression in neurons of the rat central nucleus of the amygdala: colocalization with corticoliberine (CRH) and effect of an unpredictable mild stress preconditioning.
AbstractFosB/?FosB expression in the central amygdalar nucleus (CeA) in response to repeated asenapine (ASE) treatment (an atypical antipsychotic used for the treatment of schizophrenia) was studied in normal rats and rats preconditioned with chronic unpredictable variable mild stress (CMS). The goal of this study was to reveal whether repeated ASE treatment for 14 days may: 1) induce FosB/?FosB expression in the amygdala, 2) activate CRH-synthesizing neurons in the CeA, and 3) interfere with 21 days lasting concomitant CMS preconditioning.
Four groups of animals were studied: controls and ASE-, CMS-, and CMS+ASE-treated ones. CMS consisted of the restrain, social isolation, crowding, swimming, and cold and lasted 21 days. The ASE and CMS+ASE groups were from the 7th day of the experiment treated with ASE (0.3 mg/kg, subcutaneously - s.c.) twice a day, i.e. together for 14 days. Controls and CMS groups were treated with saline (300 Ál/rat, s.c.) twice a day for 14 days. All the animals were sacrificed on the 22nd day, i.e. 16-18 hours after the last treatments. Single FosB/?FosB, FosB/?FosB colocalizations with CRH, and CRH immunolabeled perikarya were investigated in the CeA using a combined light and fluorescent immunohistochemistry.
The distribution aspect of the black FosB/?FosB profiles was homogeneous over the whole CeA and no significant differences in the number of FosB/?FosB profiles between the individual groups of the rats really occurred. The level of colocalization pattern of FosB/?FosB in CRH perikarya was also very similar between the individual groups and in each case it reached approximately 10% of double-labeling. No differences were also seen in the number of CRH immunolabeled perikarya. The density of CRH nerve projections within the CeA was very alike in the individual groups of animals investigated.
The study provides a new anatomical/functional finding about the lack of the stimulatory effect of the repeated ASE treatment on the expression of FosB/?FosB, FosB/?FosB/CRH colocalizations, and CRH immunolabeled perikarya number in the CeA. In addition, CMS preconditioning itself neither stimulated nor inhibited FosB/?FosB expression, nor altered the impact of ASE on the activity of CRH neurons in the CeA.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal