24.

So recently I've found that I haven't written in a while and it's not because my mind is void of thoughts, rather I am finding difficulty organizing many of these thoughts into something coherent. Feedback is something that I am willing to accept when it comes to my writing, but I want feedback to not be in the form of something that is a mistake I could have easily avoided.

Now I'm going to just use this space and this time before class to come up with a list of topics I think I'd be interested in writing in over the next few months. I don't think I'll be able to undertake a writing project as big as the one I undertook over the summer (that yielded vastly underwhelming feedback which I think was largely due to the controversial nature of critiquing religion). No matter what, I'd like to get my brain thinking like a writer a little bit more than I currently do. I have been thinking a lot like a scientist and although this is valuable, sometimes it's helpful to expand the ways in which I collect and organize my thoughts.

1. Negotiating the emotional aspects of long distance relationships
2. The Significance of "Brotherhood" - Expectations v. Reality
3. Self-care techniques for College Students (who don't have money)
4. Summary of Gluten-Free Adventures During the Fall
5. "Serious" Relationships
6. Positive Female Friendships 

Thoughts on Sex

Why are some people so obsessed with changing who they are because of sex? People feel the need to pretend that they are either okay with casual sex because they feel the need to fit in with college hook up culture or they feel the need to act like all sex is life changing because they worry about being judged by the people around them. It's hard to imagine a world where all my female friends and acquaintances are honest about their sexual selves. 

Something as simple as emotional honesty is totally ignored by most young people pursuing sexual relationships for the first time. Too much importance is attached to "virginity" and it's presence or absence when in reality the most important part of any sexual relationship is honesty. Many men are concerned that having sex with a virgin will make her attached to them to a point that they are not ready for. While this may be true for some women, it isn't true for all and virginity has nothing to do with levels of attachment after a sexual encounter. Many women are not honest with themselves about what they want from a "relationship" and this creates problems for them in the future. 

You cannot fuck a guy into loving you, you cannot fuck your emotional problems away and relationships are not a cure to your psychological ills. How can I pound this into the heads of the people I'm surrounded by?

I hate when people look to me and my relationship as an example of a "perfect" situation where someone you start off just sleeping with turns into a relationship. It's such an incomplete picture of what happened between Andrew and me. It's an attempt to turn an exception and a strange occurrence into a standardized experience in an effort to make this chance event something that could happen to anyone and likely will. 

How do I advise people without inserting my own experiences into my advice? This is difficult for me because many people I interact with tend not to comprehend the extent to which I am honest with myself and with others. It's not something "comfortable" or "easy" but it's necessary. Recently, I've been trying to just stay away from giving other's sexual advice. It seems to overwhelm many people when I suggest that you can be interested in both casual sex and emotional sex and having one type of sex doesn't mean you are giving up on the other for life. 

Endocrinology Paper

Something I wrote for a biology class I took last semester, Endocrinology. It's long and has a lot of jargon but I hope at least someone reads it.

Eriche S------

Endocrinology – Spritzer

Spring 2013

Neural-Diathesis Stress Model and Applications to Schizophrenia Vulnerability, Onset, Progression, and Treatment

Schizophrenia has piqued the interest of researchers for years. Recently, discovering more information about the mechanisms that cause schizophrenia as well as finding effective treatments has moved to the forefront of neuroscience research. Schizophrenia has been linked to an excess of dopamine or oversensitivity of dopamine receptors that result in positive symptoms of the disease (Birtwistle, 1998). Antipsychotics that reduce the effects of dopamine have effects on positive schizophrenia symptoms, demonstrating a correlation between schizophrenia symptoms and dopamine activation. In recent research, another axis is being explored, where cortisol release in conjunction with dopamine is highly correlated to schizophrenia onset. The neural-diathesis stress model combines the effects of stress and dopamine on schizophrenia onset, progression and treatment, and provides a more complete picture of the neuronal pathways involved, opening up avenues for more effective treatments.

Cortisol may increase susceptibility to schizophrenia acting via the hypothalamo-pituitary axis (HPA) (Walker, 1997). Anti-psychotics decreasing HPA activation demonstrate the possibility that the HPA axis and dopamine are connected in schizophrenia’s positive symptoms. HPA activation increases transmission of dopamine as well as releasing cortisol. This suggests a link between stress response and dopamine release. A dopaminergic response to stress provides evidence for a connection between dopamine and cortisol, suggesting that they do not act independently on schizophrenia’s onset and positive symptoms (Mizrahi, 2012). Stress also increases a schizophrenic patient’s susceptibility to psychotic experiences, which further suggests an interaction between stressors and a biological response.

The biological connection between stress response and dopamine on schizophrenia’s positive symptoms is neurochemical sensitization of the mesolimbic system (Mizrahi, 2012). The mechanism through which cortisol and dopamine interact is through the prefrontal cortical D₁ dopamine receptors and their regulation of D₂ dopamine receptors, connected to cortisol release. The secondary effects on D₂ are the effects that may stimulate positive schizophrenia symptomology (Scornaiencki, 2009). Scornaiencki (2009) used Sprague Dawley rats injected with D­₁ or D₂ dopamine receptor agonists forced to perform stressful swim tests in order to measure the interactions between stress and dopamine. Dopamine reactivity was greatly increased in rats after the stressful swim tests. Since D₁ receptor agonists decreased dopamine reactivity significantly in injected rats but D₂receptor agonists did not have the same effects. D₁ receptors in the prefrontal cortex regulated D₂ stress response, this pathway may be the one that is affected in schizophrenia patients and is one probable connection between the HPA and dopamine release.

Other researchers used different methodology to determine a connection between dopamine and stress response. Dexamethasone suppression tests were used to measure HPA activity in patients with schizophrenia (Hori, 2012). In this study, levels of cortisol after dexamethasone treatment were measured in controls and schizophrenic patients. Cortisol/DHEAS ratios demonstrated abnormal HPA axis function. Compared to healthy patients, schizophrenia patients showed higher cortisol levels after treatment with dexamethasone, which should have suppressed cortisol due to negative feedback. Patients were simultaneously undergoing anti-psychotic treatment, which may have confounded results, however increased cortisol activation was clear in patients with schizophrenia.

The neurological development of the prefrontal cortex is another viable connection between the HPA axis and dopamine on schizophrenia. Schizophrenia’s symptoms have often been related to prefrontal cortex dysfunction in the dopamine hypothesis as well as the neural-diathesis stress model. Dysfunction of the prefrontal cortex causes cognitive deficits, thought disorders, hallucinations and delusions in patients (Arnsten, 2011). Within the pre-frontal cortex, cell network connections are marked and altered via dynamic network connectivity. Networks between neurons are strengthened by cAMP-HCN inhibition and formed by D₁-cAMP-HCN channel weakening.

Exposure to chronic stress causes degradation of cAMP-HCN, collapsing the networks ability to fire signals appropriately (Arnsten, 2011). Chronic stress results in cortisol release as well as an increase in PKC signaling due to degradation of prefrontal cortex neuronal networks. In schizophrenia, patients have shown a lack of molecules that would normally reverse stress response as well as strengthen prefrontal cortex activity, suggesting that developing and strengthening these neuronal pathways is important. Exposure to stress ceases regulation of prefrontal cortex pathways that contain vulnerable circuitry; this is linked to the initial descent into illness – the first psychotic episode. Alterations in prefrontal cortex pathways show definitive links to positive schizophrenia symptomology.

Prefrontal cortex damage as a result of prenatal stress increases risk of schizophrenia development later in life; this model of prefrontal cortex damage integrates the HPA and dopaminergic systems as well (Martinez-Tellez, 2009). During the formation of the prefrontal cortex networks described above, some alterations take place that may directly impact the likelihood of patients developing schizophrenia. This could be important in development of prevention methods; decreasing prenatal stress levels may be easier than treating the disease directly. Inadequate stimulation of D₁ receptors that results in bad prefrontal cortex connections and loose associations between neurons is one effect of stress on prenatal prefrontal cortex damage. There is also the problem of too much D₁ stimulation which suppresses neuronal firing under mild stress conditions which increases dopamine release due to malfunctioning negative feedback loops (Arnsten, 2011).

This prenatal stress is often times due to bacterial infection; other researchers have used rat models to outline when this occurs prenatally and the role this may play in schizophrenia risk (Lin, 2012). Using lipopolysaccharide exposure, Lin (2012), examined the role of maternal bacterial infections on fetal brain development. Mothers who experienced bacterial infections produced offspring with reduced dopamine in the hippocampus and prefrontal cortex. There was a critical period for when prenatal stress would begin to have an effect on neuronal development. Martinez-Tellez (2009) determined that this critical period was around the middle of pregnancies. Infection and other prenatal stressors cause impairments in the HPA axis as well as in hippocampal dendrite morphology. These prenatal changes were shown to have post-natal effects in rat pups that were seen to have increased stress responses (Lin, 2012).  Given the link between stress and disease onset in humans, results from this study are applicable to human models.

Early exposures to stressors post-natally have also been connected to schizophrenia onset later in life. Benes (2004) suggests that mistakes in dopamine inputs to GABA pathways pre and post-natally may be responsible for schizophrenia onset in vulnerable patients. If pre-natally exposed to stressors, there are a number of post-natal factors that increase risk of schizophrenia development. Environmental triggers such as poverty, social marginalization and immigrant status have been stressors linked to increased risk in schizophrenia onset (Jones, 2006). Predispositions to schizophrenia are not the sole cause; cortisol release as a result of exposure to various environmental stressors must happen in conjunction with this predisposition (Benes, 2004). In the Benes (2004) study, rats injected with cortisol post-natally were also examined for dopaminergic responses. These rats possessed greater clusters of dopamine cells, signifying the connection between dopamine and stress within schizophrenia onset, as it relates to early stress.

One of the most highly correlated early traumas linked to schizophrenia is child abuse. A large percentage of schizophrenia patients have been abused throughout early childhood. At risk schizophrenia adolescents – who show schizotypal behaviors or schizotypal personality disorders - have higher baseline salivary cortisol levels than controls (Stilo, 2011). Consistently showing these higher cortisol levels is partially attributed to aging, but may also be attributed to early childhood trauma, described within the traumagenic neurodevelopmental model of schizophrenia (Read, 2001). Within this model, biological, psychological and social factors are combined to find more answers regarding schizophrenia onset. High levels of cortisol acting with dopamine may increase risk of disease onset, but the stressors of early childhood are very highly correlated to this excessive cortisol in the first place.

In adoption studies meant to assess the effects of child abuse on schizophrenia development, at risk children who lived with “healthy” adoptive families were compared to at risk children who lived with more abusive adoptive families. 3% of the children with health families developed schizophrenia, while 34% of at-risk patients raised by the abusive families developed schizophrenia later on (Read, 2011). Child abuse causes sensitization of stress axes to stressors, leading to minor threats being perceived as terrors, something that has relevance to schizophrenia’s positive symptoms like paranoia. Stress responses developed in childhood are long lasting; early childhood stress sensitization as the result of abuse may likely lead to baseline cortisol levels being higher throughout puberty and post-puberty during the ages where psychotic episode risk increases.

Another connection between dopamine and stress in the neural-diathesis stress model lies in the age of onset. Schizophrenia’s age of onset is roughly 19 years old, more generally described as “late adolescence” (Gogtay, 2011). Brain processes involved in puberty may play a role in schizophrenia onset due to positive feedback systems triggered by stress, which leads to a rapid increase in positive symptoms’ appearance (Thompson, 2004). In schizophrenia patients who had experienced positive symptoms triggered by an adolescent stress response, there were a higher number of dopamine (D2) receptors. Psychosocial stress worsens positive symptoms and triggers relapse (Walker, 1997).

Adolescence is a time when people are exposed to a large variety of psychosocial stressors, especially in high-pressure school systems that demand a lot academically and socially; this relationship to disease onset is not improbable. Sensitivity to these psychosocial stressors as well as a pre-existing vulnerability may trigger these initial pathways and activate positive symptoms. Since dopaminergic response to stress has been higher in patients vulnerable to schizophrenia, increased psychosocial stressors in adolescence specifically may act to trigger initial positive symptomology. However, the connection between cortisol and dopamine is not only found in early onset of the disease; there is something more than the stresses of adolescence at play in the development of schizophrenia’s symptomology.

Environmental triggers of stress response and stress sensitization in adolescents are similar to ones experienced in children; abuse seems to be more highly correlated in children. Use of cannabis and psychostimulants have been connected to increasing risk of schizophrenia; this is likely via dopamine pathway stimulation (Di Forti, 2011). These drugs have been linked to first episodes of psychosis. Adolescence is typically a time when experimentation with these drugs may come about; in conjunction with higher cortisol levels, over-activity of the two pathways may occur leading to onset of first psychotic symptoms.

Urban residence and migration have also been highly correlated to schizophrenia onset likely because of the intensity of these two stressors. Urban settings may, somewhat counterintuitively, increase feelings of social isolation; threats to the social self are seen as forming the sort of stress response that increases the risk of schizophrenia development (Jones, 2007). Di Forti (2011) shows that in urban areas with the least amounts of social cohesion, schizophrenia rates are the highest. Migrant and ethnic minority groups may also experience higher amounts of stress leading to psychotic episodes as a result of poverty, racial discrimination, unemployment and isolation from family members. Migrant and ethnic minorities are also more likely to reside in urban areas. Environmental stressors that control the release of cortisol should be avoided in high risk patients, however, in some of the cases above like migration or urban residence, this is not a realistic option; exposure to stressors and schizophrenia risk are increased among these groups.

If early childhood abuse and prenatal stressors have such a large effect on schizophrenia onset, there must be an explanation for why the average age of onset is not much earlier than “late adolescence”. Although these early responses show strong correlations to schizophrenia onset, the trigger for most psychotic episodes is thought to lie in post-pubertal maturation of neuronal pathways (Stilo, 2011). In longitudinal studies of healthy controls, age increases were positively correlated to increases in cortisol levels. Schizotypal “at-risk” patients presented with significantly higher baseline cortisol levels than controls; higher baseline cortisol levels combined with a natural increase in cortisol with age increase likelihood of psychotic episodes. Childhood, adolescent and prenatal stressors in typical schizophrenia cases may not be enough to solely cause psychotic episodes. Neuromaturation triggering latent vulnerability may explain why cortisol levels have effects on expression of schizotypal symptomology when they do. Schizotypal symptoms typically appear in adolescence with full-blown psychotic episodes as a result of increases in HPA axis activation occurring towards the end of adolescent neuromaturational processes. Cortisol effects are not only found in disease onset, but also in disease progression.

Schizophrenic patients have higher baseline cortisol levels than controls before the onset of psychotic episodes (Jones, 2007). Treatments for schizophrenia that concurrently raise cortisol levels cause positive symptoms of schizophrenia to worsen. Throughout schizophrenia’s development, continued exposure to stressors plays a role in symptom’s worsening. Hippocampal damage has been found in cohorts of schizophrenia patients; this directly affects the HPA axis and release of cortisol, leading to excess cortisol production and increases of positive symptomology, not just at the onset of schizophrenia. Sensitivity to dopamine stress responses has implications in relapse or conversion to psychosis, showing that stress response is connected to schizophrenia throughout disease progression (Mizrahi, 2012).

Raison (2003) found that the HPA axis released less cortisol over time in stress-disorders that began with high levels of cortisol; this is not in contradiction with Jones (2007), rather demonstrates the likely progression of HPA axis and hypothalamic degradation in schizophrenic patients. Prolonged stress, from continuously high levels of cortisol may eventually damage the HPA structures responsible for producing cortisol, down-regulating cortisol in the long run by either stopping the production of upstream hormones like CRH and ACTH or by alterations in enzymes that metabolize glucocorticoids.

Brenner (2009) focused longitudinal research specifically on schizophrenic patients stress response. After first psychotic episodes, patients were found to have less reactive stress responses to psychosocial stressors, which supported the Raison (2003) finding. Stress and coping mechanisms correlate to schizophrenia patients’ quality of life; high quality of life is significant to management of positive symptoms (Brenner, 2009). Schizophrenics typically report lower quality of life than healthy controls. Use of less effective coping strategies may be connected to cortisol reactivity. Emotionally focused coping and the blunted cortisol response are maladaptive for schizophrenia patients. HPA dysregulation that causes a weaker cortisol response could lead to neurological changes that debilitate cognition and lead to misjudgment of coping technique effectiveness in patients with low cortisol responses to psychosocial stress. Drug treatments are often not enough for disease management; using the neural-diathesis stress model may provide new insight in how stress responses can be used to determine more effective coping strategies for patients and improve quality of life.

Typical drug treatments for schizophrenia are dopamine partial agonists (Miyamoto, 2005). Drugs that target dopaminergic systems frequently come with a host of side effects – researchers seek out different treatments that do not act upon dopaminergic pathways. Cortisol response in different drug treatments is an area of interest for drug developers as well as researchers who seek to better understand schizophrenia causation and progression. Ritsner (2005) looked at changes in cortisol / DHEA ratios in schizophrenic patients treated with different antipsychotic drugs of the same class like haloperidol, clothiapine and risperidone in conjunction with anti-Parkinson’s drugs to control for side effects that mimic Parkinson’s disease symptoms. Higher baseline cortisol/DHEA ratios predicted that a patient would be more likely to respond to treatment.

Other research has been done looking at only plasma cortisol levels as opposed to cortisol/DHEA ratios (Meltzer, 2000 and Cohrs, 2006). Cohrs (2006) sought to clarify antipsychotic effects on schizophrenics, but rather than looking at cortisol/DHEA ratios, he looked at the upstream glucocorticoid hormone, ACTH, as well as cortisol levels in schizophrenic patients being treated with olanzapine, quetiapine and haloperidol. Olanzapine and quetiapine are atypical antipsychotics that have been shown to reduce positive symptoms as well as negative symptoms. These drugs have also been effective in treating comorbid disorders like PTSD. This study tests the hypothesis, mentioned briefly earlier, that antipsychotics will act on cortisol levels. Atypical antipsychotics are more likely to show changes, since they have been connected to reducing symptoms of comorbid depression, which is characterized by over-activation of HPA axis. Olanzapine and quetiapine decreased plasma cortisol levels as well as ACTH levels from the baseline, whereas haloperidol did not have the same effect (Cohrs, 2006). These atypical antipsychotics act both on dopaminergic systems as well as cortisol, which may make them more effective treatments than current typical dopaminergic antipsychotics.

Meltzer (2000) looked at the antipsychotic drug apomorphine and it’s effects on plasma cortisol levels in treated schizophrenic patients; unlike the Cohrs study (2006) Meltzer (2000) also looked at the effects on psychopathology to ensure effectiveness of the drug and to possibly find a correlation between drug effectiveness and plasma cortisol levels. Plasma cortisol response was significantly blunted in schizophrenic patients as opposed to controls. Patients who had previously responded to other antipsychotics showed more reactive cortisol response to apomorphine. Ritsner (2005) showed that higher levels of baseline cortisol/DHEA ratios predicted drug responsiveness; this finding could be related to Meltzer’s (2000) findings in that responders did not have higher cortisol levels as a result of previous treatment, but their higher cortisol levels allowed them to be more responsive to drugs in the first place. Cortisol response to apomorphine may also predict whether or not a patient will respond to future antipsychotic drugs.

Studies of different clinical drugs are inconclusive regarding cortisol’s role in antipsychotic drug treatment. Cortisol levels seem to result in different coping mechanisms and responsiveness to treatments; cortisol levels also change based on different treatments regimens. A lack of conclusive evidence on cortisol’s role in schizophrenia treatment means more research needs to be done to fully understand how the neural-diathesis stress model can be employed in developing schizophrenia treatments. Baseline cortisol is a good predictor for coping methods outside of antipsychotic treatment (Brenner, 2011). Cortisol response as well as cortisol levels seem to be related to antipsychotic drug treatment, but this appears to be dependent on the drug and whether or not baseline cortisol levels or cortisol/DHEA ratios will allow a patient to respond to drugs.

The neural-diathesis stress model provides some conclusive results with regards to the connection between cortisol and dopaminergic pathways. The HPA axis that regulates cortisol production is directly connected to dopaminergic pathways. These two pathways interact in schizophrenia patients; this has been demonstrated by showing that common antipsychotic drugs dull the cortisol response in patients treated. Stress via cortisol response has effects on schizophrenia risk and onset at different stages of development. Increased pre-natal stress can increase schizophrenia risk, as well as early childhood traumas like abuse. In adolescence, the cortisol increases associated with post-pubescence increase the risk of a first psychotic episode. Decreased cortisol response reduces the ability to cope well with symptoms and have a higher quality of life. Decreased cortisol response is also linked to being a non-responder with many anti-psychotic drugs.

A link is clearly present between stress and schizophrenia; the link between dopamine pathways and stress response is in the neurological development of the prefrontal cortex as well as the neurochemical sensitization of the mesolimbic system. The prefrontal cortex connection between stress and dopamine is found within the dopamine receptors; D₁ receptors in the prefrontal cortex regulate the D₂stress response. A cortisol-dopamine connection is demonstrated through cAMP-HCN, which strengthens prefrontal cortex neuronal networks; these neuronal networks are formed through D₁-cAMP-HCN channel weakening. Chronic stress damages cAMP-HCN, which in turn damages neuronal networks.

Future research should focus on solidifying the connection between cortisol and dopaminergic pathways in order to find more definitive results about the connections between the two in schizophrenic patients. Longitudinal studies looking at cortisol levels periodically throughout a schizophrenic’s life – before the first psychotic episode –throughout disease progression may provide data on when exactly cortisol levels are blunted and why this may occur. Understanding the connections between dopamine and cortisol more thoroughly could provide better information for drug developers looking to improve antipsychotics that act solely on dopamine pathways. Currently, conflicting information about cortisol response either being blunted or heightened makes this difficult.  Although more complex, large scale longitudinal research would provide the best data with regards to cortisol levels and dopamine activity’s connection throughout the progression of the disease, beginning with patients who are at risk – patients with schizotypal personalities for example – and following up with research on patients who eventually develop schizophrenia. Perhaps then we can develop better treatments of schizophrenia that manage symptoms more effectively with fewer side effects.

References

1.    
Ritsner M, Gibel A, Maayan R, et al. Cortisol Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia. Neuropsychopharmacology. 2005;30:1913-1922.   

2.     Brenner K, Liu A, Laplante DP, et al. Cortisol response to a psychosocial stressor in schizophrenia: Blunted, delayed, or normal? Psychoneuroendocrinology. 2009;34:859-868.   

3.     Brenner K, St-Hilaire A, Liu A, Laplante DP, King S. Cortisol response and coping style predict quality of life in schizophrenia. Schizophrenia Research. 2011;128:23-29.  

4.     Cohrs S, Röher C, Jordan W, et al. The atypical antipsychotics olanzapine and quetiapine, but not haloperidol, reduce ACTH and cortisol secretion in healthy subjects. Psychopharmacology. 2006;185:11-18.   

5.     Meltzer HY, Lee MA, Jayathilake K. The blunted plasma cortisol response to apomorphine and its relationship to treatment response in patients with schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2001;24:278.   

6.     Lin Y, Lin S, Wang S. Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats. Brain, behavior, and immunity. 2012;26:459-468.  

7.     Martínez-Téllez RI, Hernández-Torres E, Gamboa C, Flores G. Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring. Synapse (New York, N.Y.). 2009;63:794-804.  

8.     Simona A Stilo, Marta Di Forti, Robin M Murray. Environmental risk factors for schizophrenia: implications for prevention. Neuropsychiatry. 2011;1:457.   Link

9.     Read J, Perry BD, Moskowitz A, Connolly J. The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry. 2001;64:319-345.  

10.  Walker EF, Walder DJ, Reynolds F. Developmental changes in cortisol secretion in normal and at-risk youth. Development and psychopathology. 2001;13:721-732.  

11.  Birtwistle J, Baldwin D. Role of dopamine in schizophrenia and Parkinson's disease. Br J Nurs.1998;7:832–841.

12.  Jones SR, Fernyhough C. A new look at the neural diathesis--stress model of schizophrenia: the primacy of social-evaluative and uncontrollable situations. Schizophrenia bulletin. 2007;33:1171-1177.  

13.  Walker EF, Diforio D. Schizophrenia: A Neural Diathesis-Stress Model. Psychological Review. 1997;104:667-685.

14.  Mizrahi R, Wilson AA, Addington J, et al. Increased stress-induced dopamine release in psychosis. Biological psychiatry. 2012;71:561-567.  

15.  Hori H, Kunugi H, Teraishi T, et al. Schizotypal Personality in Healthy Adults Is Related to Blunted Cortisol Responses to the Combined Dexamethasone/ Corticotropin-Releasing Hormone Test. Neuropsychobiology. 2011;63:232-241. 

16.  Simona A Stilo, Marta Di Forti, Robin M Murray. Environmental risk factors for schizophrenia: implications for prevention. Neuropsychiatry. 2011;1:457.  

17.  Thompson JL, Pogue-Geile MF, Grace AA. Developmental Pathology, Dopamine, and Stress: A Model for the Age of Onset of Schizophrenia Symptoms. Schizophrenia Bulletin. 2004;30:875-900.   

18.  Walker EF, Diforio D, Baum K. Developmental neuropathology and the precursors of schizophrenia. Acta Psychiatrica Scandinavica. 1999;99:12-19.  

19.  Walker E, Kestler L, Bollini A, Hochman KM. Schizophrenia: etiology and course. Annual review of psychology. 2004;55:401-430.   

20.  Scornaiencki R, Cantrup R, Rushlow WJ, Rajakumar N. Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). 2009;12:1195-1208.   

21.  Gogtay N, Vyas NS, Testa R, Wood SJ, Pantelis C. Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophrenia bulletin. 2011;37:504-513.   

22.  Arnsten AFT. Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. International Journal of Developmental Neuroscience. 2011;29:215-223.   

23.  Benes FM. The role of stress and dopamine-GABA interactions in the vulnerability for schizophrenia. Journal of Psychiatric Research. 1997;31:257-275.