In recent years, the postpubescent period received increasing attention from researchers in the field of schizophrenia (Stevens, 2002). This interest stems largely from the fact that adolescence is associated with a significant rise in the risk for psychotic symptoms, particularly prodromal signs of schizophrenia (van Oel, Sitskoorn, Cremer, & Kahn, 2002; Walker, 2002). Further, rates of other psychiatric syndromes, including mood and anxiety disorders, escalate during adolescence. It has been suggested that hormonal changes may play an important role in this developmental phenomena, making ad

olescence a critical period for the emergence of mental illness (Walker, 2002).

Puberty results from increased activation of the hypothalamic-pituitary-gonadal (HPG) axis, which results in a rise in secretion of sex hormones (steroids) by the gonads in response to gonadotropin secretion from the anterior pituitary. Rising sex steroid concentrations are associated with other changes, including increased growth hormone secretion.

There is also an augmentation of activity in the hypothalamic-pituitary-adrenal (HPA) axis during adolescence. This neural system governs the release of several hormones and is activated in response to stress. Cortisol is among the hormones secreted by the HPA axis, and researchers can measure it in body fluids to index the biological response to stress. Beginning around age 12, there is an age-related increase in baseline cortisol levels in normal children. The change from pre-to postpubertal status is linked with a marked rise in cortisol (Walker, Walder, & Reynolds, 2001) and a significant rise in cortisol clearance and in the volume of cortisol distribution.

The significance of postpubertal hormonal changes has been brought into clearer focus as researchers have elucidated the role of steroid hormones in neuronal activity and morphology (Dorn & Chrousos, 1997; Rupprecht & Holsboer, 1999). Neurons contain receptors for adrenal and gonadal hormones. When activated, these receptors modify cellular function and impact neurotransmitter function. Short-term effects (nongenomic effects) of steroid hormones on cellular function are believed to be mediated by membrane receptors. Longer-term effects (genomic effects) can result from the activation of intraneuronal or nuclear receptors. These receptors can influence gene expression. Brain changes that occur during normal adolescence may be regulated by hormonal effects on the expression of genes that govern brain maturation.

Gonadal and adrenal hormone levels are linked with behavior in adolescents. In general, both elevated and very low levels are associated with greater adjustment problems. For example, higher levels of the adrenal hormones (androstenedione) are associated with adjustment problems in both boys and girls (Nottelmann et al., 1987). Children with an earlier onset of puberty have significantly higher concentrations of adrenal androgens, estradiol, thyrotropin, and cortisol. They also manifest more psychological disorders (primarily anxiety disorders), self-reported depression, and parent-reported behavior problems (Dorn, Hitt, & Rotenstein, 1999). The relationship between testosterone and aggressive behavior is more pronounced in adolescents with more conflictual parent-child relationships, and this demonstrates the complex interactions between hormonal and environmental factors (Booth, Johnson, Granger, Crouter, & McHale 2003).

It is conceivable that hormones are partially exerting their effects on behavior by triggering the expression of genes that are linked with vulnerability for behavioral disorders. Consistent with this assumption, the heritability estimates for antisocial behavior (Jacobson, Prescott, & Kendler, 2002) and depression (Silberg et al., 1999) increase during adolescence. Further, the relationship between cortisol and behavior may be more pronounced in youth with genetic vulnerabilities. For example, increased cortisol is more strongly associated with behavior problems in boys and girls with fragile X than in their unaffected siblings (Hessl et al., 2002).

To date, there has been relatively little research on the HPG axis and schizophrenia, and there is no database on gonadal hormones in adolescent schizophrenia patients. The available reports on adult schizophrenia patients suggest that estrogen may serve to modulate the severity of psychotic symptoms and enhance prognosis (Huber et al., 2001; Seeman, 1997). Specifically, there is evidence that estrogen may have an ameliorative effect by reducing dopaminergic activity.

The role of the HPA axis in schizophrenia has received greater attention. A large body of research literature suggests a link between exposure to psychosocial stress and symptom relapse and exacerbation in schizophrenia (Walker & Diforio, 1997). It has been suggested that activation of the HPA axis mediates this effect (Walker & Diforio, 1997). Dysregulation of the HPA axis, including elevated baseline cortisol and cortisol response to pharmacological challenge, is often found in unmedicated schizophrenia patients

(e.g., Lammers et al., 1995; Lee, Woo, & Meltzer, 2001; Muck-Seler, Pivac, Jakovljevic, & Brzovic, 1999). Patients with higher cortisol levels have more severe symptoms (Walder, Walker, & Lewine, 2000) and are more likely to commit suicide (Plocka-Lewandowska, Araszkiewicz, & Rybakowski, 2001).

Basic research has demonstrated that cortisol affects the activity of several neurotransmitter systems. This includes dopamine, a neurotransmitter that has been implicated in the etiology of schizophrenia (Walker & Diforio, 1997). The assumption is that increased dopamine activity plays a role in psychotic symptoms. Cortisol secretion augments dopamine activity. Thus it may be that when patients are exposed to stress and elevations in cortisol ensue, dopamine activity increases and symptoms are triggered or exacerbated.

Although there are no published reports on cortisol secretion in adolescents with schizophrenia, HPA axis function has been studied in adolescents with schizotypal personality disorder (Weinstein, Diforio, Schiffman, Walker, & Bonsall, 1999). Schizotypal personality disorder (SPD) involves subclinical manifestations of the symptoms of schizophrenia, including social withdrawal and unusual perceptions and ideas. This disorder is both genetically and developmentally linked with schizophrenia. The genetic link is indicated by the higher rate of SPD in the family members of patients diagnosed with schizophrenia. From a developmental perspective, there is extensive evidence that the defining symptoms of SPD often predate the diagnosis of schizophrenia, usually arising during adolescence.

When compared to healthy adolescents, adolescents with SPD show elevated baseline levels of cortisol (Weinstein et al., 1999) and a more pronounced developmental increase in cortisol when measured over a 2-year period (Walker et al., 2001). Further, SPD adolescents who show a greater developmental rise in cortisol are more likely to have an increase in symptom severity over time. This suggests that increased activation of the HPA axis may contribute to the worsening of symptoms as the child progresses through adolescence.

Research on the role of neurohormones in schizophrenia, especially the gonadal and adrenal hormones, should be given high priority in the future. In particular, it will be important to study hormonal processes in youth at risk for schizophrenia. There are several key questions to be addressed in clinical research. Are hormonal changes linked with the emergence of the prodromal phases of schizophrenia? Do rising levels of adrenal or gonadal hormones precede the onset of symptoms? Is there a relationship between hormonal factors and the brain changes that have been observed in the prodromal phase of schizophrenia? At the same time, basic science research is expected to yield new information about the impact of hormones on gene expression. This may lead to clinical research to explore the role of adolescent hormone changes on the gene expression in humans.

Two of the most often cited areas of the brain said to be abnormal in schizophrenia are the cortices of the frontal and temporal lobes. Indeed, damage to these regions caused by trauma, stroke, or neurological disease is more likely to be associated with psychosis than is damage to other brain regions. Recent studies using neuroimaging techniques have suggested that malfunction at the systems level—that is, at the relationship of processing in the temporal and frontal lobes combined—best characterizes the problem in patients with schizophrenia. For example, in a study of identical twins discordant for schizophrenia, differences within each twin pair in volume of the hippocampus predicted very strongly the difference in the function of the prefrontal cortex assayed physiologically during a cognitive task dependent on the function of the prefrontal cortex (Weinberger, Berman, Suddah, & Torrey, 1992).

A peculiar disturbance in the use of language, so-called thought disorder, is one of the cardinal signs of schizophrenia. Language is highly dependent on frontotemporal circuitry, which is disturbed in schizophrenia. When patients are asked to generate a list of words beginning with a specific consonant, instead of activating the frontal lobes and deactivating the temporal lobes, as seen in healthy subjects, they do the opposite. More detailed analyses have examined declarative memory encoding, storage, and retrieval as related to language. Encoding is ma nipulated by instructing subjects to process material more deeply, as, for example, to make semantic judgments about to-be-remembered words, such as whether the words represent living or nonliving, or abstract or concrete words. This deeper, more elaborate encoding is compared with a shallower, more superficial level of encoding, such as having subjects judge the font (upper case versus lower case) of each word presented. Compared with healthy controls, patients with schizophrenia show different patterns of fMRI activation for semantically encoded words, with significantly reduced left inferior frontal cortex activation but significantly increased left superior temporal cortex activation (Kubicki et al., 2003). During tests of word retrieval, patients with schizophrenia tend to show underengagement of the hippocampus, but at the same time their prefrontal cortex is overactive (Heckers et al., 1998). During performance of effortful tasks, by contrast, people with schizophrenia show increased activity in hippocampus and an alteration in the connection between hippocampus and anterior cingulate cortex (Holcomb et al., 2000; Medoff, Holcomb, Lahti, & Tamminga, 2001). These studies suggest that the information-processing strategy for encoding and retrieving learned information, which depends on an orchestrated duet between frontotemporal brain regions, is disturbed in patients with schizophrenia.

Similar results have been found in studies focused on prefrontal mediated memory, so-called working memory, in which the normal relationships between prefrontal activation and hip-pocampal deactivation are disrupted in schizophrenia (Callicott et al., 2000). Finally, recent statistical approaches to interpreting functional imaging results based on patterns of intercorrelated activity across the whole brain have demonstrated that abnormalities in schizophrenia are distributed across cortical regions. In particular, the pattern based on the normal rela-tionships between prefrontal and temporal cortical activity is especially abnormal (Meyer-Lindenberg et al., 2001). This apparent functional abnormality in intracortical connected-ness has been supported by anatomical evidence from diffusion tensor imaging, which has pointed to an abnormality in the WM links

between frontal and temporal lobes (e.g., Kubicki et al., 2002).

The evidence for abnormal function across distributed cortical circuitry is quite compelling in schizophrenia, and other regions representing other circuits are also implicated (Tamminga et al., 2002; Weinberger et al., 2001). Indeed, it is not clear that any particular area of cortex is normal under all conditions. This may reflect simply the interconnectedness of the brain or it may suggest that schizophrenia is especially characterized by a “dysconnectivity.” It is impossible at the current level of our understanding of the disease to differentiate between these possibilities.

Schizophrenia disrupts not only circuitry linking brain regions but also the microcircuitry within brain regions, as shown by abnormal electrophysiologic activity during simple, early-stage “automatic processing” of stimuli, processing relatively independent of directed, conscious control. For example, healthy subjects automatically generate a robust EEG response in and near primary auditory cortex to tones differing slightly in pitch from others in a series (“mismatch” response), whereas the processing response in schizophrenia to the mismatch is much less pronounced (Wible et al., 2001).

Neurophysiological studies have focused largely on function of the cerebral cortex, but the pharmacological treatment of schizophrenia targets principally the dopamine system, which has long implicated the striatum and related subcortical sites. In fact, cortical function and activity of the subcortical dopamine system are intimately related, consistent with circuitry models of brain function. Animal studies have demonstrated conclusively that perturbations in cortical function, especially prefrontal function, disrupt a normal tonic brake on dopamine neurons in the brainstem, leading to a loss of the normal regulation of these neurons and to their excessive activation (Weinberger et al., 2001). It is thought that the prefrontal cortex helps guide the dopamine reward system toward the reinforcing of contextually appropriate stimuli. In the absence of such normal regulation, reward and motivation may be less appropriately targeted.

Neuroimaging studies of the dopamine system in patients with schizophrenia, particularly those who are actively psychotic, have found evidence of overactivity in the striatum (Laruelle, 2000). Recently, two studies reported that this apparent overactivation of the subcortical dopamine system is strongly predicted by measures of abnormal prefrontal cortical function (Bertolino et al., 2000; Meyer-Lindenberg et al., 2002). Moreover, reducing dopaminergic transmission with dopamine antagonists in subcortical dopamine-rich regions is associated with substantial alterations in frontal cortex function (Holcomb et al., 1996), presumably mediated through circuits connecting the striatum to the frontal cortex (Alexander & Crutcher, 1990). These data illustrate that what happens in the prefrontal cortex is very important to how other brain systems function and that the behavioral disturbances of schizophrenia involve dysfunction of diverse and interconnected brain systems.

Contrary to long-held ideas that the brain was mostly grown-up after childhood, it is now clear that adolescence is a time of explosive growth and development of the brain. While the number of nerve cells does not change after birth, the richness and complexity of the connections between cells do, and the capacity for these networks to process increasingly complex information changes accordingly. Cortical regions that handle abstract information and that are critical for learning and memory of abstract concepts—rules, laws, codes of social conduct—seem to become much more likely to share information in a parallel processing fashion as adulthood approaches. This pattern of increased cortical information sharing is reflected in the patterns of connections between neurons in different regions of the cortex. Thus, the dendritic trees of neurons in the prefrontal cortex become much more complex during adolescence, which indicates that the information flow between neurons