Christine E. Marx

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

Antipsychotic Drugs: Comparison in Animal Models of Efficacy, Neurotransmitter Regulation, and Neuroprotection

Various lines of evidence indicate the presence of progressive pathophysiological processes occurring within the brains of patients with schizophrenia. By modulating chemical neurotransmission, antipsychotic drugs may influence a variety of functions regulating neuronal resilience and viability and have the potential for neuroprotection. This article reviews the current literature describing preclinical and clinical studies that evaluate the efficacy of antipsychotic drugs, their mechanism of action and the potential of first- and second-generation antipsychotic drugs to exert effects on cellular processes that may be neuroprotective in schizophrenia. The evidence to date suggests that although all antipsychotic drugs have the ability to reduce psychotic symptoms via D2 receptor antagonism, some antipsychotics may differ in other pharmacological properties and their capacities to mitigate and possibly reverse cellular processes that may underlie the pathophysiology of schizophrenia.

Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline pregnenolone (rs=−0.76, p=0.037), pregnenolone sulfate (rs=−0.83, p=0.015), and allopregnanolone levels (rs=−0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Olanzapine and clozapine increase the GABAergic neuroactive steroid allopregnanolone in rodents

The neuroactive steroid allopregnanolone is a potent γ-aminobutyric acid type A (GABAA) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5–10.0 mg/kg), clozapine (5.0–20.0 mg/kg), risperidone (0.1–1.0 mg/kg), haloperidol (0.1–1.0 mg/kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine- and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.

Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia

BACKGROUND Cytokines demonstrate diverse actions in the brain and modulate systemic and central nervous system (CNS) responses to injury, infection, and inflammation. Cytokines in the CNS are elevated during infection and ischemia, two neurodevelopmental insults associated with increased schizophrenia risk. We hypothesize that cytokine-mediated neuronal injury during development may contribute to schizophrenia pathophysiology, causing subtle alterations in neuronal number and density. METHODS We examined cytokine regulation of neuronal number in embryonic day 18 rat cortical cultures using MAP-2 immunohistochemistry. Mixed cultures derived from frontal cortex were fixed and stained after 48-hour exposure to the proinflammatory interleukin-1beta (IL-1beta), interleukin-6 (IL-6), or tumor necrosis factor-alpha (TNF-alpha; 0, 10, 100, or 1000 units/mL). RESULTS IL-1beta (maximum effect 35%) and IL-6 (maximum effect 29%) produced dose-dependent decreases in the number of cells (neurons) immunoreactive for MAP-2 antibody, suggesting decreased neuronal survival. TNF-alpha also tended to decrease MAP-2 immunostaining at the highest dose tested. CONCLUSIONS Our data suggest a role for cytokines in the modulation of neuronal survival during neurodevelopment, a finding potentially relevant to schizophrenia pathophysiology. If cytokine-mediated neuronal injury proves to be a common response to gestational insults associated with increased schizophrenia risk, the pharmacologic modulation of these molecules may have clinical utility.

Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics.

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n=14–15 per group, 59–60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABAA and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.

The neurosteroid allopregnanolone is reduced in prefrontal cortex in Alzheimer's disease

BACKGROUND Few data are currently available investigating neurosteroids (NS) in Alzheimers disease (AD). The NS allopregnanolone may be decreased in serum and plasma in patients with AD, but it is unclear if allopregnanolone is also reduced in brain. Because a number of NS exhibit neuroprotective effects and impact cognitive performance in rodent models, these molecules may be relevant to the pathophysiology of neurodegenerative disorders. We therefore investigated prefrontal cortex (PFC) NS levels in AD. METHODS Neurosteroid levels (allopregnanolone, pregnenolone, dehydroepiandrosterone [DHEA]) were determined in postmortem PFC in 14 male subjects with AD and 15 cognitively intact male control subjects by gas chromatography/mass spectrometry preceded by high-performance liquid chromatography purification. RESULTS Subjects with AD exhibit significant reductions in allopregnanolone compared with cognitively intact control subjects (median levels = 2.50 ng/g vs. 5.59 ng/g, respectively; p = .02). Allopregnanolone levels are inversely correlated with neuropathological disease stage (Braak), r = -.49, p = .007. Median DHEA levels are elevated in subjects with AD (p = .01). CONCLUSIONS Subjects with AD demonstrate significant reductions in PFC allopregnanolone levels, a finding that may be relevant to neuropathological disease stage severity. Neurosteroids may have utility as candidate biomarkers in AD.

Olanzapine increases allopregnanolone in the rat cerebral cortex

BACKGROUND The neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) has anxiolytic and anticonvulsant properties, potentiating GABA(A) receptor chloride channel function with 20-fold higher potency than benzodiazepines. Behavioral studies demonstrate that olanzapine has anxiolyticlike properties in animals, but the mechanism responsible for these effects is not clear. We examined the effect of acute olanzapine administration on cerebral cortical allopregnanolone and its relationship to serum progesterone and corticosterone levels in rats. METHODS Male Sprague-Dawley rats were habituated to intraperitoneal (IP) saline injection for 5 days. On the day of the experiment, rats were injected with olanzapine (0, 2.5, 5.0, or 10.0 mg/kg IP, 10-11 rats per condition). Rats were sacrificed 1 hour later, and cerebral cortical allopregnanolone levels and serum progesterone and corticosterone levels were measured by radioimmunoassay. RESULTS Olanzapine increases cerebral cortical allopregnanolone up to fourfold, depending on dose. Positive correlations were observed between cerebral cortical allopregnanolone and serum progesterone levels and between cerebral cortical allopregnanolone and serum corticosterone levels. CONCLUSIONS Olanzapine-induced increases in the potent GABA(A) receptor modulator allopregnanolone may alter GABAergic neurotransmission, possibly contributing to antipsychotic efficacy. If allopregnanolone alterations are linked to psychotic symptom relief, neurosteroids may represent molecules for pharmacologic intervention.

Association of trauma exposure with psychiatric morbidity in military veterans who have served since September 11, 2001

OBJECTIVE This study examined the association of lifetime traumatic stress with psychiatric diagnostic status and symptom severity in veterans serving in the US military after 9/11/01. METHOD Data from 356 US military veterans were analyzed. Measures included a standardized clinical interview measure of psychiatric disorders, and paper-and-pencil assessments of trauma history, demographic variables, intellectual functioning, posttraumatic stress disorder (PTSD) symptoms, depression, alcohol misuse, and global distress. RESULTS Ninety-four percent of respondents reported at least one traumatic stressor meeting DSM-IV criterion A for PTSD (i.e., life threatening event to which the person responded with fear, helplessness or horror), with a mean of four criterion A traumas. Seventy-one percent reported serving in a war-zone, with 50% reporting occurrence of an event meeting criterion A. The rate of current psychiatric disorder in this sample was: 30% PTSD, 20% major depressive disorder, 6% substance abuse or dependence and 10% for the presence of other Axis I psychiatric disorders. After accounting for demographic covariates and combat exposure, childhood physical assault and accident/disasters were most consistently associated with increased likelihood of PTSD. However, PTSD with no comorbid major depressive disorder or substance use disorder was predicted only by combat exposure and adult physical assault. Medical/unexpected-death trauma and adult physical assault were most consistently associated with more severe symptomatology. CONCLUSIONS Particular categories of trauma were differentially associated with the risk of psychiatric diagnosis and current symptom severity. These findings underscore the importance of conducting thorough assessment of multiple trauma exposures when evaluating recently post-deployed veterans.

Access to Medical Care Among Persons With Psychotic and Major Affective Disorders

OBJECTIVE People with serious mental illness have higher mortality rates than the general population, and this difference is not explained by such causes as suicide or accidents. This study therefore examined access and barriers to medical care among persons with serious mental illness. METHODS Using a nationally representative sample, the authors examined access and barriers to medical care among individuals reporting psychotic and mood disorders. The National Health Interview Survey (NHIS) and NHIS-Disability Component for 1994 and 1995 were merged to provide a sample of 156,475 people over age 18. Individuals with psychotic disorders, bipolar disorder, or major depression were compared with persons without mental disorders on the following outcomes: having a primary care physician, being unable to get needed medical care, being unable to get a needed prescription medication, and delaying medical care because of cost. RESULTS Persons with psychotic disorders (odds ratio [OR]=.55, 95% confidence interval [CI]=.44-.69) and bipolar disorder (OR=.74, CI=.56-.98) had significantly reduced odds of having a primary care physician compared with people without mental disorders. For any barriers to care, persons with psychotic disorders, bipolar disorder, or major depressive disorder had greatly increased odds (ORs=2.5-7.0) of reporting difficulties in accessing care. CONCLUSIONS Persons with psychotic disorders and bipolar disorder reported markedly more difficulty in obtaining a primary care physician and greater barriers to care than the general population. Interventions are needed to improve provision of primary medical care to this population.