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Professor of Psychiatry, University of Cincinnati, Cincinnati, Ohio; Director, CME Programs, Psychiatry, University of Cincinnati Hospital, Cincinnati, Ohio
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During the past decade, advances in the neurobiology of schizophrenia generated both grim and hopeful information. A flurry of neuroimaging studies in first-episode psychosis revealed a progressive loss of cortical and subcortical gray matter in schizophrenia associated with acute psychotic episodes[1-6] In childhood-onset schizophrenia, the cortical volume loss was estimated at 1%-3% per year during the first 5 years.[7] Individuals at high risk for schizophrenia also experienced brain tissue loss during the transition from the prodromal phase to psychosis.[8] The most-affected brain regions were consistently found to be the frontal and temporal cortices, the hippocampus, the amygdala, and the thalamus.[3,9] Initially, it was assumed that this was brain atrophy, neurotoxicity, or neurodegeneration that involved loss of neurons in the gray matter. However, it has become apparent that the brain volume decrement was due to shrinkage of the neuropil surrounding the neurons, including reduction in dendrite length by a half and a decrease in the number and size of dendritic extensions.[10,11] Furthermore, a decline in neurotropin 3 (NT-3) was also reported in several studies,[12] suggesting that brain tissue loss during psychosis may be caused by a decline in growth factors that are critical in brain development, neuroplasticity, and synaptic connectivity.
The discovery of severely impaired neuroplasticity led to a shift in the conceptualization of schizophrenia from a neurodevelopmental to a neurodegenerative model, or to a combined model. Clinicians soon associated the clinical and functional deterioration in schizophrenia with the progressive neurodegeneration in this brain disorder. Researchers began to explore the pathogenesis of brain tissue loss in schizophrenia and discovered several interrelated causes. These include:
Despite these discouraging findings, encouragement came with a breakthrough in neuroscience research. A group of Scandinavian researchers showed that functional neurons can, in fact, be generated in the adult human brain in several distinct regions including the dentate gyrus of the hippocampus and the subventricular zone.[21] This process of adult neurogenesis occurs throughout the lifespan and involves proliferation of stem cells into neural progenitor cells of which about 10% survive.[22] The surviving cells differentiate into either neurons or glia, and soon thereafter the newly formed dendrites of the neurons receive glutamatergic input and join the ranks of the existing neuronal network in structure and function.[23]
Initially, the implication of hippocampal neurogenesis was recognized for major depression and stress, in which magnetic resonance imaging and postmortem studies documented hippocampal atrophy.[24] Subsequent research found that all antidepressant drugs and electroconvulsive therapy stimulate hippocampal neurogenesis, leading to a neuroplasticity model for stress-related depression and its treatment.[25] Furthermore, mood stabilizers such as lithium and valproate, which are widely used for the treatment of bipolar disorder, were also found to have neuroprotective properties such as promotion of neurogenesis and regeneration of cortical grey matter.[26,27] These findings are also important given the findings of atrophic brain changes in recurrent bipolar disorder.[28]
The relevance of neuroprotection to schizophrenia emerged as recently as 2000, possibly because the first-generation antipsychotics (FGAs) never gave a promising neurogenesis signal in atrophic brain regions in schizophrenia such as the cerebral cortex or the hippocampus. The main neuroplastic effect associated with FGAs is an increase in caudate nucleus volume,[29] which is considered an undesirable structural and functional effect possibly associated with dopamine upregulation and eventual tardive dyskinesia. The second-generation antipsychotics (SGAs) do not induce caudate hyperplasia[30] and in fact may reverse it.[29]
Except for 1 study of acute haloperidol administration in gerbils by Dawirs and colleagues,[31] who reported an increase in dentate gyrus (DG) and subventricular zone (SVZ) using bromodeoxyuridine (BrdU), an injected labeled nucleic acid incorporated into newly formed cells, as a measure of neurogenesis, no animal study has found any effect of FGAs on neurogenesis. Malberg and colleagues,[32] who were among the first to report increased hippocampal neurogenesis with antidepressants, found no effect from haloperidol. Similarly, Chandramohan and colleagues[33] found no neuronal proliferation or survival in the DG of the hippocampus with haloperidol; negative findings were also reported by Halim and colleagues,[34] Schmitt and colleagues,[35] and Wand and colleagues.[36]
Several studies indicate that not only does haloperidol fail to stimulate neurogenesis in rats, but it also appears to be neurotoxic by inducing apoptotic cell death.[37,38] This may be in part due to the decline of neurotropins, such as brain-derived neurotropic factor (BDNF), which can be reversed by administering FGAs or erythropoietin,[39] which stimulates BDNF.
In contrast to haloperidol, several SGAs were reported to stimulate neurogenesis in the adult rat, except for clozapine, which according to 2 reports has no effect.[34,35] Studies with olanzapine have shown:
Risperidone was also found to stimulate neurogenesis in the SVZ in the study[33] that showed the same effect for olanzapine. In 2 sets of experiments by Nasrallah and colleagues, 1 study showed a small but significant neurogenesis effect by risperidone in the olfactory epithelium,[41] whereas the second study showed a trend but no statistically significant BrdU uptake in the olfactory epithelium, SVZ, or the DG of the hippocampus.[42] Paliperidone, an SGA that is the active metabolite of risperidone and was recently approved for the treatment of schizophrenia, was associated with significant BrdU increases compared with placebo in the olfactory epithelium in both studies[41,42] and in the SVZ in the second study.[42] In similar studies, fluoxetine significantly increased neurogenesis in the hippocampus, but failed to show any increase compared with placebo in the other 2 neurogenic regions, the olfactory epithelium and SVZ. These results suggest that paliperidone stimulates neurogenesis more robustly than risperidone, but also a differential effect of antipsychotics and antidepressants on hippocampal and SVZ neurogenesis.
Quetiapine has been reported to reverse the suppression of hippocampal neurogenesis caused by repeated stress in rats.[43] This implies that quetiapine stimulates neurogenesis, although the study was not done in healthy rats as were the studies of other SGAs described above. However, in another study,[44] quetiapine (10 mg/kg) and venlafaxine (5 mg/kg) each effectively prevented a decrease of the neuroprotective protein heme oxygenase-2 in the hippocampus of stressed rats. Even at lower doses, the 2 drugs worked synergistically. As of January 2008, no studies have been published of neurogenesis with the SGAs aripiprazole and ziprasidone.
As mentioned earlier, the neuroplastic effects of the FGAs appear to be restricted to inducing proliferation of receptors in the basal ganglia, with hyperplasia of the striatum and changes in the morphology and the number of synapses, mainly of the glutamatergic type. Similar changes in the substantia nigra have also been noted.[45] SGAs also influence neuroplasticity, but less in the striatum and more in brain regions implicated in schizophrenia such as the prefrontal and limbic areas. SGAs may enhance synaptic connectivity, which could lead to repairing the diminished neuropil in the cortex of people with schizophrenia. Because of the difficulty of confirming such neuroplastic changes in living patients, morphometric neuroimaging approaches provide the best opportunity to detect volumetric changes over time, or using proton magnetic resonance spectroscopy (MRS) to measure changes in the neuronal marker, N-acetylaspartate (NAA).
The first published study of the effects of an SGA on total or regional cerebral volume was by Lieberman and colleagues,[46] which compared olanzapine with haloperidol in first-episode psychosis during 1 year of treatment; the study included a healthy control group. Analysis of 2-year longitudinal follow-up data showed a whole-brain gray matter volume loss of 12.80 ± 2.51 cm3 (1.9%) for the haloperidol group vs 3.70 ± 1.72 cm3 (0.5%) for the olanzapine group, a significant difference. This is far less severe than in Alzheimer's dementia, in which the annual volume loss is about 5% per year. This well-controlled study suggests that olanzapine is neuroprotective, haloperidol is neurotoxic, or both, and that olanzapine may enhance neuronal resilience in schizophrenia compared with haloperidol.
Close to the same time, however, a carefully done study in which primates received olanzapine or haloperidol for 17-27 months found a decline of about 8%-11% in brain weight and volume with both olanzapine and haloperidol compared with the sham-treated group.[47] The volume reduction was observed in all brain regions but was most noticeable in the frontal and parietal lobes. It is difficult to reconcile the contradictory findings of these studies, but one can assume that the physiologic effect of antipsychotics on the monkey brain may be different from the effect on the brain of humans with acute psychosis.
In another neuroimaging study comparing an FGA (fluphenazine decanoate) with an SGA (risperidone), which included a healthy control group, the risperidone-treated group was found to have significantly greater white matter volume than the fluphenazine decanoate group and than the control group.[48] The authors speculate that risperidone may stimulate the genesis of glial cells, which create the myelin that pervades brain white matter. White matter deficits have been widely documented in schizophrenia,[49] and the study suggests a differential effect of FGAs and SGAs on white matter in schizophrenia. It should be noted that gray matter volume was lower in both the fluphenazine and risperidone groups than in the control group.
Three other studies in first-episode psychosis also suggest that risperidone is associated with an increase in gray matter: in the left caudate and nucleus accumbens,[50] in the thalamic nuclei,[51] and in the superior and middle temporal gyri.[52] A decrease in gray matter in the left rectus gyrus and in white matter was observed in 1 of these studies.[52] Overall, these data suggest that risperidone can induce both gray and white matter neuroplasticity in the first 2-3 months of treatment.
Two MRS studies examined the effects of SGAs on NAA, which is a marker for neurons and reflects neurogenesis in humans. Both studies were done in first-episode manic subjects, and the findings have yet to be documented in schizophrenia. In the first study, olanzapine was associated with a significant increase in NAA in the medial ventral prefrontal region in patients who remitted compared with patients who did not remit after 4 weeks.[53] In the second study, quetiapine was found to significantly increase NAA in the anterior cingulated cerebellar vermis and right ventral prefrontal cortex in adolescents with bipolar disorder after 12 weeks of treatment (MP Delbello, personal communication, 2007). Both studies provide evidence of neuroprotective effects including neurogenesis with olanzapine and quetiapine. Long-term studies with various SGAs would help establish whether the patterns of regional neuroplasticity change over time.
A large and growing body of literature[54] confirm that neurotropins such as nerve growth factor (NGF) and BDNF are reduced in treatment-naive schizophrenia. Since neurotropins play an important role in neuroplasticity and protection against apoptosis, it is reasonable to speculate that a deficit of neurotropins in schizophrenia may be related to the reduced neuropil and atrophic cortical and subcortical changes in schizophrenia. BDNF, for example, has a strong influence on hippocampal volume,[55] known to be diminished in schizophrenia. BDNF is also vital for stem cells,[56] and injecting BDNF into the hippocampus has been shown to stimulate neurogenesis.[57]
FGAs and SGAs have different effects on neurotropins in schizophrenia. In animal experiments, haloperidol causes pronounced reductions in NGF and BDNF, which is reversed by olanzapine and risperidone.[58,59] In a study of first-episode and chronic schizophrenia, NGF was found to be reduced by more than 60% in drug-naive patients, but it was increased by risperidone. However, patients chronically treated with haloperidol and other FGAs were found to have NGF as low as patients with untreated schizophrenia.[60,61] Quetiapine was found to increase NGF acutely in rats, which has been shown to stimulate BDNF expression and to reverse the immobilization stress-induced decrease of BDNF in rat hippocampus,[62] and produce marked elevation of BDNF and fibroblast growth factor 2 (FGF-2) mRNA in rat hippocampus when the NMDA receptor antagonist MK-801 is administered,[63] and to significantly elevate mRNA expression in the neocortex and hippocampus of rats in the absence of stress.[64]
All the leading neurotransmitters that have been implicated in schizophrenia play a role in neurogenesis.
Neuroplasticity and neuroprotection have become the focus of intense research over the past few years especially in psychiatric disorders associated with progressive brain tissue loss such as schizophrenia, bipolar disorder, and major depression. The recent discovery that the psychotropic medications used in treating those disorders are neuroprotective and induce neurogenesis has opened a novel avenue of exploring the causes and healing of neuropsychiatric diseases. A paradigm shift is taking place whereby impairment of adult neurogenesis is being conceptualized as a key mechanism for both psychosis and depression. The previous paradigm in which pharmacologic therapies exert their efficacy primarily on neurochemical pathways is evolving toward a model in which neurotransmitter actions trigger various neuroplasticity cascades to rebuild the neural pathways ravaged by recurrent episodes of psychosis or depression. The stimulation of neurogenesis or neurotropin release may be a means by which SGAs restore structural brain integrity, not just chemical stability. This unexpected paradigm for healing mental illness has emerged during the past 5 years and is still in the early stages of exploration. Studying the long-term effects of SGAs on neural pathways is needed before conclusions can be drawn about the possible reversal of cognitive deficits and negative symptoms, core clinical manifestations of schizophrenia.
These encouraging early findings may launch novel approaches to developing new drugs to treat mental illness. Specific neuroprotective properties may become benchmarks as a complement to or substitute for behavioral effects in taking a new molecule from the laboratory to the clinic. Given the complexity of the neural pathways involved in mental illness, further advances in psychopharmacology may include an array of innovative approaches to brain repair.
This activity is supported by an independent educational grant from Vanda Pharmaceuticals.
