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Significance There are no biomarkers for schizophrenia (SCZ), a disorder of dysfunctional neural networks. We demonstrate that a master regulator of cytoskeleton (“CRMP2”) and, hence, neural circuitry, may form the basis for such a biomarker because its activity is uniquely imbalanced in SCZ patients. We show that SCZ patients are characterized by an excess of active CRMP2 not only in their brains (where it is correlated with dendritic abnormalities) but also in their peripheral blood lymphocytes. The abundance of active CRMP2 and insufficiency of opposing inactive p-CRMP2 likely disrupts neuronal function. Because peripheral blood CRMP2 appears to reflect intracerebral processes, it could form the basis of a rapid, minimally invasive, sensitive, and specific clinical diagnostic aid for SCZ in young patients., There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2’s activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients

Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia and bipolar disorder previously were shown to exhibit dendritic arbor pathology. This study sought to determine whether MARCKS, its regulatory protein dysbindin-1, and two proteins, identified using microarray data, CDC42BPA and ARHGEF6, were associated with dendritic arbor pathology in the DLPFC from schizophrenia and bipolar disorder subjects. Using western blotting, relative protein expression was assessed in the DLPFC (BA 46) grey matter from subjects with schizophrenia (n = 19), bipolar disorder (n = 17) and unaffected control subjects (n = 19). Protein expression data were then correlated with dendritic parameter data obtained previously. MARCKS and dysbindin-1a expression levels did not differ among the three groups. Dysbindin-1b expression was 26% higher in schizophrenia subjects (p = 0.01) and correlated inversely with basilar dendrite length (r = -0.31, p = 0.048) and the number of spines per basilar dendrite (r = -0.31, p = 0.048), but not with dendritic spine density (r = -0.16, p = 0.32). The protein expression of CDC42BPA was 33% higher in schizophrenia subjects (p = 0.03) but, did not correlate with any dendritic parameter (p > 0.05). ARHGEF6 87 kDa isoform expression did not differ among the groups. CDC42BPA expression was not altered in frontal cortex from rats chronically administered haloperidol or clozapine. Dysbindin-1b appears to play a role in dendritic arbor pathology observed previously in the DLPFC in schizophrenia.

Nearly 60 years ago Seymour Kety proposed that research on genetics and brain pathology, but not on neurochemistry, would ultimately lead to an understanding of the pathophysiology of schizophrenia. This article will demonstrate the prescience of Kety's proposal; advances in our knowledge of brain structure and genetics have shaped our current understanding of the pathophysiology of schizophrenia. Brain-imaging techniques have shown that schizophrenia is associated with cortical atrophy and ventricular enlargement, which progresses for at least a decade after the onset of psychotic symptoms. Cortical atrophy correlates with negative symptoms and cognitive impairment, but not with psychotic symptoms, in schizophrenia. Studies with the Golgi-staining technique that illuminates the entire neuron indicate that cortical atrophy is due to reduced synaptic connectivity on the pyramidal neurons and not due to actual loss of neurons. Results of recent genetic studies indicate that several risk genes for schizophrenia are within two degrees of separation from the N-methy-D-aspartate receptor (NMDAR), a subtype of glutamate receptor that is critical to synapse formation and synaptic plasticity. Inactivation of one of these risk genes that encodes serine racemase, which synthesizes D-serine, an NMDAR co-agonist, reproduces the synaptic pathology of schizophrenia. Thus, widespread loss of cortical synaptic connectivity appears to be the primary pathology in schizophrenia that is driven by multiple risk genes that adversely affect synaptogenesis and synapse maintenance, as hypothesized by Kety.

Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759-765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis.This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis.We used ex vivo ¹³C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-¹³C]glucose and [1,2-¹³C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months.Administration of haloperidol for 1 month produced no changes in ¹³C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased ¹³C labeling of glutamine by [1,2-¹³C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort.Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment.

The molecular pathogenesis of bipolar disorder (BPD) is poorly understood. Using human-induced pluripotent stem cells (hiPSCs) to unravel such mechanisms in polygenic diseases is generally challenging. However, hiPSCs from BPD patients responsive to lithium offered unique opportunities to discern lithium's target and hence gain molecular insight into BPD. By profiling the proteomics of BDP-hiPSC-derived neurons, we found that lithium alters the phosphorylation state of collapsin response mediator protein-2 (CRMP2). Active non-phosphorylated CRMP2, which binds cytoskeleton, is present throughout the neuron; inactive phosphorylated CRMP2, which dissociates from cytoskeleton, exits dendritic spines. CRMP2 elimination yields aberrant dendritogenesis with diminished spine density and lost lithium responsiveness (LiR). The "set-point" for the ratio of pCRMP2: CRMP2 is elevated uniquely in hiPSC-derived neurons from LiR BPD patients, but not with other psychiatric (including lithium-nonresponsive BPD) and neurological disorders. Lithium (and other pathway modulators) lowers pCRMP2, increasing spine area and density. Human BPD brains show similarly elevated ratios and diminished spine densities; lithium therapy normalizes the ratios and spines. Consistent with such "spine-opathies," human LiR BPD neurons with abnormal ratios evince abnormally steep slopes for calcium flux; lithium normalizes both. Behaviorally, transgenic mice that reproduce lithium's postulated site-of-action in dephosphorylating CRMP2 emulate LiR in BPD. These data suggest that the " lithium response pathway" in BPD governs CRMP2's phosphorylation, which regulates cytoskeletal organization, particularly in spines, modulating neural networks. Aberrations in the posttranslational regulation of this developmentally critical molecule may underlie LiR BPD pathogenesis. Instructively, examining the proteomic profile in hiPSCs of a functional agent-even one whose mechanism-of-action is unknown-might reveal otherwise inscrutable intracellular pathogenic pathways., Funding Agencies:NIH's Library of Integrated Network-based Cellular Signatures Program Viterbi Foundation Neuroscience Initiative Stanley Medical Research Institute R21MH093958 R33MH087896 R01MH095088 Tau Consortium California Institute of Regenerative Medicine training grants University of California, San Diego T32 training grant in psychiatry California Bipolar Foundation International Bipolar Foundation Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Ministry of Education, Science, Sports and Culture in Japan 42890001 RC2MH090011

The authors report clinical features and treatment response in 25 patients with catatonia admitted to an inpatient psychiatric unit specializing in psychotic disorders. Electroconvulsive therapy, benzodiazepines, and clozapine had beneficial effects on catatonic features, whereas typical antipsychotics resulted in clinical worsening.

Schizophrenia is a severe, persistent mental illness associated with substantial disability. The pattern of inheritance is consistent with multiple genes, and genetic predisposition interacts with environmental factors. Several neurotransmitter systems, particularly the dopamine system, have been implicated. Antipsychotics work primarily by blocking dopamine D 2 receptors, but alterations in dopamine neurotransmission cannot explain the myriad symptoms of schizophrenia. Glutamate, γ-aminobutyric acid, and acetylcholine neurotransmitter systems play roles in the pathophysiology of schizophrenia, and alterations in glial function are implicated. Changes in astrocyte function lead to problems with energy metabolism, oligodendrocyte deficits to problems with myelination and lipid metabolism, and microglial activation to alterations in immune function and inflammation. Cortical neuronal atrophy, reduced dendritic complexity, and decreased spines indicate a substantial loss of cortical synaptic connectivity. This complex neuropathology concurs with the complex genetics of schizophrenia. Greater understanding of the pathogenesis and pathophysiology of schizophrenia should lead to improved treatment and prevention.

Background: Decreased availability of the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-serine is thought to promote NMDAR hypofunction and contribute to the pathophysiology of schizophrenia, including neuroanatomical abnormalities, such as cortical atrophy and ventricular enlargement, and neurochemical abnormalities, such as aberrant glutamate and γ-aminobutyric acid (GABA) signaling. It is thought that these abnormalities directly relate to the negative symptoms and cognitive impairments that are hallmarks of the disorder. Because of the genetic complexity of schizophrenia, animal models of the disorder are extremely valuable for the study of genetically predisposing factors. Our laboratory developed a transgenic mouse model lacking serine racemase (SR), the synthetic enzyme of d-serine, polymorphisms of which are associated with schizophrenia. Null mutants (SR−/−) exhibit NMDAR hypofunction and cognitive impairments. We used 9.4 T magnetic resonance imaging (MRI) and proton spectroscopy (MRS) to compare in vivo brain structure and neurochemistry in wildtype (WT) and SR−/− mice. Methods: Mice were anesthetized with isoflurane for MRI and MRS scans. Results: Compared to WT controls, SR−/− mice exhibited 23% larger ventricular volumes (p

We previously observed dendritic spine loss in the dorsolateral prefrontal cortex (DLPFC) from schizophrenia and bipolar disorder subjects. In the current study, we sought to determine if the mRNA expression of genes known to regulate the actin cytoskeleton and spines correlated with spine loss.Five candidate genes were identified using previously obtained microarray data from the DLPFC from schizophrenia and control subjects. The relative mRNA expression of the genes linked to dendritic spine growth and function, i.e. IGF1R, MARCKS, PPP1R9A, PTPRF, and ARHGEF2, was assessed using quantitative real-time PCR (qRT-PCR) in the DLPFC from a second cohort including schizophrenia, bipolar disorder, and control subjects. Functional pathway analysis was conducted to determine which actin cytoskeleton-regulatory pathways the genes of interest interact with.MARCKS mRNA expression was increased in both schizophrenia and bipolar disorder subjects. PPP1R9A mRNA expression was increased in bipolar disorder subjects. For IGF1R, mRNA expression did not differ significantly among groups; however, it did show a significant, negative correlation with dendrite length. MARCKS and PPP1R9A mRNA expression did not correlate with spine loss, but they interact with NMDA receptor signaling pathways that regulate the actin cytoskeleton and spines.MARCKS and PPP1R9A might contribute to spine loss in schizophrenia and bipolar disorder through their interactions, possibly indirect ones, with NMDA signaling pathways that regulate spine structure and function.

In their excellent article published in this issue of Biological Psychiatry, MacDonald et al. (1) report on altered expression of proteins involved in glutamate signaling pathways in the primary auditory cortex of subjects with schizophrenia. In particular, they focused on protein co-expression that is inferred when the levels of different proteins are correlated across a cohort of subjects. In schizophrenia subjects, protein co-expression was found to be decreased overall. However, the co-expression of a small cluster of postsynaptic density proteins, unique to schizophrenia subjects, was surprisingly increased but correlated negatively with dendritic spine density. Spines are highly dynamic structures, and the actin cytoskeleton plays a crucial role in their morphology and function. In the cell, actin exists in two forms: globular (G-actin) and filamentous (F-actin). G-actin is polymerized to form F-actin that is an important component of the actin cytoskeleton. Actin filaments are polarized, and unless capped by actin-capping proteins, undergo treadmilling with polymerization occurring at the barbed end and depolymerization at the pointed end. Several actin-binding proteins have been identified that regulate the length, cross-linking, stability and mechanical properties of actin filaments. Synaptic activity has a profound impact on the generation and morphology of dendritic spines, and most excitatory glutamatergic neurotransmission occur at synapses localized to spines. Stimulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors affects the formation of spines and their morphology by reorganizing the actin cytoskeleton (2). NMDA receptor activation also results in the trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type glutamate receptors to dendritic spines (3). AMPA receptor stimulation causes the reorganization of the spine actin cytoskeleton and alteration of spine morphology (2). Maintenance of spines requires the persistent activation of AMPA receptors by spontaneously released glutamate (4). MacDonald et al. utilized liquid chromatograph-selected reaction monitoring/mass spectrometry (LC-SRM/MS) to analyze 223 peptides generated from 155 proteins isolated from the auditory cortex from schizophrenia and control subjects. Functional annotation analysis using DAVID identified 4 proteins that were expressed differentially in schizophrenia and participate in glutamate signaling pathways. These proteins are GRIA3, GRIA4, ATP1A3, and GNAQ. GRIA3 and GRIA4 code for AMPA receptor subunits, and ATP1A3 is a sodium/potassium transporter involved in NMDA receptor function (5). Thus, this study has identified alterations in glutamate signaling molecules in a brain area (e.g., auditory cortex) that exhibits dendritic spine loss. In addition to protein expression analyses, MacDonald et al. also conducted protein co-expression analyses using an adaptation of the weighted gene co-expression network analysis (WGCNA) approach. In general, protein co-expression was reduced in schizophrenia subjects. However, a cluster of proteins, unique to the schizophrenia subjects, showed increased co-expression. This unique cluster was enriched with proteins involved in the cytoskeleton, synapses, and the postsynaptic density. In addition, there was a significant negative correlation between protein expression within this unique cluster and spine density in the auditory cortex in schizophrenia subjects. Thus, this study identified a unique cluster of proteins that might play a significant role in the pathophysiology of schizophrenia. The study by MacDonald et al. has several important strengths. The authors used sophisticated techniques to analyze protein expression and rigorous models to assess functional analyses and protein co-expression. Schizophrenia and control subjects were well matched for age and other demographic variables. In addition, the post-mortem intervals (PMIs) were relatively low. The authors also attempted to control for the potential confound of antipsychotic medication treatment by measuring the protein expression of GRIA4, GRIA3, ATP1A3 and GNAQ in rhesus monkeys administered haloperidol or clozapine for 6 months. In the Discussion section, the authors address the two major limitations of this study: cortical layer and cell type specificity. Spine loss was observed previously in the deep layer III of the auditory cortex (6). This study collected protein from tissue blocks containing all cortical layers. In addition, spine loss occurs chiefly on pyramidal cells in the auditory cortex, and this study included all cell types. As the authors suggest, proteomic analysis utilizing laser microdissection coupled with multiple label quantitative fluorescence microscopy would overcome these significant limitations. In addition to laminar and cellular specificity, future studies ought to include a cohort of subjects with bipolar disorder. Recently, dendritic spine loss was observed in the DLPFC deep layer III pyramidal cells from bipolar disorder subjects (7). Thus, dendritic spine loss might not be specific to schizophrenia, but rather a marker of severe psychopathology or perhaps, psychosis. Although the reductions in dendritic length and in spine density in Golgi studies in schizophrenia may individually appear modest, the total reduction in glutamatergic synapses (spine density X dendritic length) is substantial, ranging from 20 to nearly 40 percent, depending on the study (6, 7). This loss of dendritic spines is consistent with the approximate 30 percent decrease in GRIA3 and 4 described in the auditory cortex by MacDonald et al. Using co-expression network analysis, they also observe a robust inverse relationship between spine density and a family of proteins that play a critical role in spine structure and function (i.e, two ankyrin 1 and 2, alpha1 spectrin and a vesicle recovery protein). A plausible explanation is that neurons attempt to compensate for the loss of excitatory synapses by increasing the functional and structural integrity of the remaining spines. Consistent with this interpretation, Hengen et al. have described homeostatic mechanisms that maintain stable circuit activity by keeping neuronal function within a set-point range in spite of disrupted synaptic input (8). Recent evidence supports NMDA receptor hypofunction as a related component of schizophrenia pathology with several schizophrenia susceptibility genes within one degree of separation from the NMDA receptor including serine racemase, which synthesizes the cortical NMDA receptor co-agonist, D-serine, and NR2A, a NMDA receptor subunit (9). Since activation of NMDA receptors promotes the incorporation of AMPA receptors into the synapse, the up-regulation of Gα(q), which mediates the effects of mGluR5 activation (5), could serve to enhance NMDA receptor function through its phosphorylation as another mechanism to partially overcome the loss of excitatory synapses. Thus, the alterations in glutamatergic signaling molecules in schizophrenia documented in this study may help explain the disorganized cortical neuronal activity observed in schizophrenia (10) but also highlight compensatory processes that might forestall a catastrophic collapse of cortical processing in the context of this substantial loss of glutamatergic synaptic connectivity in schizophrenia. In summary, MacDonald et al. provide an elegant and technically sophisticated analysis of protein expression and co-expression related to dendritic spine loss in the auditory cortex from schizophrenia subjects. The study marshalls evidence for substantial reductions in glutamatergic neurotransmission in the auditory cortex and identifies a novel cluster of proteins whose expression negatively correlated with spine loss and may represent compensatory responses to the primary synaptic pathology.

Publisher Summary This chapter reviews the compelling evidence that schizophrenia is a brain disease with a high degree of heri­tability. The conceptualization of schizophrenia as a specific dis­ease occurred at the turn of the last century. The schizophrenia disease has its age of symptomatic onset in late adolescence and early adult­hood in males and somewhat later in females, who tend to be less severely affected. Since schizophrenia starts in young adulthood and is known as a lifelong disorder, it produces a substantial degree of persistent disability. Schizophrenia does not follow a Mendelian inheritance pattern and cannot be attributed to a single gene or genetic abnormality. The pattern of distribution of schizophrenia within affected families, with a rapid tailing off of concor­dance in identical twins (approximately 60%) versus fraternal twins and first-degree relatives (10%) versus second-degree relatives (3%), is consistent with complex genetics, in which many genes of small effect interact to contribute to the phe­notype. Retrospective and prospective studies of children, who are at genetic high risk for schizophrenia, indicate that subtle abnor­malities in cognitive function and attention, social oddness and motor clumsiness are often present years before the onset of psychosis. The variation in symptomatic features of schizophrenia across individuals and the common nature of the disorder strongly suggest that there can be multiple causes that result in the phenotype.

Schizophrenia affects approximately 1% of the population and continues to be associated with poor outcome because of the limited efficacy of and noncompliance with existing antipsychotic medications. An alternative hypothesis invoking the excitatory neurotransmitter, glutamate, arose out of clinical observations that NMDA receptor antagonists, the dissociative anesthetics like ketamine, can replicate in normal individuals the full range of symptoms of schizophrenia including psychosis, negative symptoms, and cognitive impairments. Low dose ketamine can also re-create a number of physiologic abnormalities characteristic of schizophrenia. Postmortem studies have revealed abnormalities in endogenous modulators of NMDA receptors in schizophrenia as well as components of a postsynaptic density where NMDA receptors are localized. Gene association studies have revealed several genes that affect NMDA receptor function whose allelic variants are associated with increased risk for schizophrenia including genes encoding D-amino acid oxidase, its modulator G72, dysbindin, and neuregulin. The parvalbumin-positive, fast-firing GABAergic interneurons that provide recurrent inhibition to cortical-limbic pyramidal neurons seem to be most sensitive to NMDA receptor hypofunction. As a consequence, disinhibition of glutamatergic efferents disrupts cortical processing, causing cognitive impairments and negative symptoms, and drives subcortical dopamine release, resulting in psychosis. Drugs designed to correct the cortical-limbic dysregulated glutamatergic neurotransmission show promise for reducing negative and cognitive symptoms of schizophrenia as well as its positive symptoms.

Background Both in vivo and postmortem studies suggest that oligodendrocyte and myelination alterations are present in individuals with schizophrenia. However, it is unclear whether prolonged treatment with antipsychotic medications contributes to these disturbances. We recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine was associated with a 10%–18% lower glial cell number in the parietal grey matter. Consequently, in this study we sought to determine whether the lower glial cell number was due to fewer oligodendrocytes as opposed to lower numbers of astrocytes. Methods With fluorescent immunocytochemical techniques, we optimized the visualization of each cell type throughout the entire thickness of tissue sections, while minimizing final tissue shrinkage. As a result, we were able to obtain robust stereological estimates of total oligodendrocyte and astrocyte numbers in the parietal grey matter with the optical fractionator method. Results We found a significant 20.5% lower astrocyte number with a non-significant 12.9% lower oligodendrocyte number in the antipsychotic-exposed monkeys. Similar effects were seen in both the haloperidol and olanzapine groups. Conclusions These findings suggest that studies investigating glial cell alterations in schizophrenia must take into account the effect of antipsychotic treatment.

Both in vivo and post-mortem investigations have demonstrated smaller volumes of the whole brain and of certain brain regions in individuals with schizophrenia. It is unclear to what degree such smaller volumes are due to the illness or to the effects of antipsychotic medication treatment. Indeed, we recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine, at doses producing plasma levels in the therapeutic range in schizophrenia subjects, was associated with significantly smaller total brain weight and volume, including an 11.8-15.2% smaller gray matter volume in the left parietal lobe. Consequently, in this study we sought to determine whether these smaller volumes were associated with lower numbers of the gray matter's constituent cellular elements. The use of point counting and Cavalieri's principle on Nissl-stained sections confirmed a 14.6% smaller gray matter volume in the left parietal lobe from antipsychotic-exposed monkeys. Use of the optical fractionator method to estimate the number of each cell type in the gray matter revealed a significant 14.2% lower glial cell number with a concomitant 10.2% higher neuron density. The numbers of neurons and endothelial cells did not differ between groups. Together, the findings of smaller gray matter volume, lower glial cell number, and higher neuron density without a difference in total neuron number in antipsychotic-exposed monkeys parallel the results of post-mortem schizophrenia studies, and raise the possibility that such observations in schizophrenia subjects might be due, at least in part, to antipsychotic medication effects.

Background: The axon terminals of GABAergic chandelier cells form linear arrays, termed cartridges, that synapse on the axon initial segment of neocortical pyramidal cells. These cartridges are immunoreactive for the GABA membrane transporter-1, and the density of GABA membrane transporter-1-immunoreactive cartridges in the prefrontal cortex has been reported to be reduced in schizophrenia. The goal of this study was to determine if reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in schizophrenia are restricted to the prefrontal cortex. Methods: Relative GABA membrane transporter-1-immunoreactive cartridge density was determined in auditory association area 42, a region previously implicated in the pathophysiology of schizophrenia, in 14 matched pairs of subjects with schizophrenia and normal comparison subjects. The results were compared with similar data from prefrontal area 46 in the same subjects. Results: Mean GABA membrane transporter-1-immunoreactive cartridge density in area 42 was decreased by 9.8% in layers II–IIIa, and by 11.9% in layer VI in subjects with schizophrenia, although these differences did not achieve statistical significance. However, the magnitude of the reductions in the density of GABA membrane transporter-1-immunoreactive cartridges in area 42 of the subjects with schizophrenia was not significantly smaller than those in area 46. Conclusions: In subjects with schizophrenia, alterations in chandelier neuron axon cartridges appear to be more marked in the prefrontal cortex than in another cortical region implicated in the illness, although such changes might not be restricted to the prefrontal cortex.

Importance Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition. Objective To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder. Design, Setting, and Participants This study used postmortem human brain tissue from individuals with schizophrenia (n = 14), individuals with bipolar disorder (n = 9), and unaffected control participants (n = 19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed. Main Outcomes and Measures The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters. Results The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/μm) compared with control participants (0.31 [0.05] spines/μm) ( P = .02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/μm) but just missed significance when compared with control participants ( P = .06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [ P = .003]; individuals with bipolar disorder vs controls: 25.8% reduction [ P = .005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] μm, respectively) compared with controls (301.8 [75.1] μm) (individuals with schizophrenia vs controls: 18.3% reduction [ P = .005]; individuals with bipolar disorder vs controls: 18.6% reduction [ P = .005]). Conclusions and Relevance Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features.