Current Psychiatry

Discuss this article at www.facebook.com/CurrentPsychiatry

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

Dr. Zhang reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

Discuss this article at www.facebook.com/CurrentPsychiatry

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

Dr. Zhang reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

Discuss this article at www.facebook.com/CurrentPsychiatry

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

Dr. Zhang reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

Discuss this article at www.facebook.com/CurrentPsychiatry

Together with a clinical assessment, neuroimaging increases diagnostic accuracy of detecting neuropathology. Direct patient benefit from scanning is best documented in those with overt, new clinical signs and symptoms of neurologic or psychiatric disease.^1,2

Computerized tomography (CT) and magnetic resonance imaging (MRI) are the most common head scanning techniques used in emergency medicine.³ CT is quicker and cheaper, has less movement artifact, and is excellent at delineating acute hemorrhage, calcification, and bony anatomy.^3,4 Unfortunately, CT exposes patients to radiation and poorly visualizes white matter or posterior fossa pathology.⁴

MRI is outstanding for well-defined tissue contrast in multiplanar views and excellent for identifying demyelination or metastatic processes,⁵ but may be contraindicated for patients with implanted metallic objects such as pacemakers, certain vascular clips or stents, and certain orthopedic devices.^3-5 Some patients cannot tolerate the narrow space surrounding them during an MRI.^4,5

Safety concerns with CT during pregnancy are well established, but are less clear with MRI. The opposite is true of contrast enhancement; gadolinium with MRI is better tolerated than CT procedures, for which contrast risks include allergy and renal dysfunction. When scanning for a hemorrhage, select a CT scan for patients in whom you suspect bleeding developed within the past 3 days; MRI may be better at screening for older bleeds.

For a list of indications for which a patient should undergo a CT or MRI, see the Table.^1-5

Table

Indications for CT or MRI

Disclosure

Dr. Lippmann reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Together with a clinical assessment, neuroimaging increases diagnostic accuracy of detecting neuropathology. Direct patient benefit from scanning is best documented in those with overt, new clinical signs and symptoms of neurologic or psychiatric disease.^1,2

Computerized tomography (CT) and magnetic resonance imaging (MRI) are the most common head scanning techniques used in emergency medicine.³ CT is quicker and cheaper, has less movement artifact, and is excellent at delineating acute hemorrhage, calcification, and bony anatomy.^3,4 Unfortunately, CT exposes patients to radiation and poorly visualizes white matter or posterior fossa pathology.⁴

MRI is outstanding for well-defined tissue contrast in multiplanar views and excellent for identifying demyelination or metastatic processes,⁵ but may be contraindicated for patients with implanted metallic objects such as pacemakers, certain vascular clips or stents, and certain orthopedic devices.^3-5 Some patients cannot tolerate the narrow space surrounding them during an MRI.^4,5

Safety concerns with CT during pregnancy are well established, but are less clear with MRI. The opposite is true of contrast enhancement; gadolinium with MRI is better tolerated than CT procedures, for which contrast risks include allergy and renal dysfunction. When scanning for a hemorrhage, select a CT scan for patients in whom you suspect bleeding developed within the past 3 days; MRI may be better at screening for older bleeds.

For a list of indications for which a patient should undergo a CT or MRI, see the Table.^1-5

Table

Indications for CT or MRI

Disclosure

Dr. Lippmann reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Together with a clinical assessment, neuroimaging increases diagnostic accuracy of detecting neuropathology. Direct patient benefit from scanning is best documented in those with overt, new clinical signs and symptoms of neurologic or psychiatric disease.^1,2

Computerized tomography (CT) and magnetic resonance imaging (MRI) are the most common head scanning techniques used in emergency medicine.³ CT is quicker and cheaper, has less movement artifact, and is excellent at delineating acute hemorrhage, calcification, and bony anatomy.^3,4 Unfortunately, CT exposes patients to radiation and poorly visualizes white matter or posterior fossa pathology.⁴

MRI is outstanding for well-defined tissue contrast in multiplanar views and excellent for identifying demyelination or metastatic processes,⁵ but may be contraindicated for patients with implanted metallic objects such as pacemakers, certain vascular clips or stents, and certain orthopedic devices.^3-5 Some patients cannot tolerate the narrow space surrounding them during an MRI.^4,5

Safety concerns with CT during pregnancy are well established, but are less clear with MRI. The opposite is true of contrast enhancement; gadolinium with MRI is better tolerated than CT procedures, for which contrast risks include allergy and renal dysfunction. When scanning for a hemorrhage, select a CT scan for patients in whom you suspect bleeding developed within the past 3 days; MRI may be better at screening for older bleeds.

For a list of indications for which a patient should undergo a CT or MRI, see the Table.^1-5

Table

Indications for CT or MRI

Disclosure

Dr. Lippmann reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because documentation is an important part of medical practice,¹ numerous tools have been developed to help physicians across all specialties, including the best-known acronym SOAP, which stands for Subjective, Objective, Assessment, and Plan. The SOAP note has been used in mental health settings,² although this format may fall short for psychiatrists because objective tests are not diagnostic. Also, there’s no clear guidance to document specific information, such as behavioral risk assessment.

The acronym PROMISE—Problems, Resolved, Outcomes, Medications, Instructions, Safety, and Education—may be better suited for psychiatric documentation. The PROMISE note provides an easy-to-remember method to document specific information that might be overlooked in a less detailed format, such as normal findings, adherence and tolerability to medications, outcome ratings, and risk assessment.

Problems are described as ongoing symptoms, signs, and stressors. Resolved indicates improvement and normal findings. Outcome measures include patient or clinician rating scales. Medications documents the effectiveness and tolerability of current and past medications. Instructions are directives given; the rationale—cost-benefit analysis—can be documented in this section as well. Safety describes a behavioral risk assessment, including demographic, historical, clinical, and environmental risk and protective factors regarding suicidal or homicidal behavior. Education describes the verbal or written material shared with the patient.

Psychotherapists can use the same template. For them the M would stand for Methods of psychotherapy practiced in the session.

For an example of the PROMISE note used in practice, see the Table.

Table

Example of a patient’s PROMISE note

Disclosure

Dr. Bastiaens reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because documentation is an important part of medical practice,¹ numerous tools have been developed to help physicians across all specialties, including the best-known acronym SOAP, which stands for Subjective, Objective, Assessment, and Plan. The SOAP note has been used in mental health settings,² although this format may fall short for psychiatrists because objective tests are not diagnostic. Also, there’s no clear guidance to document specific information, such as behavioral risk assessment.

The acronym PROMISE—Problems, Resolved, Outcomes, Medications, Instructions, Safety, and Education—may be better suited for psychiatric documentation. The PROMISE note provides an easy-to-remember method to document specific information that might be overlooked in a less detailed format, such as normal findings, adherence and tolerability to medications, outcome ratings, and risk assessment.

Problems are described as ongoing symptoms, signs, and stressors. Resolved indicates improvement and normal findings. Outcome measures include patient or clinician rating scales. Medications documents the effectiveness and tolerability of current and past medications. Instructions are directives given; the rationale—cost-benefit analysis—can be documented in this section as well. Safety describes a behavioral risk assessment, including demographic, historical, clinical, and environmental risk and protective factors regarding suicidal or homicidal behavior. Education describes the verbal or written material shared with the patient.

Psychotherapists can use the same template. For them the M would stand for Methods of psychotherapy practiced in the session.

For an example of the PROMISE note used in practice, see the Table.

Table

Example of a patient’s PROMISE note

Disclosure

Dr. Bastiaens reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Because documentation is an important part of medical practice,¹ numerous tools have been developed to help physicians across all specialties, including the best-known acronym SOAP, which stands for Subjective, Objective, Assessment, and Plan. The SOAP note has been used in mental health settings,² although this format may fall short for psychiatrists because objective tests are not diagnostic. Also, there’s no clear guidance to document specific information, such as behavioral risk assessment.

The acronym PROMISE—Problems, Resolved, Outcomes, Medications, Instructions, Safety, and Education—may be better suited for psychiatric documentation. The PROMISE note provides an easy-to-remember method to document specific information that might be overlooked in a less detailed format, such as normal findings, adherence and tolerability to medications, outcome ratings, and risk assessment.

Problems are described as ongoing symptoms, signs, and stressors. Resolved indicates improvement and normal findings. Outcome measures include patient or clinician rating scales. Medications documents the effectiveness and tolerability of current and past medications. Instructions are directives given; the rationale—cost-benefit analysis—can be documented in this section as well. Safety describes a behavioral risk assessment, including demographic, historical, clinical, and environmental risk and protective factors regarding suicidal or homicidal behavior. Education describes the verbal or written material shared with the patient.

Psychotherapists can use the same template. For them the M would stand for Methods of psychotherapy practiced in the session.

For an example of the PROMISE note used in practice, see the Table.

Table

Example of a patient’s PROMISE note

Disclosure

Dr. Bastiaens reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman,

At the general hospital where I work, doctors and nurses sometimes ask me to fill out psychiatric “hold” documents to keep seriously ill medical or surgical patients from leaving the hospital. Last week, they asked me to stop Mr. J, a man with diabetes and a gangrenous lower leg, from leaving against medical advice (AMA). If he left, he would die. But if I filled out the psychiatric “hold,” I’d be saying the man needed civil commitment for a mental illness, which wasn’t true. If this happens again, what should I do?
Submitted by “Dr. Q”

“It is tempting, if the only tool you have is a hammer, to treat everything as if it were a nail,” wrote Abraham Maslow.¹ The situation Dr. Q describes is one that psychiatrists frequently encounter because in some situations, a psychiatric “hold” can seem like the only way to stop a physically ill patient from leaving the hospital AMA. But pounding on this problem with a civil commitment hammer is the wrong response.

What’s wrong with using psychiatric holds in these situations? Do doctors have any other equipment in their medical toolbox for stopping an improvident AMA departure? To find out, we’ll look at:

• what a psychiatric hold does
• why holds don’t apply to medical-surgical treatment
• alternative responses to patients who lack capacity to refuse care.

Psychiatric holds

All states have laws that permit involuntary psychiatric hospitalization. The wording and procedural details in these laws vary across jurisdictions, but all states allow civil (ie, noncriminal) commitment of mentally ill persons who have gross impairments of judgment, behavior, reality-testing, or everyday functioning if their recent behavior show that they pose a danger because of their mental illness.² Table 1³ lists examples of the types of dangers that are potential reasons for civil commitment.

Table 1

Types of risks covered in civil commitment statutes

State laws also allow certain individuals (eg, police) to apprehend and transport mentally ill persons to facilities for psychiatric evaluation. Doctors may hold these persons temporarily until a court decides whether a longer involuntary hospitalization is justified. The documents used to initiate psychiatric holds have various informal names—”5150” (California), “pink slip” (Ohio), “pink paper” (Massachusetts), “Baker Act Form” (Florida)—but their function is the same: permitting lawful restraint of patients whose dangerousness results from their mental illness.

Urgent medical and surgical care

What about medical or surgical patients who refuse care despite being told they’ll die without it? Might involuntary psychiatric hospitalization procedures be a convenient way to keep them from coming to harm?

The answer: probably not, for 4 reasons:

1. Once a psychiatric hold has been executed, the person who is subject to detention must be transferred to an appropriate facility within a specified period (usually 24 hours) for further evaluation and care.^4,5 In this context, “appropriate facility” means a state-approved psychiatric treatment setting. A hospital’s medical or surgical unit usually would not qualify.
2. The lawful use of a psychiatric hold is to declare that someone needs involuntary psychiatric examination for dangerousness arising “as a result of mental illness”—not for danger from a nonpsychiatric medical problem.⁶ Some civil commitment statutes specify that persons who have serious nonpsychiatric illness but no mental health problems that satisfy civil commitment criteria are to be offered voluntary treatment only.⁷
3. A psychiatric hold only authorizes short-term detention. It does not allow forcing what patients such as Mr. J need: medical or surgical treatment. A psychiatric hold would not solve the problem that Mr. J’s doctors are facing.
4. Doctors who execute psychiatric holds in good faith—sincerely believing a patient meets the legal criteria—enjoy statutory immunity from later accusations of malpractice or false imprisonment.⁸ Using civil commitment mechanisms when one does not actually believe those mechanisms apply might void this immunity.

Nonconsent: 2 varieties

For present purposes, let’s think of nonconsenting medical-surgical patients as coming in 2 varieties:

Variety 1: patients with compromised mental status. Often, medical-surgical patients cannot express objections to treatment because they are unconscious, delirious, or incoherent. Nurses and doctors assume such patients would want proper care and proceed with what they believe is in the patients’ best interest, often with input from family members.

Variety 2: lucid patients who refuse treatment. Patients who do not have obvious psychiatric problems may refuse necessary medical or surgical treatment for various reasons: obstinacy, distrust of doctors, fear, ignorance, incorrect but firmly held ideas about body functioning, cultural differences, or religious beliefs. None of these reasons is necessarily psychopathological, and none provides justification for a psychiatric hold.

Key determinant: Competence

Refusing treatment may be a bad choice and sometimes is evidence of a mental disorder, but it is not, by itself, a mental disorder. When a Variety 2 adult patient refuses care, the key question is, “Is this a competent refusal?” Assessment of a patient’s capacity to make medical decisions is not a skill unique to psychiatrists. Other specialists make judgments about capacity routinely—if only implicitly—when they elicit their patients’ informed consent for care. But when, as in Mr. J’s case, a seriously ill medical-surgical patient refuses lifesaving treatment, our medical colleagues often get psychiatrists involved. Consulting a psychiatrist in such circumstances makes sense, for at least 4 reasons:

• Although assessment of decision-making isn’t the special province of psychiatry, psychiatrists often have more experience assessing the capacity of persons whose thinking seems impaired.
• Psychiatrists also have more experience in detecting subtle indications of mental disorders (eg, mild dementia, depression, psychosis) that can compromise decision-making capacity.
• A nonpsychiatrist may believe that a patient is making a competent refusal but still wants a psychiatrist’s perspective to better understand the patient’s reasoning or to confirm the initial belief.
• Getting an independent opinion is a prudent way to make sure one’s emotions are not adversely influencing a critical judgment about a patient’s treatment.

Determining whether a patient has the requisite capacity to refuse care involves a situation-specific assessment of 4 aspects of mental functioning: expressing a choice coherently, understanding relevant information, appreciating this information, and using the information rationally. Table 2⁹ describes these functional areas in more detail.

Table 2

Evaluating the quality of a patient’s decision: 4 dimensions

If capacity is lacking, what next?

As Judge Benjamin Cardozo ruled nearly a century ago, “Every human being of adult years and sound mind has a right to determine what shall be done with his own body.”¹⁰ In a case such as Mr. J’s, where a patient wants to leave the hospital or refuses medical treatment despite grave risk to himself, staff members should not let him leave until his treating doctors have tried to clarify his reasons for leaving and determined whether he has the capacity to give informed consent and refuse treatment. Psychiatrists may be consulted in this process, although the final judgment about capacity rests with the responsible physician. If an assessment shows that the patient has the capacity to make medical decisions, his treatment refusal is binding, even when it creates a clear risk of death.

What should happen if an assessment shows that a gravely ill patient lacks capacity to refuse treatment? Clinicians should consult with the hospital attorney about their facility’s policies and how to implement them properly.

Thinking about the possible legal implications of their actions, treating clinicians might worry that if they detain an unwilling patient without authorization from a court or guardian, they would risk being sued later for false imprisonment. But attorneys are likely to advise clinicians that they have more to fear liability-wise from letting incompetent patients leave the hospital than from detaining them for their own safety. As an Ohio court commented about a police officer who stopped a patient from leaving the hospital:

• What in the name of all that is reasonable should the officer have done? The court finds that the officer acted properly under the circumstances known to him at the time—and the reasonableness of an officer’s actions must be judged at the exigent split second on the street…¹¹

Rather than allowing an incompetent patient to come to harm, attorneys may advise physicians to write an order to keep the patient in the hospital. Then, physicians can obtain consent for treatment from family members, making them aware of any physical or chemical restraint that might be needed to continue the patient’s treatment. Depending on the situation and the reasons for the lack of capacity, hospital staff members may later need to help a family member obtain a court’s authorization for emergency guardianship to allow non-urgent care to continue.

Treating physicians also should document the thinking and findings that support their actions. Table 3 provides an outline for this documentation.

Table 3

Detaining a patient for medical-surgical care: 7 components of documentation

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007; 357(18):1834-1840.
• Disability Rights California. Involuntary psychiatric treatment: California’s 72-hour hold and 14-day certification. www.disabilityrightsca.org/pubs/502401.pdf.
• Treatment Advocacy Center. Know the laws in your state. www.treatmentadvocacycenter.org/get-help/know-the-laws-in-your-state.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

Dr. Mossman thanks David Schwallie, Esq, for his helpful insights about the topics discussed in this article.

Dear Dr. Mossman,

At the general hospital where I work, doctors and nurses sometimes ask me to fill out psychiatric “hold” documents to keep seriously ill medical or surgical patients from leaving the hospital. Last week, they asked me to stop Mr. J, a man with diabetes and a gangrenous lower leg, from leaving against medical advice (AMA). If he left, he would die. But if I filled out the psychiatric “hold,” I’d be saying the man needed civil commitment for a mental illness, which wasn’t true. If this happens again, what should I do?
Submitted by “Dr. Q”

“It is tempting, if the only tool you have is a hammer, to treat everything as if it were a nail,” wrote Abraham Maslow.¹ The situation Dr. Q describes is one that psychiatrists frequently encounter because in some situations, a psychiatric “hold” can seem like the only way to stop a physically ill patient from leaving the hospital AMA. But pounding on this problem with a civil commitment hammer is the wrong response.

What’s wrong with using psychiatric holds in these situations? Do doctors have any other equipment in their medical toolbox for stopping an improvident AMA departure? To find out, we’ll look at:

• what a psychiatric hold does
• why holds don’t apply to medical-surgical treatment
• alternative responses to patients who lack capacity to refuse care.

Psychiatric holds

All states have laws that permit involuntary psychiatric hospitalization. The wording and procedural details in these laws vary across jurisdictions, but all states allow civil (ie, noncriminal) commitment of mentally ill persons who have gross impairments of judgment, behavior, reality-testing, or everyday functioning if their recent behavior show that they pose a danger because of their mental illness.² Table 1³ lists examples of the types of dangers that are potential reasons for civil commitment.

Table 1

Types of risks covered in civil commitment statutes

State laws also allow certain individuals (eg, police) to apprehend and transport mentally ill persons to facilities for psychiatric evaluation. Doctors may hold these persons temporarily until a court decides whether a longer involuntary hospitalization is justified. The documents used to initiate psychiatric holds have various informal names—”5150” (California), “pink slip” (Ohio), “pink paper” (Massachusetts), “Baker Act Form” (Florida)—but their function is the same: permitting lawful restraint of patients whose dangerousness results from their mental illness.

Urgent medical and surgical care

What about medical or surgical patients who refuse care despite being told they’ll die without it? Might involuntary psychiatric hospitalization procedures be a convenient way to keep them from coming to harm?

The answer: probably not, for 4 reasons:

1. Once a psychiatric hold has been executed, the person who is subject to detention must be transferred to an appropriate facility within a specified period (usually 24 hours) for further evaluation and care.^4,5 In this context, “appropriate facility” means a state-approved psychiatric treatment setting. A hospital’s medical or surgical unit usually would not qualify.
2. The lawful use of a psychiatric hold is to declare that someone needs involuntary psychiatric examination for dangerousness arising “as a result of mental illness”—not for danger from a nonpsychiatric medical problem.⁶ Some civil commitment statutes specify that persons who have serious nonpsychiatric illness but no mental health problems that satisfy civil commitment criteria are to be offered voluntary treatment only.⁷
3. A psychiatric hold only authorizes short-term detention. It does not allow forcing what patients such as Mr. J need: medical or surgical treatment. A psychiatric hold would not solve the problem that Mr. J’s doctors are facing.
4. Doctors who execute psychiatric holds in good faith—sincerely believing a patient meets the legal criteria—enjoy statutory immunity from later accusations of malpractice or false imprisonment.⁸ Using civil commitment mechanisms when one does not actually believe those mechanisms apply might void this immunity.

Nonconsent: 2 varieties

For present purposes, let’s think of nonconsenting medical-surgical patients as coming in 2 varieties:

Variety 1: patients with compromised mental status. Often, medical-surgical patients cannot express objections to treatment because they are unconscious, delirious, or incoherent. Nurses and doctors assume such patients would want proper care and proceed with what they believe is in the patients’ best interest, often with input from family members.

Variety 2: lucid patients who refuse treatment. Patients who do not have obvious psychiatric problems may refuse necessary medical or surgical treatment for various reasons: obstinacy, distrust of doctors, fear, ignorance, incorrect but firmly held ideas about body functioning, cultural differences, or religious beliefs. None of these reasons is necessarily psychopathological, and none provides justification for a psychiatric hold.

Key determinant: Competence

Refusing treatment may be a bad choice and sometimes is evidence of a mental disorder, but it is not, by itself, a mental disorder. When a Variety 2 adult patient refuses care, the key question is, “Is this a competent refusal?” Assessment of a patient’s capacity to make medical decisions is not a skill unique to psychiatrists. Other specialists make judgments about capacity routinely—if only implicitly—when they elicit their patients’ informed consent for care. But when, as in Mr. J’s case, a seriously ill medical-surgical patient refuses lifesaving treatment, our medical colleagues often get psychiatrists involved. Consulting a psychiatrist in such circumstances makes sense, for at least 4 reasons:

• Although assessment of decision-making isn’t the special province of psychiatry, psychiatrists often have more experience assessing the capacity of persons whose thinking seems impaired.
• Psychiatrists also have more experience in detecting subtle indications of mental disorders (eg, mild dementia, depression, psychosis) that can compromise decision-making capacity.
• A nonpsychiatrist may believe that a patient is making a competent refusal but still wants a psychiatrist’s perspective to better understand the patient’s reasoning or to confirm the initial belief.
• Getting an independent opinion is a prudent way to make sure one’s emotions are not adversely influencing a critical judgment about a patient’s treatment.

Determining whether a patient has the requisite capacity to refuse care involves a situation-specific assessment of 4 aspects of mental functioning: expressing a choice coherently, understanding relevant information, appreciating this information, and using the information rationally. Table 2⁹ describes these functional areas in more detail.

Table 2

Evaluating the quality of a patient’s decision: 4 dimensions

If capacity is lacking, what next?

As Judge Benjamin Cardozo ruled nearly a century ago, “Every human being of adult years and sound mind has a right to determine what shall be done with his own body.”¹⁰ In a case such as Mr. J’s, where a patient wants to leave the hospital or refuses medical treatment despite grave risk to himself, staff members should not let him leave until his treating doctors have tried to clarify his reasons for leaving and determined whether he has the capacity to give informed consent and refuse treatment. Psychiatrists may be consulted in this process, although the final judgment about capacity rests with the responsible physician. If an assessment shows that the patient has the capacity to make medical decisions, his treatment refusal is binding, even when it creates a clear risk of death.

What should happen if an assessment shows that a gravely ill patient lacks capacity to refuse treatment? Clinicians should consult with the hospital attorney about their facility’s policies and how to implement them properly.

Thinking about the possible legal implications of their actions, treating clinicians might worry that if they detain an unwilling patient without authorization from a court or guardian, they would risk being sued later for false imprisonment. But attorneys are likely to advise clinicians that they have more to fear liability-wise from letting incompetent patients leave the hospital than from detaining them for their own safety. As an Ohio court commented about a police officer who stopped a patient from leaving the hospital:

• What in the name of all that is reasonable should the officer have done? The court finds that the officer acted properly under the circumstances known to him at the time—and the reasonableness of an officer’s actions must be judged at the exigent split second on the street…¹¹

Rather than allowing an incompetent patient to come to harm, attorneys may advise physicians to write an order to keep the patient in the hospital. Then, physicians can obtain consent for treatment from family members, making them aware of any physical or chemical restraint that might be needed to continue the patient’s treatment. Depending on the situation and the reasons for the lack of capacity, hospital staff members may later need to help a family member obtain a court’s authorization for emergency guardianship to allow non-urgent care to continue.

Treating physicians also should document the thinking and findings that support their actions. Table 3 provides an outline for this documentation.

Table 3

Detaining a patient for medical-surgical care: 7 components of documentation

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007; 357(18):1834-1840.
• Disability Rights California. Involuntary psychiatric treatment: California’s 72-hour hold and 14-day certification. www.disabilityrightsca.org/pubs/502401.pdf.
• Treatment Advocacy Center. Know the laws in your state. www.treatmentadvocacycenter.org/get-help/know-the-laws-in-your-state.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

Dr. Mossman thanks David Schwallie, Esq, for his helpful insights about the topics discussed in this article.

Dear Dr. Mossman,

At the general hospital where I work, doctors and nurses sometimes ask me to fill out psychiatric “hold” documents to keep seriously ill medical or surgical patients from leaving the hospital. Last week, they asked me to stop Mr. J, a man with diabetes and a gangrenous lower leg, from leaving against medical advice (AMA). If he left, he would die. But if I filled out the psychiatric “hold,” I’d be saying the man needed civil commitment for a mental illness, which wasn’t true. If this happens again, what should I do?
Submitted by “Dr. Q”

“It is tempting, if the only tool you have is a hammer, to treat everything as if it were a nail,” wrote Abraham Maslow.¹ The situation Dr. Q describes is one that psychiatrists frequently encounter because in some situations, a psychiatric “hold” can seem like the only way to stop a physically ill patient from leaving the hospital AMA. But pounding on this problem with a civil commitment hammer is the wrong response.

What’s wrong with using psychiatric holds in these situations? Do doctors have any other equipment in their medical toolbox for stopping an improvident AMA departure? To find out, we’ll look at:

• what a psychiatric hold does
• why holds don’t apply to medical-surgical treatment
• alternative responses to patients who lack capacity to refuse care.

Psychiatric holds

All states have laws that permit involuntary psychiatric hospitalization. The wording and procedural details in these laws vary across jurisdictions, but all states allow civil (ie, noncriminal) commitment of mentally ill persons who have gross impairments of judgment, behavior, reality-testing, or everyday functioning if their recent behavior show that they pose a danger because of their mental illness.² Table 1³ lists examples of the types of dangers that are potential reasons for civil commitment.

Table 1

Types of risks covered in civil commitment statutes

State laws also allow certain individuals (eg, police) to apprehend and transport mentally ill persons to facilities for psychiatric evaluation. Doctors may hold these persons temporarily until a court decides whether a longer involuntary hospitalization is justified. The documents used to initiate psychiatric holds have various informal names—”5150” (California), “pink slip” (Ohio), “pink paper” (Massachusetts), “Baker Act Form” (Florida)—but their function is the same: permitting lawful restraint of patients whose dangerousness results from their mental illness.

Urgent medical and surgical care

What about medical or surgical patients who refuse care despite being told they’ll die without it? Might involuntary psychiatric hospitalization procedures be a convenient way to keep them from coming to harm?

The answer: probably not, for 4 reasons:

1. Once a psychiatric hold has been executed, the person who is subject to detention must be transferred to an appropriate facility within a specified period (usually 24 hours) for further evaluation and care.^4,5 In this context, “appropriate facility” means a state-approved psychiatric treatment setting. A hospital’s medical or surgical unit usually would not qualify.
2. The lawful use of a psychiatric hold is to declare that someone needs involuntary psychiatric examination for dangerousness arising “as a result of mental illness”—not for danger from a nonpsychiatric medical problem.⁶ Some civil commitment statutes specify that persons who have serious nonpsychiatric illness but no mental health problems that satisfy civil commitment criteria are to be offered voluntary treatment only.⁷
3. A psychiatric hold only authorizes short-term detention. It does not allow forcing what patients such as Mr. J need: medical or surgical treatment. A psychiatric hold would not solve the problem that Mr. J’s doctors are facing.
4. Doctors who execute psychiatric holds in good faith—sincerely believing a patient meets the legal criteria—enjoy statutory immunity from later accusations of malpractice or false imprisonment.⁸ Using civil commitment mechanisms when one does not actually believe those mechanisms apply might void this immunity.

Nonconsent: 2 varieties

For present purposes, let’s think of nonconsenting medical-surgical patients as coming in 2 varieties:

Variety 1: patients with compromised mental status. Often, medical-surgical patients cannot express objections to treatment because they are unconscious, delirious, or incoherent. Nurses and doctors assume such patients would want proper care and proceed with what they believe is in the patients’ best interest, often with input from family members.

Variety 2: lucid patients who refuse treatment. Patients who do not have obvious psychiatric problems may refuse necessary medical or surgical treatment for various reasons: obstinacy, distrust of doctors, fear, ignorance, incorrect but firmly held ideas about body functioning, cultural differences, or religious beliefs. None of these reasons is necessarily psychopathological, and none provides justification for a psychiatric hold.

Key determinant: Competence

Refusing treatment may be a bad choice and sometimes is evidence of a mental disorder, but it is not, by itself, a mental disorder. When a Variety 2 adult patient refuses care, the key question is, “Is this a competent refusal?” Assessment of a patient’s capacity to make medical decisions is not a skill unique to psychiatrists. Other specialists make judgments about capacity routinely—if only implicitly—when they elicit their patients’ informed consent for care. But when, as in Mr. J’s case, a seriously ill medical-surgical patient refuses lifesaving treatment, our medical colleagues often get psychiatrists involved. Consulting a psychiatrist in such circumstances makes sense, for at least 4 reasons:

• Although assessment of decision-making isn’t the special province of psychiatry, psychiatrists often have more experience assessing the capacity of persons whose thinking seems impaired.
• Psychiatrists also have more experience in detecting subtle indications of mental disorders (eg, mild dementia, depression, psychosis) that can compromise decision-making capacity.
• A nonpsychiatrist may believe that a patient is making a competent refusal but still wants a psychiatrist’s perspective to better understand the patient’s reasoning or to confirm the initial belief.
• Getting an independent opinion is a prudent way to make sure one’s emotions are not adversely influencing a critical judgment about a patient’s treatment.

Determining whether a patient has the requisite capacity to refuse care involves a situation-specific assessment of 4 aspects of mental functioning: expressing a choice coherently, understanding relevant information, appreciating this information, and using the information rationally. Table 2⁹ describes these functional areas in more detail.

Table 2

Evaluating the quality of a patient’s decision: 4 dimensions

If capacity is lacking, what next?

As Judge Benjamin Cardozo ruled nearly a century ago, “Every human being of adult years and sound mind has a right to determine what shall be done with his own body.”¹⁰ In a case such as Mr. J’s, where a patient wants to leave the hospital or refuses medical treatment despite grave risk to himself, staff members should not let him leave until his treating doctors have tried to clarify his reasons for leaving and determined whether he has the capacity to give informed consent and refuse treatment. Psychiatrists may be consulted in this process, although the final judgment about capacity rests with the responsible physician. If an assessment shows that the patient has the capacity to make medical decisions, his treatment refusal is binding, even when it creates a clear risk of death.

What should happen if an assessment shows that a gravely ill patient lacks capacity to refuse treatment? Clinicians should consult with the hospital attorney about their facility’s policies and how to implement them properly.

Thinking about the possible legal implications of their actions, treating clinicians might worry that if they detain an unwilling patient without authorization from a court or guardian, they would risk being sued later for false imprisonment. But attorneys are likely to advise clinicians that they have more to fear liability-wise from letting incompetent patients leave the hospital than from detaining them for their own safety. As an Ohio court commented about a police officer who stopped a patient from leaving the hospital:

• What in the name of all that is reasonable should the officer have done? The court finds that the officer acted properly under the circumstances known to him at the time—and the reasonableness of an officer’s actions must be judged at the exigent split second on the street…¹¹

Rather than allowing an incompetent patient to come to harm, attorneys may advise physicians to write an order to keep the patient in the hospital. Then, physicians can obtain consent for treatment from family members, making them aware of any physical or chemical restraint that might be needed to continue the patient’s treatment. Depending on the situation and the reasons for the lack of capacity, hospital staff members may later need to help a family member obtain a court’s authorization for emergency guardianship to allow non-urgent care to continue.

Treating physicians also should document the thinking and findings that support their actions. Table 3 provides an outline for this documentation.

Table 3

Detaining a patient for medical-surgical care: 7 components of documentation

Related Resources

• Appelbaum PS. Clinical practice. Assessment of patients’ competence to consent to treatment. N Engl J Med. 2007; 357(18):1834-1840.
• Disability Rights California. Involuntary psychiatric treatment: California’s 72-hour hold and 14-day certification. www.disabilityrightsca.org/pubs/502401.pdf.
• Treatment Advocacy Center. Know the laws in your state. www.treatmentadvocacycenter.org/get-help/know-the-laws-in-your-state.

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

Dr. Mossman thanks David Schwallie, Esq, for his helpful insights about the topics discussed in this article.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.