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Home Books Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e
CHAPTER 17: Schizophrenia and Bipolar Disorder
Schizophrenia and Bipolar Disorder. In: Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Nestler E.J., & Hyman S.E., & Holtzman D.M., & Malenka R.C.(Eds.),Eds. Eric J. Nestler, et al.eds. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e. McGraw Hill; 2014. Accessed January 29, 2023. https://accessbiomedicalscience.mhmedical.com/content.aspx?bookid=1204&sectionid=72650640
Schizophrenia and bipolar disorder. Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Nestler E.J., & Hyman S.E., & Holtzman D.M., & Malenka R.C.(Eds.),Eds. Eric J. Nestler, et al. (2014). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e. McGraw Hill. https://accessbiomedicalscience.mhmedical.com/content.aspx?bookid=1204&sectionid=72650640
"Schizophrenia and Bipolar Disorder." Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3e Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Nestler E.J., & Hyman S.E., & Holtzman D.M., & Malenka R.C.(Eds.),Eds. Eric J. Nestler, et al. McGraw Hill, 2014, https://accessbiomedicalscience.mhmedical.com/content.aspx?bookid=1204&sectionid=72650640.
LITHIUM AND OTHER MOOD-STABILIZING DRUGS
Schizophrenia is characterized by psychotic symptoms such as hallucinations and delusions (often referred to as "positive" symptoms), negative or deficit symptoms such as lack of motivation and social withdrawal, and cognitive impairments affecting attention, working memory, declarative memory, language fluency, and diverse aspects of social cognition.
Bipolar disorder is characterized by extreme mood swings between mania (characterized by euphoria or irritability, grandiosity, increased energy, and decreased need for sleep) and depression (characterized by sadness, loss of interest, decreased energy, disturbed sleep and appetite, ideas of worthlessness, guilt, and suicidal ideation). Affected individuals may return to normal mood states (euthymia) between acute episodes, but many have residual symptoms. Psychotic symptoms may occur in either manic or depressed episodes, most often congruent with mood. Bipolar patients with psychosis may have cognitive deficits similar to those seen in individuals with schizophrenia.
A milder form of the illness, bipolar II disorder is also recognized in which hypomania (mild mania) alternates with depression. Such patients do not generally suffer psychotic symptoms.
Some individuals experience a mixture of symptoms characteristic of schizophrenia and bipolar disorder and are currently given the diagnosis of schizoaffective disorder.
The heritability of schizophrenia and bipolar disorder is estimated to be very high, in the range of 65% to 80%. In contrast, the heritability of unipolar depression is less, approximately 35%, with greater environmental influence.
Despite their high heritabilities, the genetic risk of schizophrenia and bipolar disorder is highly polygenic, with many hundreds of genetic variants each contributing small increments of risk in the population, with different combinations of loci acting in different individuals. Genetic studies have found significant sharing of genetic risk variants between schizophrenia and bipolar disorder.
Schizophrenia is characterized by loss of gray matter in frontal and temporal regions of the cerebral cortex. Unaffected first-degree relatives may have milder gray matter loss with similar spatial patterns.
First-degree relatives of individuals with schizophrenia may have attenuated symptoms such as suspiciousness, social isolation, eccentric beliefs, and mild cognitive impairments without psychosis. This condition is currently diagnosed as schizotypal disorder.
Antipsychotic drugs are effective for the positive (psychotic) symptoms of schizophrenia, for acute manic episodes, and when combined with an antidepressant for psychotic depression. They are also efficacious in preventing acute relapses in schizophrenia, and often in combination with mood-stabilizing drugs in bipolar disorder. They lack efficacy for the negative and cognitive symptoms of schizophrenia.
The therapeutic action of antipsychotic drugs depends on their ability to antagonize D2 dopamine receptors. This mechanism of action can also cause significant Parkinson-like motor side effects. Second-generation antipsychotic drugs partly mitigate motor side effects by blocking other neurotransmitter receptors (most significantly 5HT2A receptors) but have their own significant side effects, in particular, weight gain and elevation of serum glucose and lipids.
Lithium is effective both for acute mania and for mood stabilization in bipolar disorder. Certain anticonvulsant drugs, such as valproate, are also effective. However, which of these drugs' many pharmacological actions is responsible for their therapeutic efficacy remains unknown.
Schizophrenia, bipolar disorder, and schizoaffective disorder, like all psychiatric disorders, are still diagnosed solely by clinical observation and history of illness. Despite increasing knowledge of these conditions, objective diagnostic tests have not yet been identified that can be applied with great enough sensitivity (avoidance of false-negatives) and specificity (avoidance of false-positives) to be acceptable for clinical or research use. Thus, neither of the two major diagnostic manuals, the Diagnostic and Statistic Manual of Mental Disorders, 5th ed. (DSM-5), published by the American Psychiatric Association, nor the International Classification of Diseases, 10th ed. (ICD-10), published by the World Health Organization, lists any objective medical diagnostic tests for these disorders. In fact, the difficulty in finding objective tests or biomarkers may partly result from reliance on current diagnostic systems as the "gold standards." Even for schizophrenia, bipolar disorder, and major depression, which have been closely studied for more than a century, it is clear that the DSM-5 errs in drawing them as discrete, discontinuous categories. Such a categorical model works well for most infectious diseases, for example, but most common, chronic human illnesses tend to be highly heterogeneous with respect to symptoms, severity, disease course, and treatment responsiveness. Psychiatric disorders, including those discussed in this chapter, would be better captured as quantitative deviations from health on multiple dimensions (similar to type 2 diabetes or coronary artery disease). One artifact of the excessively narrowly drawn categories of the DSM-5 is that a substantial fraction of patients with any psychiatric diagnosis have two or more or, as is common with the disorders discussed in this chapter, shifting diagnoses over time. Genetics is now providing some insight into this complex picture as both shared and unshared genetic and environmental risk factors have been discovered for schizophrenia and bipolar disorder. (Overlapping genetic risk factors are well documented for many disorders in medicine including rheumatoid arthritis and psoriasis as well as Crohn disease and ulcerative collitis.) Ultimately, as science progresses, psychiatric diagnosis is likely to look very different from the DSM-5.
Despite the serious shortcomings of DSM-5 diagnoses, well-studied disorders such schizophrenia, bipolar disorder, and autism are not arbitrary fictions; these clinical diagnoses yield very high heritabilities (0.65–0.80) across different countries and cultures. That "rough and ready" utility of these diagnoses for some areas of research such as genetics, however, does not mean that they are useful for others, or that they represent valid "natural kinds."
Schizophrenia is associated with very severe symptoms and significant disability. It typically begins in late adolescent years or the early twenties; it may rarely begin in childhood, or as late as the early forties. The global mean prevalence of schizophrenia is between 0.5% and 1.0% with local variation. The male to female ratio is approximately 1.4 to 1, with males also tending to have earlier onset. The lifetime prevalence of psychoses of all causes has been estimated to range between 3% and 4% of populations worldwide. Because of its early age of onset, chronic course, and severely impairing effects, schizophrenia ranks among the top 20 global causes of years of healthy life lost to disability, despite its relatively low prevalence.
Symptom Clusters in Schizophrenia
Schizophrenia is characterized by three major symptom clusters denoted as positive (or psychotic), negative (or deficit), and cognitive 17–1. In addition, many patients with schizophrenia have disturbances of mood, most often depression.
17–1 Schizophrenia: A Case History
Martin is a 35-year-old man who is currently homeless and living in shelters or on the street. His childhood was unremarkable until high school, when he began to withdraw from his peers. He tended to eat and play by himself at school and spent much of his time reading science fiction. In college Martin developed a preoccupation with mysticism and religion, often writing lengthy but confusing manifestos that described his beliefs. His parents became concerned at the end of his sophomore year when final exams were approaching, and he seemed to become more and more preoccupied with his theories that he believed would revolutionize society. Finally, Martin broke off contact with his parents, believing that they had been recruited into a conspiracy to prevent him from developing his philosophy. During his junior year, Martin's behavior continued to change. He began to wear large hats because he believed that people could hear his thoughts and were trying to steal them. When he heard news stories about overseas civil disturbances or wars, he believed that they were being waged between forces trying to help him and others who were trying to stop him. One night, as Martin was putting aluminum foil around his dorm room to prevent people from using electrical devices to steal his ideas, he began to hear two voices discussing his work and his philosophy. Their discussion confirmed his fear that his ideas had been stolen. He became more and more frightened and angry as the voices began to ridicule his ideas, until finally he fled his apartment. On the street he saw a policeman he believed was sent to kidnap him. Martin attacked the policeman in what he believed to be self-defense.
Martin was brought to a psychiatric hospital where he was given antipsychotic medication combined with short-term treatment with a benzodiazepine in order to calm him until the antipsychotic drug could begin to exert its therapeutic effects. With treatment, his auditory hallucinations and paranoid delusions subsided over the course of a few weeks, but he remained adamant that he did not want to see his parents. Soon after he was released from the hospital, Martin stopped taking his medications because they made him feel tired and gain weight. He attempted to continue his studies but within 6 months dropped out of school because of the return of paranoid delusions about people stealing his ideas and because he was having great difficulty keeping up with his assignments. For the next 6 years he tried to work at a series of jobs but was unable to keep any of them because of unexplained absences and frequent clashes with his supervisors and coworkers. During these years he was hospitalized involuntarily six times and tried on many different first- and second-generation antipsychotic drugs. Each time he was given an antipsychotic medication, there was an initial reduction in his paranoia and auditory hallucinations. He rarely continued to take these drugs for more than a few months, however, because of the side effects he experienced or because the hallucinations began to return despite medication.
At one point Martin reconciled with his parents and lived with them for several years, but they became increasingly frustrated with his resistance to taking his medications followed by frightening outbursts and hospitalization. Because discussions about this issue caused considerable tension, Martin would occasionally become very angry and disappear to live with his one remaining friend or on the street for weeks at a time. He began drinking alcohol and using marijuana and cocaine, because he was bored and because these substances would help him ignore the voices that frequently bothered him. Eventually, when he was 29, Martin had a major fight with his parents over his illicit drug use and he moved out of their house, never to return.
During the past 6 years Martin has been living in shelters and on the street. He receives medication from a local public health clinic. Although he continues to take such medication inconsistently, he takes it more frequently because he has come to recognize that it helps him stay out of the hospital. He knows some of the other people at the shelters he visits, but in general people make him uncomfortable and he keeps to himself. His parents occasionally send him money, but he only talks to them about once a year. Although he still thinks of his philosophy occasionally, it makes less sense to him than it used to. Mostly he spends time alone, making small talismans out of wire and glass to help him feel safe.
The positive (psychotic) symptoms of schizophrenia include hallucinations and delusions 17–2. Negative (deficit) symptoms represent significant impairments of normal functions including loss of motivation, a marked decrease in adaptive social interactions, blunting of affect, and impoverishment of the content of thought and speech. The cognitive symptoms of schizophrenia impair many measurable functions including attention, working memory, declarative memory, verbal memory and fluency, and diverse aspects of social cognition. Most significant as a cause of inability of patients to function at school or work is impaired cognitive control: the reduced ability to regulate thought, emotion, and behavior in accordance with goals. Long before the advent of modern cognitive science, the German psychiatrist Emile Kraepelin described the mind in schizophrenia as an orchestra without a conductor. Because of cognitive impairments and negative symptoms, people with schizophrenia continue to be disabled even when their psychotic symptoms are successfully controlled with available medications.
17–2 Psychosis
Schizophrenia is the best known, but by no means the only, condition in which individuals experience psychotic symptoms. Psychotic symptoms also can occur in bipolar disorder (during both manic and depressive episodes) and in unipolar depression (Chapter 15). There are also nonaffective psychoses that are relatively rarely seen in the clinic, for example, paranoid disorder in which a person may have delusions as his or her most salient or perhaps only symptom. In such cases the affected individual, lacking the other severe impairments of schizophrenia, might establish a lifestyle in which his or her delusions are not challenged—and might never doubt these beliefs—and thus never seek treatment. Finally psychotic symptoms may occur in the context of dementia, delirium, or intoxication. For example, as a person with Alzheimer disease begins to lose track of possessions, he or she may develop the delusion that his or her caregivers are stealing from him or her, leading to significant distress and occasionally disruptive behaviors (Chapter 18).
Psychosis is generally defined as the experiencing of abnormal subjective phenomena, combined with an inability to recognize that these experiences are not "objectively real." Hallucinations, for example, are sensory perceptions disconnected from external or physiological stimuli. Individuals may report hearing voices that others cannot hear or seeing things that others cannot see, but the experience seems to be coming from the external world. In schizophrenia the most common form that hallucinations take are auditory, often in the form of voices. For example, affected individuals may hear voices carrying on a conversation, perhaps about them or directed to them. The voices can be derogatory or can issue commands (often a highly dangerous state). Illusions cannot be considered psychotic symptoms if they are problems intrinsic to sensory systems or common misperceptions such as mirages. They are counted as psychotic symptoms when they are severely distorted perceptions or misinterpretations of real stimuli, for example, seeing an object as pulsating that others clearly see as still. Delusions are fixed, false beliefs (ie, impervious to evidence or reasoning) that are not shared by others in an individual's culture. In schizophrenia delusions are often bizarre or paranoid. An example of a bizarre delusions is the belief that the dental fillings in one's teeth are radio transmitters. A paranoid delusion is a fixed, false, and untestable belief that one is being spied upon, followed, or persecuted. Individuals with psychosis, most often those with schizophrenia, may also describe an experience of thought insertion or deletion, that is, that some outside agent has added or removed thoughts from their brain.
When psychotic symptoms occur as a component of a mood disorder, they are generally, but not always, congruent with the person's elevated, depressed, or irritable mood. Thus, during a manic episode a person may have the delusion that he or she is a prophet or deity, or endowed with supernatural powers. During psychotic depression a person may hear voices hectoring him or her as worthless or may have a delusion that he or she is rotting from the inside and emitting an intolerable odor. When psychotic symptoms occur as a component of a mood disorder, they remit when the underlying mood disorder responds to treatment (which usually includes an antipsychotic drug).
Symptoms of depression or mania can also occur in cases in which chronic schizophrenia-like symptoms predominate; these patients are often said to have schizoaffective disorder, although evidence from family and genetic studies suggests that this is an artificial, highly heterogeneous grouping.
It is hypothesized that the different symptom clusters characteristic of schizophrenia result from abnormalities in different, although partially overlapping, neural circuits. For example, psychotic symptoms are thought to reflect abnormalities in subcortical dopamine systems, while impairment in cognitive control is thought to reflect abnormalities in circuits based in the prefrontal cortex. The involvement of diverse neural circuits is thought to result from pathological processes that unfold during development and affect diverse cells, synapses, and circuits in the brain.
The Schizophrenia Prodrome
A diagnosis of schizophrenia is typically made only with the first episode of florid psychotic symptoms, but there is generally—perhaps always—a prodromal period in mid to later teen years. The schizophrenia prodrome may first manifest with declining school or vocational performance, increasing social isolation, unstable mood, irritability, anxiety, and increasingly odd and eccentric thoughts. It may initially be challenging to distinguish the schizophrenia prodrome from depression, drug use, or other pathological conditions of adolescence. As the schizophrenia prodrome progresses, however, the affected individual begins to have mild or attenuated psychotic symptoms (see 17–2), at which point it becomes easier to distinguish from other forms of adolescent psychopathology.
When individuals with the schizophrenia prodrome are carefully examined, they exhibit broad declines in cognitive functioning from their earlier baselines as well as the emergence of negative symptoms 17–1. These cognitive impairments and negative symptoms are not typically as severe as they will become after a first psychotic episode. Nonetheless, a significant fraction of the impairment that characterizes schizophrenia may be established before the first psychotic symptoms emerge. It has been hypothesized that cognitive and negative symptoms may, in fact, be a risk factor for psychosis. In some studies using structural magnetic resonance imaging (MRI), individuals with prodromal schizophrenia show cerebral cortical thinning, most severe in frontal and temporal cortices 17–2, that occurs more rapidly and to a greater extent than that observed in typically developing adolescents. However, measures of cortical thickness cannot currently be used as biomarkers of the schizophrenia prodrome since adolescence is a period in which synaptic pruning normally occurs 17–3. If measures of change in cortical thickness are to yield useful diagnostic information, they will have to meet the challenging test of reliably showing a faster rate of change or a distinctly more significant degree or spatial pattern of loss than control subjects, a difficult proposition against a normal background of dynamic cortical remodeling.
Schematic trajectory of the schizophrenia prodrome. The Y-axis represents an integrated measure of multiple cognitive tests and tests of emotion processing (eg, interpreting facial expressions of emotion). (Used with permission from Raquel Gur, University of Pennsylvania.)
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Statistical brain atlases plotting differences in the mean annualized rates of change in cortical thickness among clinical high-risk (aka "prodromal") subjects who converted to psychosis (n=35) as compared with clinical high-risk subjects who did not convert (n=239) over a 12-month interval. Converters showed a greater rate of thinning (warmer colors) in left and right superior frontal, middle frontal, and medial orbitofrontal gyri and in the right superior and inferior parietal cortex, superior temporal gyrus, and parahippocampal gyrus. After applying a correction for multiple testing (p ≤ 0.01), only the differences in right superior frontal, middle frontal, and medial orbitofrontal regions remained significant. The small clusters showing greater expansion (cooler colors) in the converters did not survive correction for multiple comparisons. (Used with permission from Tyrone Cannon, PhD and Yoonho Chung, BS, Based on results reported in Cannon TD, Chung Y, He G, et al. Progressive reduction in cortical thickness as psychosis develops: a multisite longitudinal neuroimaging study of youth at elevated clinical risk. Biol Psychiatry. 2014 Jun 12 [in press].)
17–3 Synaptic Pruning
Synaptic pruning is the process of synapse elimination that is an essential component of brain development, but which is also recognized as playing a pathological role in both neurodevelopmental and neurodegenerative disorders. The precise topography of brain circuitry and the strength of synaptic connections that emerge during development result from an interplay of genetic information and experience. For example, activity-dependent processes play an important role in strengthening and promoting the survival of active synapses versus weakening and eliminating synapses that are less active. Such activity-dependent developmental mechanisms have been best studied in models of the formation of binocular vision, but similar principles play a role in diverse neural systems throughout development.
Adolescence initiates the last major stage of brain maturation. Changes in executive function and social cognition have been well documented (and are reflected in the separation of juvenile from adult criminal law). The characteristic neurobiological processes of this stage of brain development are increasing myelination of axons in prefrontal cortex and synaptic pruning, the elimination of weak, inefficient synapses. Both of these processes extend into early adulthood. The degree of synapse elimination is so significant that it presumably explains the thinning of the cerebral cortex that can be observed even in typically developing adolescents by longitudinal MRI studies.
The mechanisms underlying adolescent synapse elimination are not fully understood, nor are the signals by which it is initiated—although a role for gonadal steroids or other mediators involved in sexual maturation has been suspected. The mechanism by which weak synapses are eliminated appears to involve the complement cascade, which, in the periphery, is an important component of innate immunity, serving, eg, to kill pathological cells and clear away cellular debris (Chapter 12). In the process of synapse elimination, microglia, some of which appear to be derived from blood monocytes, produce C1q, the first molecule in the complement cascade (see figure); in addition, astroglia induce C1q expression in neurons. C1q from both sources then tags weak synapses; the precise molecular signals that identify weak synapses have not yet been elucidated. C1q binding activates the classical complement pathway, leading to cleavage of complement component C3 and binding of its fragment C3b. Synapses tagged by C3b are then phagocytosed by microglia. Given this role, it has been hypothesized that the complement system may play a pathological role in the excessive synapse elimination that occurs in schizophrenia. There is also evidence from Alzheimer disease models that microglia and the complement system become activated and contribute to the loss of synapses and cells characteristic of that disorder.
The figure illustrates a hypothesized role for complement in synapse elimination. According to this scheme, strong synapses (formed by yellow neuron), which are effective in driving postsynaptic responses, actively eliminate nearby, weaker synapses (formed by blue neuron) by inducing two signals: a local protective signal and a longer-range elimination signal. Astrocytes are proposed to secrete unknown factors (factor X) that induce complement C1 complex expression in active neurons along with unknown protective factors. Activation of complement pathways (C1 complex, C3, activated fragments of C3) then drives elimination of weaker neurons via microglial-dependent mechanisms.
(Adapted with permission from Stephan AH, Barres BA, Stevens B. The complement system: An unexpected role in synaptic pruning during development and disease. Annu Rev Neurosci. 2012;35:369–389.)
The schizophrenia prodrome creates the possibility of early intervention, ideally before severe pathophysiological changes have occurred, such as excessive and inappropriate dendritic pruning and synaptic loss. In multiple clinical trials conducted in prodromal subjects, antipsychotic drugs have convincingly failed to delay the onset of psychosis (but do produce serious side effects), suggesting that entirely different mechanisms of action will be needed. Indeed, the therapeutic goals should be to alter pathological developmental processes, and thus to move beyond the palliation of late-stage psychotic symptoms. Such efforts will require an improved understanding of the molecular and cellular basis of the underlying abnormalities. Cognitive remediation designed for prodromal subjects has shown early promise in delaying conversion to psychosis. As many as 20% of apparently prodromal individuals at high risk of conversion to psychosis make a durable recovery independently of treatment for reasons that are not understood.
Once a first psychotic episode has occurred, the course of schizophrenia is chronic, with periods of milder "residual" psychotic symptoms punctuated by relapses of florid psychosis. Treatment of a first episode with antipsychotic drugs generally brings a full remission of the positive symptoms. Unfortunately, while antipsychotic drugs extend the period between relapses, relapses do occur and over time respond less completely to treatment. In addition, negative and cognitive symptoms, which are generally present before the onset of psychosis, worsen over time, eventually reaching a plateau well below the affected person's baseline, and are unresponsive to current pharmacological treatments. The side effect burden of antipsychotic drugs contributes to their discontinuation by patients, which can lead to more frequent relapses.
Genetic and Nongenetic Risk Factors for Schizophrenia
Based on twin studies, it has long been recognized that genes play a major role in risk of schizophrenia and bipolar disorder. Monozygotic (MZ) twin pairs, whose DNA sequences are 100% identical, have a concordance for schizophrenia of nearly 50%. Given a population prevalence of 0.5% to 1.0%, this is a 50- to 100-fold increase in risk for the MZ cotwin of an affected member of the twin pair. In contrast, dizygotic twin pairs, who share, on average, 50% of their DNA sequences, have a concordance for schizophrenia of approximately 15%. In addition, adoption studies found that risk of schizophrenia is determined by the biological rather than adoptive families. Overall, twin methodologies give heritabilities of 0.65 to 0.8 for schizophrenia and bipolar disorder, meaning that 65% to 80% of the phenotypic variance is explained by genes. This is among the highest rates of heritability for relatively common human diseases. (Diseases caused by highly penetrant single gene mutations—so-called Mendelian disorders—are rare because they more strongly diminish the likelihood of having offspring.)
Family and twin studies have also found that nonpsychotic first-degree relatives of individuals who meet criteria for schizophrenia often exhibit cognitive impairment and cortical thinning intermediate between population norms and their relatives with schizophrenia. An observation first made in adoption studies, but highly replicated in family studies thereafter, is that individuals genetically related to persons with schizophrenia may exhibit social isolation, suspiciousness, eccentric beliefs, and magical thinking, but lack frank psychotic symptoms such as hallucinations and delusions. When such symptoms produce impairment in functioning, the individual is diagnosed with schizotypal disorder (or in some older nomenclatures, by the misnomer, schizotypal personality disorder).
Despite the high heritabilities of schizophrenia and bipolar disorder, success in discovering specific disease risk–associated genetic variants was unsuccessful until recent advances in genomic technologies made it possible to search for genetic risk factors at the scale necessary to investigate a highly polygenic phenotype, that is, one in which each of a very large number of genes contributes small increments of risk. While the aggregate risk conferred by genes is large for schizophrenia and bipolar disorder, it is partitioned among numerous genes—likely many hundreds, perhaps more than 1000—of which no single gene is necessary or sufficient.
At the time of this writing, a global consortium has used DNA microarrays to genotype more than 40,000 patients with schizophrenia and 40,000 control subjects for common genetic variants and has determined the complete DNA sequence for the exomes (all protein-coding genes) of several thousand schizophrenia patients and control subjects. The microarrays ("gene chips") permit the determination of the version of a DNA segment a person has at approximately 750,000 genomic loci and then enables the investigator to ask whether each variant studied increases the risk of schizophrenia in the population studied. The result has been the discovery of more than 100 genetic loci that influence the risk of schizophrenia and a prediction that there are likely to be more than 1000 genes (5% of the human genome) in which variation influences the risk of this syndrome. Some of the risk variants that have been identified influence such well-known neural proteins as L-type and T-type Ca2+ channel subunits 17–3 as well as components of the postsynaptic specializations of excitatory synapses (see 5–1 in Chapter 5). Given the goal of understanding disease pathogenesis and developing disease-altering treatments, efforts are under way to discover the majority of risk-associated loci. This will permit the identification of pathways that can yield targets for treatment development. The genetic analysis of bipolar disorder is lagging somewhat behind schizophrenia, based on the identification of populations and collection of samples, but is likely to catch up soon.
An emerging molecular "parts list" for schizophrenia. Analysis of both common and rare genetic variants associated with schizophrenia is beginning to yield an initial list of proteins that appear to be associated with risk. Most common risk-associated variants likely affect levels of gene expression, while rare variants within exons may influence protein function. Shown here is an α1 subunit of the L-type Ca2+ channel (encoded by CACNA1C), which forms a pore, and a β subunit (eg, encoded by CACNB2), which is regulatory. Functioning channels include additional regulatory subunits (depicted by orange oval). A common variant linked to CACNA1C is among the most strongly associated risk alleles for both schizophrenia and bipolar disorder; common variants within CACNB2 are strongly associated not only with schizophrenia but also with risk for several other psychiatric disorders. In addition, both common and rare variants associated with schizophrenia cluster in postsynaptic specializations of excitatory synapses (see 5–1 in Chapter 5). (Adapted with permission from McCarroll SA, Hyman SE. Progress in the genetics of polygenic brain disorders: significant challenges for neurobiology. Neuron. 2013;80(3):578–587.)
Syndromal forms of autism (ie, autism associated with such features as low IQ, seizures, and dysmorphic facies), and less commonly schizophrenia, can be associated with chromosomal deletions, duplications, or more complex rearrangements, all referred to as copy number variants (CNVs). CNVs may affect DNA segments ranging from several hundred kilobases to several megabases in length and may affect multiple genes. Several CNVs are among the most penetrant genetic risk factors for schizophrenia, for example, the 22q11.2 syndrome, which results from a deletion of variable length affecting approximately 3 megabases of DNA and up to 44 genes in the middle of chromosome 22. The 22q11.2 syndrome, previously called velocardiofacial syndrome (for its facial and cardiac defects) or DiGeorge syndrome (for its discoverer), is characterized by cleft palate, congenital heart disease, facial dysmorphology, hypoparathyroidism, and other abnormalities. Approximately 25% of individuals with the 22q11.2 syndrome develop schizophrenia; however, approximately 20% receive a diagnosis of autism and the majority warrant neither psychiatric diagnosis. As is the case with most CNVs that have been studied, the most penetrant central nervous system (CNS) phenotype is intellectual disability (mental retardation). To summarize an evolving story, CNVs that cause neuropsychiatric symptoms primarily produce impairments across multiple cognitive domains (intellectual disability), but may also significantly increase the risk of autism or schizophrenia. The resulting psychiatric phenotypes, if any, depend not only on the presence of a particular CNV but also on the polygenic background in which the CNV occurs. The incomplete penetrance and variable expressivity (multiple phenotypes) exhibited by the 22q11.2 deletion and most other CNVs illustrate the genetic complexity of the risk for neuropsychiatric disorders.
One chromosomal rearrangement that deserves mention, not for its scientific significance, but for the attention it has garnered, resulted from a balanced exchange between chromosomes 1 and 11 in a Scottish family. The family member who first came to medical attention had schizophrenia, and thus a gene damaged by the translocation was named disrupted in schizophrenia (DISC-1). DISC-1 plays interesting roles in brain development and plasticity and thus appears to be a plausible risk gene. However, examination of the Scottish family over multiple generations reveals that affected individuals with the translocation predominantly have severe depression; several have schizophrenia, a small number have bipolar disorder; and several family members with the translocation have no psychiatric diagnosis. Moreover, well-powered population studies have not found an association between DISC-1 and schizophrenia. Despite the name given to DISC-1 and its interesting biology, it does not at present appear to figure in the pathogenesis of schizophrenia.
In addition to genetic risk factors for schizophrenia, epidemiological studies have identified several environmental risk factors that have been replicated by different groups. These include urban birth, increasing paternal age, season of birth, intrauterine exposure to viral infection, and adolescent use of cannabis. Maternal starvation during pregnancy has been identified as a risk factor for schizophrenia based on famine in the Netherlands following World War II and in China. Risk factors such as urban birth and migration are clearly proxies for causal factors that are not yet identified. Perhaps greater knowledge of genetic risk factors will be helpful in better understanding the causal mechanisms of environmental risk factors.
Given the still early stage of the genetic analysis of schizophrenia, it is only possible to speculate about molecular mechanisms of pathogenesis. One very general hypothesis is that genetic risk involves some combination of synapses vulnerable to inappropriate pruning and perhaps other developmental mechanisms that eliminate far too many synapses. This hypothesis is consistent with microscopic postmortem findings, which do not find cell loss in the cerebral cortex of patients with schizophrenia, but rather significant loss of dendritic arbors and synaptic spines from cortical neurons. The loss of neural processes would be consistent with the observation of smaller cell bodies (which would require less volume to support the metabolic needs of diminished processes) and thus denser cell packing in cortical layers. The most consistent gross anatomic finding, based on structural MRI and postmortem brain examinations, is thinning of cerebral cortical gray matter, with the greatest tissue loss in prefrontal and temporal regions (see 17–2), and a compensatory enlargement of the lateral and third cerebral ventricles. Loss of dendritic spines and thus synapses in prefrontal and temporal cortex could explain the cognitive deficits of schizophrenia as well as the milder cognitive impairments of first-degree relatives who have cortical thickness intermediate between schizophrenia and healthy individuals. Consistent with intermediate performance on cognitive tasks, first-degree relatives show resting-state connectivity intermediate between healthy controls and patients with schizophrenia 17–4.
Axial views of functional connectivity (resting-state correlational strength) among the major nodes of the default-mode network which increases from healthy controls to 1st-degree relatives of patients with schizophrenia to patients with schizophrenia. a) medial prefrontal cortex (mPFC); b) posterior cingulate cortex (PCC); c & d) left and right lateral parietal cortex. The mPFC and PCC are associated with self-referential processing. (Photo contributed by Susan Gabrieli, PhD and John D. E. Gabrieli, PhD.)
The excessive elimination of cerebral cortical synapses in schizophrenia implicates the major excitatory and inhibitory neurotransmitter systems glutamate and γ-aminobutyric acid (GABA), respectively. A role for excitatory synapses in the pathogenesis of schizophrenia is supported further by early genetic findings, which include genes encoding several subunits of NMDA, AMPA, and metabotropic glutamate receptors (eg, GRIA1, GRIN2A, GRIN2B, GRM3) or regulatory proteins (NRGN).
Historically, it was hypothesized that NMDA glutamate receptors are involved in the pathogenesis of schizophrenia because phencyclidine, ketamine, and related drugs (see chemical structures in Chapter 16), which act as open channel blockers of NMDA receptors (Chapter 5), produce psychotic-like symptoms and cognitive deficits reminiscent of some symptoms of schizophrenia. In fact, phencyclidine or ketamine administration in animals, and ketamine administration in human volunteers, continues to be used as a model in pharmaceutical development for schizophrenia-like effects. These observations notwithstanding, it is not clear whether phencyclidine or ketamine administration to healthy animals or human volunteers recapitulates molecular mechanisms of schizophrenia or produces phenocopies of the syndrome. This is a significant issue in the development of therapeutics, since the reversal of pharmacologically induced deficits in an animal model (eg, ketamine administration) will only benefit patients with schizophrenia if the underlying pathogenic mechanism in the human patients has been appropriately modeled in the animals.
Both phencyclidine and ketamine were developed as dissociative anesthetics. Both have significant abuse potential; both release dopamine, may be experienced as rewarding, and can prove highly addictive (Chapter 16). Phencyclidine is not legally marketed for human use, and is known on the street as PCP or angel dust. Ketamine, although also abusable (with a street name of special K), has continued to be used in anesthesia and analgesia and more recently has gained attention for exerting rapid, even if transient, antidepressant effects in humans (Chapter 15). Both drugs produce a sense of depersonalization and dissociation of subjective experience from sensory stimuli. Thus, in addition to having antinociceptive properties, they also decrease the aversiveness of normally painful stimuli.
This monoamine neurotransmitter has long been implicated in the production of psychotic symptoms based on the fact that all effective antipsychotic drugs (described below) are D2 dopamine receptor antagonists (Chapter 6). Moreover, high and repeated doses of amphetamines or cocaine, which increase synaptic levels of dopamine, or L-DOPA, which is converted to dopamine by L-aromatic amino acid decarboxylase, can cause delusions and hallucinations. Historically, these findings led to an early hypothesis that schizophrenia is caused by excessive levels of dopaminergic neurotransmission. With the recognition that schizophrenia results from abnormal developmental processes and that psychotic symptoms are a late manifestation of the disease process (coming at the end of the prodrome), it would be more fruitful to investigate dopamine for its contributions to psychotic symptoms rather than to the schizophrenia syndrome as a whole.
Interestingly, the gene encoding the dopamine D2 receptor has recently emerged as a genome-wide significant risk factor for schizophrenia. Nevertheless, the mechanism by which blockade of D2 receptors reduces psychotic symptoms remains unclear. Antipsychotic drugs block D2 receptors on initial drug exposure, but their antipsychotic effects (as opposed to sedative effects) emerge only after days or weeks of drug treatment, suggesting that significant molecular and cellular adaptations must first occur.
Animal and cellular models
Despite the evolutionary distance between mice and humans (most recent common ancestor ~90 million years ago) and thus the vast differences between human and mouse cerebral cortex, among many other differences, it is possible to produce useful mouse models of monogenic brain disorders such as fragile X syndrome, Rett syndrome, and rare monogenic forms of autism (Chapter 14). In contrast, there is no animal model for schizophrenia. No monogenic forms of the illness have been found from which to construct genetic mouse models. Even the most highly penetrant genetic risk factor known, the 22q11.2 deletion syndrome described earlier, depends in humans on a polygenic background to determine whether affected individuals develop schizophrenia or autism, or have no mental illness. Given that all 22q11.2 patients have intellectual disability, it is difficult to interpret the psychiatric significance of any behavioral deficits in mice with a knockout of the orthologous chromosomal region. Moreover, the hypothesized pathophysiological basis of schizophrenia, excessive cortical pruning resulting in loss of neuropil and associated with cognitive decline, has not been described in such mice. Perhaps as the genetic analysis of the syndrome progresses and as new genome engineering technologies advance, it will be possible to "knock-in" large numbers of human risk alleles in mice or other animals in order to study molecular and cellular aspects of the pathogenesis of schizophrenia. In the mean time, attempts have been made to model specific symptom clusters.
Currently, amphetamine administration in mice and rats is used to screen for the in vivo efficacy of D2 dopamine receptor antagonists, but this is not a model of psychotic symptoms. How can one document hallucinations or delusions in a rodent or even a nonhuman primate? Modeling the negative and cognitive symptoms is more plausible, but abnormalities in these behavioral domains are common across several psychiatric syndromes and hence lack specificity. Another limitation in the use of rodents is that prefrontal cortical regions that are thought to be impaired in schizophrenia are highly rudimentary in rodents compared with primates (Chapter 14). Given the lack of genetic animal models and the challenge of studying specific symptom clusters, many groups use pharmacological challenges, such as NMDA receptor antagonists or psychostimulants, as noted above, measuring end points such as locomotor activity or prepulse inhibition—the ability of a prior stimulus (eg, noise) to suppress startle responses to a subsequent noise. However, it is far from certain that these drugs cause neurobiological abnormalities that recapitulate those seen in schizophrenia, or that the behaviors measured reflect core symptoms of the illness. Likewise, groups have demonstrated behavioral abnormalities in rodents that are treated during development with drugs that inhibit cell division or with drugs that induce an inflammatory response, but until we learn more about the pathophysiology of schizophrenia in humans, it is impossible to know the extent to which these approaches in animals are relevant to the human syndrome.
Based on these challenges in developing bona fide animal models of schizophrenia, investigators are turning increasingly to the study of induced neurons. While cellular models cannot be used to study circuit abnormalities of behavior, they can be used to study molecular and cellular abnormalities produced by individual risk alleles or, using patient-derived cells, abnormalities produced by a complex genetic liability to schizophrenia (or bipolar disorder or any other genetically influenced illness). In the most commonly used methods, fibroblasts from patients and control subjects are reprogrammed into induced pluripotent stem cells (iPS cells) that can then be differentiated into diverse cell types including neurons (see 1–1 in Chapter 1). Alternatively, fibroblasts can be reprogrammed directly into neurons. These technologies are very recent, and it is still not possible to reliably generate mature neuronal cell types of interest—however, progress is this regard is occurring rapidly. Abnormalities in morphology, synapse formation, and migration have been reported for neuron-like cells derived from patients with schizophrenia; however, this work is difficult to interpret at this stage because it has not yet been possible to determine whether the phenotypic differences are caused by schizophrenia risk genes, as opposed to other genetic differences (not associated with disease) in the cells. Using modern genome engineering technologies, it is becoming increasingly feasible to swap risk-associated alleles into and out of iPS lines, making it likely that these technical problems can be solved. In psychiatry and neurology, and indeed across all fields of medicine, the shared goal is to produce cellular models of genetically influenced disorders that can be used to screen for novel therapeutics in vitro.
Mood disorders are heterogeneous, but are generally divided into two major classes based on symptoms and patterns of familial transmission. As discussed in Chapter 15, individuals with unipolar depression experience episodes of depression only and are more likely to come from families with both anxiety disorders and depression. Individuals with bipolar disorder experience mania as well as depression. It has been observed that bipolar disorder and schizophrenia may occur in the same families along with intermediate conditions that often go by the name of schizoaffective disorder. Based on genome-wide association studies, they share approximately 70% of the common genetic variants associated with each disease phenotype. Recent reports also describe cognitive deficits and cortical thinning in bipolar patients who suffer psychotic episodes, albeit less severe than those observed in schizophrenia. Finally, as noted, there are poorly delineated intermediate states lumped as schizoaffective disorder that involve full symptoms of bipolar disorder as well as psychotic symptoms that extend in time after the resolution of acute episodes of mania or depression. The similarities between schizophrenia and bipolar disorder notwithstanding, there are also important differences. In bipolar disorder, even in the presence of psychosis, the abnormalities of mood are prominent; some patients return close to baseline functioning between episodes; and bipolar patients benefit from Li+, whereas patients with schizophrenia do not.
When bipolar disorder includes full episodes of mania, it is often described as type 1 bipolar disorder. Individuals with milder episodes of mania (hypomania) and full episodes of depression are said to have type 2 bipolar disorder. Individuals affected by bipolar I disorder generally have a far more severe and disabling course. The prevalence of bipolar I disorder is approximately 1% of the population worldwide and affects men and women equally.
Mania is characterized by a severe disturbance in mood, either euphoria or irritability, or the two in combination. Mania is typically accompanied by dramatic increases in energy, decreased need for sleep and nourishment, impulsiveness, and excessive engagement in reward-directed behaviors such as spending sprees, use of alcohol or other drugs of abuse, and engagement in excessive sexual behavior. During manic episodes individuals may become grandiose, often delusionally so. Affected individuals may think of themselves as gods, prophets, or global leaders, or as controlling world events. Mania also may be characterized by thoughts that are moving so fast as to be confusing to the affected individual (flight of ideas), and by rapid, pressured (difficult to interrupt) speech. As noted, psychotic symptoms occur frequently during manic episodes. The content of delusions and hallucinations is generally consistent with the person's elevated mood. For example, people with mania may have delusions that they possess special powers. The symptoms that characterize depressive episodes in bipolar disorder are also mood congruent, but negative in valence.
Individuals affected by bipolar disorder have recurrent episodes of the illness, both manias and depression. However, the rate of cycling between mania, depression, and normal mood (euthymia) varies widely. Individuals with rapid cycling (in which mood states can change several times per week) tend to respond poorly to treatment. Between periods of mania and depression, a fraction of people with bipolar disorder may be relatively free of symptoms, but a larger fraction have residual symptoms, most often depression.
Research on the neurobiology of bipolar disorder has proceeded slowly, in part reflecting the lack of convincing animal models. The symptoms of bipolar disorder would seem to implicate the brain's reward circuitry and prefrontal cortical circuits in mania, as well as circuits similar or identical to those involved in unipolar depression during bipolar depressed episodes. Circadian clock-related mechanisms (discussed in Chapter 13) have also been implicated, based on the rapid cycling between mania, depression, and euthymia, and the ability of sleep deprivation to induce manic episodes, in some patients with bipolar disorder. Interestingly, mice with genetic disruption of the Clock gene display many symptoms—increased activity, enhanced reward, reduced fear, and decreased sleep—reminiscent of a manic episode. It is hoped that progress in the genetic analysis of bipolar disorder, which is proceeding effectively at the time of this writing, will help with pathophysiological understanding of the syndrome and ultimately better treatments.
Chlorpromazine and reserpine, the first antipsychotic drugs, were introduced in the early 1950s. Chlorpromazine, in particular, revolutionized the treatment of psychotic disorders including schizophrenia, bipolar disorder, and psychotic depression. Chlorpromazine 17–5 was initially developed in 1951 as an antihistamine for use as a preanesthetic. The drug was observed to be highly sedating both in animals (where it was said to induce "artificial hibernation" in part because it lowered body temperature) and in surgical patients. Its effectiveness in psychotic patients was later demonstrated. Beyond the simple sedation produced by barbiturates, and widely used to manage patients with schizophrenia or mania, chlorpromazine produced remission of psychotic symptoms such as hallucinations and delusions over a period of weeks. Especially in higher doses chlorpromazine also produced extrapyramidal motor side effects reminiscent of Parkinson disease such as tremor and rigidity. In the early 1960s, chlorpromazine and the subsequently discovered antipsychotic drug haloperidol 17–5 were found to increase the turnover of catecholamines (dopamine and norepinephrine) in rodent brain, an observation which led to the discovery that antipsychotic drugs act by blocking dopamine receptors.
Chemical structures of representative first-generation antipsychotic drugs.
The recognition that antipsychotic drugs block dopamine receptors tied their therapeutic effects to their Parkinson-like side effects, which were caused by the same mechanism. (Thus, extrapyramidal side effects represent "on-target" toxicity of antipsychotic drugs.) Soon motor side effects such as catalepsy became a screening tool for new antipsychotic drugs in laboratory animals. The term neuroleptic, Greek for neuron clasping, was applied to the first generation of antipsychotic drugs, referring to the motor side effects of these medications. As receptor binding studies were developed in the 1970s, the therapeutic effects of antipsychotic drugs were clearly associated with blockade of D2 dopamine receptors (see below).
Studies of chlorpromazine roughly coincided with the discovery of the antipsychotic properties of reserpine. Reserpine, the active component of snakeroot or Rauvolfia serpentina, had been used as a traditional medicine in India. It was initially used as an antihypertensive agent in the United States until clinical trials demonstrated its effectiveness as an antipsychotic drug. At therapeutic doses reserpine caused motor side effects similar to those associated with the use of chlorpromazine. It was later discovered that reserpine acts by depleting dopamine and other monoamine stores and thereby decreasing monoamine neurotransmission, an action mediated via blockade of the vesicular monoamine transporter (Chapter 6). Thus, despite very different molecular targets, both reserpine and chlorpromazine were shown to interfere with dopamine neurotransmission.
Mechanism of Antipsychotic Drug Action
Effects of antipsychotic drugs on D2 dopamine receptors
Receptor binding studies, primarily in the rat striatum—a rich source of such receptors—identified two major dopamine binding sites, termed D1 and D2. Although some older antipsychotic drugs, such as chlorpromazine, are potent antagonists of both receptor types, antagonism of the D2 receptor strongly correlates with antipsychotic efficacy 17–6. Haloperidol, for example, a butyrophenone compound that is a potent antipsychotic medication, has a high affinity for the D2 but not the D1 receptor. Molecular cloning studies later revealed that the D1 binding site consists of D1 and D5 receptors and that the D2 binding site consists of D2, D3, and D4 receptors (Chapter 6). Among these the D2 receptor is the critical molecular target of antipsychotic drug action.
Relationship between clinical potencies of antipsychotic medications (as measured by therapeutic dose) and their affinities for various receptors. Each graph shows clinical potency as a function of binding to D2 dopamine, 5HT2A/C serotonin, α1-adrenergic, and H1 histamine receptors. Clinical potency correlates with affinity for D2 dopamine receptors. In fact, dosing and D2 dopamine receptor affinity were not entirely independent of each other, as receptor affinity is used to select doses to test in clinical trials. More recently, affinity and receptor occupancy can be judged in human subjects using positron emission tomography. (Reproduced with permission from Snyder SH. 1996. Drugs and the Brain. New York: Scientific American Library.)
The mechanism by which antagonism of D2 receptors produces antipsychotic effects is not fully understood. Antipsychotic drugs usually take several weeks to exert their full antipsychotic effects; thus, it is not direct antagonism of D2 receptors that decreases psychosis; rather it is slowly developing adaptations in cells, synapses, and neural circuits resulting from sustained blockade of D2 receptors. In addition, D2 dopamine receptors are both presynaptic and postsynaptic (Chapter 6) and are expressed on neurons in the striatum at very high levels, and at lower levels in the prefrontal cortex, amygdala, and hippocampus (where D1 dopamine receptors predominate). Pyramidal neurons in the prefrontal cortex receive glutamatergic inputs both from other cortical regions and from the thalamus. These corticocortical and thalamocortical glutamatergic synapses are modulated by local GABAergic interneurons and by numerous afferent projections, which include not only dopamine projections from the ventral tegmental area but also serotonergic, noradrenergic, cholinergic, and multiple peptidergic inputs. How sustained D2 receptor blockade reorders the functioning of this circuitry remains an intense area of investigation.
Side effects of antipsychotic drugs
Although antipsychotic drugs revolutionized the treatment of schizophrenia and other psychotic disorders, their efficacy is limited to psychotic (positive) symptoms and is incomplete. Most patients have residual psychotic symptoms and continue to have florid psychotic relapses. Moreover, the drugs have serious side effects. Side effects of the first generation of antipsychotic drugs resulted from both "on-target" effects mediated by D2 receptor blockade and "off-target effects" mediated by actions at many other receptors 17–1.
17–1Pharmacologic Properties of First Generation Antipsychotic Drugs
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17–1 Pharmacologic Properties of First Generation Antipsychotic Drugs
Approximate Dose Equivalent (mg)
Sedative Effect
Hypotensive Effect
Anticholinergic Effect
Extrapyramidal Effect
Chlorpromazine (Thorazine) 100 High High Medium Low
Triflupromazine (Vesprin) 30 High High Medium Medium
Mesoridazine (Serentil) 50 Medium Medium Medium Medium
Thioridazine (Mellaril) 95 High High High Low
Acetophenazine (Tindal) 15 Low Low Low Medium
Fluphenazine (Prolixin, Permitil) 2 Medium Low Low High
Perphenazine (Trilafon) 8 Low Low Low High
Trifluoperazine (Stelazine) 5 Medium Low Low High
Thioxanthenes
Chlorprothixene (Taractan) 75 High High High Low
Thiothixene (Navane) 5 Low Low Low High
Dibenzodiazepines
Loxapine (Loxitane, Daxolin) 10 Medium Medium Medium High
Clozapine (Clozaril) 100 High High High Very low
Butyrophenones
Droperidol (Inapsine—injection only) 1 Low Low Low High
Haloperidol (Haldol) 2 Low Low Low High
Indolone
Molindone (Moban) 10 Medium Low Medium High
Diphenylbutylpiperidine
Pimozide (Orap) 1 Low Low Low High
Reproduced with permission from Rosenbaum JF, Arana GW, Hyman SE: Handbook of Psychiatric Drug Therapy. 5th ed. Philadelphnia, PA: Lippincott Williams & Wilkins; 2005.
Side effects caused by D2 dopamine receptor antagonism include extrapyramidal motor side effects and hyperprolactinemia. The synthesis and release of prolactin by anterior pituitary lactotrophs are inhibited by dopamine, which is released from the arcuate nucleus of the hypothalamus acting on D2 receptors (Chapter 10). Thus, antipsychotic drugs with high affinity for D2 receptors cause elevated levels of prolactin that can result in sexual dysfunction and rarely galactorrhea.
Extrapyramidal side effects can be divided into four major categories. The first consists of a syndrome that resembles Parkinson disease. This syndrome is characterized by rigidity, difficulty in initiating movements, mask-like facial expressions, and a resting tremor. A second type is acute dystonia, which is characterized by a sudden and spastic contraction of muscles—often those of the face and neck. Dystonic reactions may be dramatic, painful, and disturbing to individuals who experience them. A third category of extrapyramidal side effects consists of akathisia, characterized by a subjective sense of anxiety and intense restlessness. The fourth category is tardive dyskinesia, late-onset involuntary abnormal choreiform movements. Tardive dyskinesia occurs only with long-term drug exposure and is not readily reversible after cessation of drug treatment. An often debilitating side effect, risk of tardive dyskinesia has limited the use of first-generation antipsychotic drugs in countries where there is access to second-generation drugs.
Because D2 receptor antagonism is both the therapeutic mechanism of antipsychotic drugs and the cause of both elevated prolactin levels and extrapyramidal side effects, all antipsychotic drugs have some liability for these side effects. However, the risk correlates with the affinity of a drug for the D2 dopamine receptor and the dose of the drug used. High-potency antipsychotic drugs, such as haloperidol, have a high affinity for D2 receptors, and thus have a greater liability for these side effects than lower-potency drugs, such as chlorpromazine. In addition, many low-potency first-generation antipsychotic drugs possess anticholinergic (antimuscarinic) properties that tend to ameliorate extrapyramidal side effects, although not hyperprolactinemia (Chapters 6 and 17). In fact, when high-potency first-generation antipsychotic drugs are used, they are often coadministered with drugs that have antimuscarinic properties such as benztropine or diphenhydramine.
"Off-target side effects" of antipsychotic drugs include sedation, which results from the blockade of H1 histamine receptors, muscarinic cholinergic receptors, and possibly α1-adrenergic receptors in the CNS. Hypotension results from the antagonism of α1-adrenergic receptors in the periphery. Autonomic side effects such as dry mouth, blurred vision, urinary retention, and constipation (Chapter 9) are caused by the antagonism of muscarinic cholinergic receptors again in peripheral tissues. Delirium, which may occur in the elderly or in patients receiving multiple anticholinergic drugs, is most often due to blockade of muscarinic cholinergic receptors in the CNS (Chapter 14). Even among the first-generation drugs there is a wide diversity of affinities for different neurotransmitter receptors (see 17–1) permitting some ability to trade off side effects depending on the situation of a particular patient.
Second-generation antipsychotic drugs
First-generation antipsychotic drugs were very successful in their ability to treat the psychotic symptoms of schizophrenia and other disorders. They had significant limitations, however, because of side effects, as noted above. The prototype for all second-generation antipsychotic drugs is clozapine, which was discovered in the 1960s 17–7. Clozapine was initially believed to be an ordinary low-potency antipsychotic drug. However, it produced far less severe extrapyramidal side effects than expected. Despite this apparent benefit, its wide use was delayed for many years because approximately 1% of patients treated with clozapine develop agranulocytosis (a significant decrease in white blood cells), a potentially fatal but usually reversible side effect. Clozapine had other problematic side effects as well, among them, sedation, weight gain, and a decrease in seizure threshold. However, a clinical trial in the 1980s demonstrated that clozapine could produce significant benefit to schizophrenic patients who had failed to respond to other antipsychotic drugs. The combination of unique efficacy and diminished risk of motor side effects stimulated the development of new drugs, using some of the properties of clozapine as a prototype, while trying to avoid its liabilities.
Chemical structures of clozapine and several second-generation antipsychotic drugs.
Pharmacology of second-generation antipsychotic drugs
Detailed examination of the receptor binding properties of clozapine revealed that it has antagonist or possibly inverse agonist properties at many neurotransmitter receptors 17–8. An important characteristic that explains its low risk of extrapyramidal side effects and lack of effect on prolactin levels appears to be its relatively low affinity for D2 receptors. Serotonergic mechanisms had once elicited interest as a possible contributor to psychotic disorders because lysergic acid diethylamide (LSD) and related psychedelic drugs produce hallucinations as partial agonists at the 5HT2A serotonin receptor (Chapter 6). It was recognized, however, that the effects of LSD and related hallucinogens were quite unlike the symptoms of schizophrenia. Nevertheless, clozapine rekindled interest in serotonin because it is a high-affinity antagonist of multiple serotonin receptors including the 5HT2A receptor. While there is no compelling evidence that 5HT2A receptor blockade produces antipsychotic effects—for example, highly selective 5HT2A antagonists do not exert antipsychotic effects by themselves or potentiate the actions of D2 antagonists—several lines of evidence suggest that blockade of 5HT2A receptors limits the extrapyramidal side effect liability of antipsychotic medications. As a result, a high ratio of 5HT2A to D2 receptor affinity became a design principle for many second-generation drugs. Examples 17–7 include risperidone, olanzapine (a close chemical analog of clozapine), quetiapine, ziprasidone, sertindole, and asenapine. Aripiprazole 17–7 is similar to the aforementioned drugs by virtue of being a high-affinity antagonist at 5HT2A receptors. However, it differs in that the other second-generation drugs are D2 receptor antagonists (and some, perhaps inverse agonists), whereas aripiprazole is a high-affinity D2 receptor partial agonist. As a partial agonist, aripiprazole can act as an agonist or antagonist depending on the strength of endogenous dopamine neurotransmission. It would act as an agonist in low dopaminergic states and as an antagonist in hyperdopaminergic states. In practice, it has low extrapyramidal side effect liability and does not elevate prolactin.
Pie graphs comparing pharmacological profiles of haloperidol, clozapine, and several putative atypical antipsychotic drugs. (Reproduced with permission from Casey DE: The relationship of pharmacology to side effects. J Clin Psychiatry. 1997;58 Suppl 10:55–62.)
A recent finding with potential implications for the mechanism of action of antipsychotic drugs is that D2 receptor signaling bifurcates intracellularly (Chapter 6). Depending on the particular agonist or antagonist, receptor actions are biased toward either the classical Gi/Go signaling pathway or a β-arrestin–dependent pathway that activates AKT (previously called protein kinase B) and glycogen synthase kinase-3β (GSK3β), both of which are serine/threonine protein kinases discussed in Chapter 4. This is an example of ligand-directed signaling, which could be exploited in the development of novel antipsychotic drugs, based on emerging evidence that the antipsychotic and extrapyramidal side effects of D2 antagonists might be differentially mediated via these two signaling cascades. GSK3β inhibition has been implicated in the actions of Li+ as will be discussed in later sections of this chapter.
Comparative clinical trial data and clinical experience suggest that second-generation drugs are not generally more efficacious than first-generation drugs, and that both classes are less efficacious than clozapine. Like first-generation drugs, the second-generation drugs lack any significant efficacy for cognitive and negative symptoms. While second-generation drugs have a lower liability for causing extrapyramidal side effects than first-generation drugs, they are not free of such side effects. Moreover, they have a significant risk of causing weight gain and metabolic derangements such as hyperglycemia and hyperlipidemia, termed metabolic syndrome. The latter side effects of the newer agents can be severe, with patients gaining as much as 10% to 20% of body weight with chronic treatment, and are believed to be mediated at least in part via antagonism of 5HT2C receptors, which are known to be important in the control of feeding behavior (Chapter 10).
Despite decades of investigation, the mechanism responsible for clozapine's unique clinical properties remains to be identified. Clozapine binds many receptors (see 17–8). For example, it has relatively high affinity for the 5HT2C, 5HT3, and 5HT6 receptors as well as the 5HT2A receptor. In addition, clozapine and its metabolites bind many additional neurotransmitter receptors. One view is that it is the mixture of receptor actions that is important, but this remains hypothetical.
Other strategies for treating schizophrenia
As described, the NMDA glutamate receptor has been proposed as a target for antipsychotic drug action based on the psychotomimetic properties of NMDA open channel blockers such as ketamine and phencyclidine (see 16–4 in Chapter 16). Perhaps more convincing is the observation that several ionotropic and metabotropic glutamate receptor subunits and other components of postsynaptic excitatory synapses are implicated in schizophrenia pathogenesis by unbiased, large-scale genome-wide association studies, as stated above.
Chemical structure of drugs that act on glutamate receptors.
If NMDA receptor hypofunction contributes to schizophrenia symptoms, agents that augment NMDA receptor function might be useful treatments. Such reasoning led to clinical trials involving the use of glycine in the treatment of schizophrenia. As discussed in Chapter 5, glycine promotes NMDA receptor function by binding to a positive allosteric regulatory site on the receptor complex. D-Cycloserine, which is a partial agonist at this site and may lead to the in vivo formation of glycine, has been administered as an adjunct to antipsychotic drugs in clinical trials. The outcomes of these trials have been mixed, some positive and others negative, but overall the effects appear to be modest. Based on binding properties it is not clear that trials of D-cycloserine fully test the hypothesis that the positive allosteric regulatory site might be a valid target for schizophrenia treatment. There remains interest in several alternative approaches, such as: (1) the use of D-serine—thought to be an endogenous agonist at the glycine site; (2) the activation of serine racemase that generates D-serine from L-serine; or (3) the inhibition of the plasma membrane glycine transporter-1 (GlyT1) that might increase levels of glycine at excitatory synapses (Chapter 5). However, none of these approaches has yet been validated in clinical studies.
Partial agonists of the type II metabotropic glutamate receptor subtypes, mGlu2 and mGlu3, have been studied as possible treatments for schizophrenia. These are presynaptic G protein–coupled autoreceptors (Chapter 5) that, when stimulated, decrease glutamate release 17–10. The logic of using these drugs for schizophrenia was based on the observation that the psychotomimetic drugs ketamine and phencyclidine, which act as postsynaptic NMDA receptor channel blockers, lead to compensatory excessive presynaptic glutamate release, which could then overstimulate AMPA glutamate receptors that would be unblocked (see 15–10 in Chapter 15). A nonselective mGlu2/3 agonist (pomaglumetad or LY2140023) was successful in decreasing behavioral abnormalities in putative animal models of schizophrenia, but failed in human clinical trials. Given uncertainties as to whether LY2140023 engaged its molecular targets (mGlu2/3 receptors), the hypothesis that agonists, partial agonists, or positive allosteric modulators (PAMs) of these receptors might have therapeutic utility in treating psychosis remains to be definitively tested. Interest in the hypothesis has been rekindled by the emergence of GRM3, the gene encoding mGlu3, as genome-wide significant in schizophrenia. That said, there is well-justified disillusionment, as outlined earlier, with animal models of schizophrenia and animal-based assays meant to predict truly novel antipsychotic drugs in humans. Decades of failure to identify new mechanisms of action in schizophrenia (and indeed all psychiatric disorders) have raised the important question of whether, where ethically possible, compounds shown to be safe in animals would be better tested for efficacy in humans than in animals.
Modulation of glutamatergic neurotransmission by agonists or positive allosteric modulators (PAMs) of metabotropic glutamate receptors mGlu2 and mGlu3. As shown, the receptors (predominantly mGlu2) are found on presynaptic neurons where they inhibit neurotransmitter release (including that of glutamate) and postsynaptically where they modify the actions of glutamate at ionotropic glutamate receptors (ie, AMPA and NMDA receptors). mGlu3 receptors are also found on glia where they regulate activity of glial glutamate transporters, which would further modify glutamatergic transmission. It is not known which of these actions might mediate the hypothesized antipsychotic activity of mGlu2/3 agonists or PAMs.
Treatments are also under development with the aim of enhancing cognition in schizophrenia, with many similar drugs also under development for the palliation of memory loss in neurodegenerative disorders such as Alzheimer disease (Chapter 18). Much is known about the pharmacology of attention, working memory, and declarative memory (Chapter 14). However, clinical trials to date have been disappointing. One approach is the development of partial agonists of the α7 nicotinic acetylcholine receptor (nAChR7) or PAMs of certain muscarinic cholinergic receptors, all of which are enriched in memory circuits in the brain. Interest in nicotinic agonists is driven by observations that cigarette smoking is extremely common in people with schizophrenia, suggesting the hypothesis that nicotine might ameliorate some of the symptoms experienced by these patients. Other compounds in development target the cyclic AMP pathway, which has long been implicated in memory function. These include inhibitors of certain subtypes of phosphodiesterases (PDEs), the enzymes that metabolize cyclic AMP (Chapter 4). Inhibitors of PDE4 have failed in clinical trials because they cause nausea; thus, efficacy has not been well tested. Trials are now under way for inhibitors of PDE10, which is highly enriched in striatum. Nausea has also made it difficult to develop D1 dopamine receptor agonists, which are known from animal models to promote attention, working memory, and memory consolidation via actions in prefrontal cortex and hippocampus. In addition to pharmacology, there is much promise in early studies of cognitive psychotherapies both for prodromal schizophrenia and for the cognitive impairments of the full-blown disorder.
Overall, the first- and second-generation antipsychotic drugs remain the mainstays of treatment for the psychotic symptoms of schizophrenia, bipolar disorder, and psychotic depression, and for the agitation and psychosis seen in some patients with neurodegenerative disorders (Chapter 18). There remains significant unmet medical need for less toxic and more efficacious antipsychotic drugs and especially for treatments of the disabling negative and cognitive symptoms of schizophrenia that are untreated by medications available today.
The lightest solid element in the periodic table, lithium, circulates in blood as a monovalent cation. It is highly effective, at a concentration of 0.5 to 1.2 mM, in the treatment of acute mania and as a mood stabilizer, decreasing the risk of recurrence of manic and depressive episodes in individuals with bipolar disorder. As with antidepressants and antipsychotic drugs, the beneficial clinical effects of Li+ emerge after weeks of treatment.
Li+ has many protein targets, which has made it difficult to identify its mechanism of action with certainty. At therapeutic blood levels, Li+ affects: (1) the coupling of some neurotransmitter receptors to G proteins, (2) the expression of Gαi and subtypes of adenylyl cyclase, (3) the modification of G proteins by ADP-ribosylation, (4) cAMP-dependent and Ca2+-dependent protein phosphorylation, (5) GSK3β, and (6) the phosphatidylinositol second messenger pathway in the brain. Some of these effects are brain region specific. Which, if any, of these actions mediates Li+'s antimanic and mood-stabilizing properties remains unknown.
Inositol depletion hypothesis
Over two decades ago, Li+ was found to inhibit several inositol phosphatases in the phosphatidylinositol signaling cascade (see 4–9 in Chapter 4), which led to the inositol depletion hypothesis. Many neurotransmitter receptors, including α1-adrenergic, 5HT2A,2C-serotonergic, and M1,3,5 muscarinic cholinergic receptors, are linked to the enzyme phospholipase C by means of the G protein Gq. Phospholipase C hydrolyzes phosphatidylinositol bisphosphate (PIP2), a plasma membrane phospholipid, to yield two second messengers: diacylglycerol and inositol triphosphate (IP3). Diacylglycerol activates protein kinase C, and IP3 binds its receptor on the endoplasmic reticulum to release intracellular Ca2+ (Chapter 4).
Phosphatidylinositol is synthesized from free inositol and a lipid moiety. Most cells can obtain free inositol directly from plasma, but neurons cannot because inositol does not cross the blood–brain barrier. Consequently, neurons must either recycle inositol by dephosphorylating inositol phosphates after they are generated from the hydrolysis of phosphatidylinositols or synthesize it de novo from glucose-6-phosphate, a product of glycolysis. At therapeutic concentrations, Li+ inhibits several inositol phosphatases, most significantly inositol monophosphatase (IMPase). Such inhibition blocks the ability of neurons to generate free inositol from recycled inositol phosphates or glucose-6-phosphate. Thus, Li+-exposed neurons have a diminished ability to resynthesize PIP2 after it is hydrolyzed in response to neurotransmitter receptor activation. Accordingly, it has been hypothesized that when firing rates of neurons are abnormally high, Li+-treated neurons are depleted of PIP2, and neurotransmission dependent on this second messenger system is dampened.
This hypothesis is intriguing because it suggests that the effects of Li+ may be evident only in cells with abnormally high firing rates and that Li+ may be capable of treating both manic and depressive states because of its effects on multiple neurotransmitter systems. However, the story is more complex. Chronic inhibition of inositol phosphatases may lead to a buildup of active inositol phosphates, including IP3, and thus may facilitate rather than dampen the actions of neurotransmitters on this pathway. Indeed, whether long-term Li+ administration dampens or facilitates phosphatidylinositol-dependent signal transduction in the brain is not clear. Moreover, the critical cells in the brain that are targets of Li+'s therapeutic action remain unknown, and it is not known which of the many phosphatidylinositol-dependent neurotransmitter systems must be dampened (or facilitated) to produce Li+'s clinical effects. More importantly, this hypothesis does not explain why several weeks must elapse before Li+ exhibits a therapeutic effect.
Regulation of the Wnt pathway and glycogen synthase kinase-3β
Currently, the leading hypothesis of Li+ action in bipolar disorder is inhibition of GSK3β 17–4. In addition to its therapeutic properties in bipolar disorder, Li+ has teratogenic effects in several animal models, for example, embryos of Xenopus laevis, an African clawed toad. Li+ causes abnormal dorsalization of the embryo (ie, the production of two spines). This effect was definitively traced to inhibition of GSK3β, whereas highly selective blockers of IMPase do not produce teratogenic effects in Xenopus. Moreover, Li+ is capable of altering cell fate in mutants of the yeast Dictyostelium discoideum that lack phospholipase C and thus cannot generate IP3. As well, certain other mood-stabilizing drugs also inhibit GSK3β, among many other actions (see below). However, while preclinical experiments have implicated GSK3β as Li+'s therapeutic target, the lack of a convincing animal model of bipolar disorder has made it difficult to establish this hypothesis with confidence. What is needed is a selective inhibitor of GSK3β that is safe to administer to bipolar patients and to test its clinical efficacy. Perhaps then this long-standing question of the target of Li+ will be answered, opening avenues to new therapeutic approaches.
17–4 WNT–DSH–GSK3β Signaling Pathway
WNTs comprise a large family of secreted proteins that regulate cell proliferation and differentiation in species as divergent as nematodes, flies, frogs, and humans. In mammals, WNTs have been implicated in brain development. The initial gene discovery in mammals was of Int-1, a gene that became activated to produce tumors when the mouse mammary tumor virus integrated next to it in the mouse genome. Int-1 was found to be the mouse version of wingless (Wg), a developmental control gene first discovered in Drosophila. The contraction of Int-1 with Wg resulted in the term WNT, of which many members are now known.
WNT ligands bind to receptor molecules of the Frizzled family to initiate a signal transduction cascade involving a cytosolic protein dishevelled (DSH). It is of interest that DSH knockout mice are defective in social behavior and grooming and have subtle neurologic abnormalities reminiscent of those seen in schizophrenia. WNT signaling through Frizzled and DSH inhibits the serine–threonine protein kinase known as glycogen synthase kinase-3β (GSK3β) (see figure) (Chapter 4). GSK3β inhibits the function of β-catenin: phosphorylation of β-catenin by GSK3β leads to β-catenin's degradation. By inhibiting GSK3β activity, WNT signaling (and Li+) leads to stabilization of β-catenin, which in turn translocates to the nucleus, where it interacts with the transcription factor dTCF/LEF-1 to activate expression of WNT-responsive genes. Efforts are under way to identify genes that might be affected in the brain by Li+ inhibition of GSK3β. GSK3β produces many other actions through the phosphorylation of additional targets. For example, GSK3β is one of the protein kinases responsible for the hyperphosphorylation of tau (a microtubule-associated protein), which is believed to be a cause of neurofibrillary tangles in Alzheimer disease and frontotemporal dementias (Chapter 18).
Other drugs for bipolar disorder
Several drugs initially developed as anticonvulsants (Chapter 19) are widely used in place of Li+ or as adjuncts to Li+ in the treatment of bipolar disorder. Valproate is effective at ameliorating the symptoms of manic episodes and reducing the likelihood of recurrent episodes, and is better tolerated by some patients than Li+. As discussed in Chapter 19, valproate, like Li+, has numerous actions, making it difficult to identify which action is primarily responsible for its mood-stabilizing properties. Thus, valproate is a use-dependent Na+ channel blocker, a Ca2+ channel blocker, and increases synaptic levels of GABA via unknown mechanisms. Valproate is also a nonselective inhibitor of histone deacetylases (Chapter 4). There is no evidence to connect any of these specific actions of valproate to its therapeutic effects in bipolar disorder. Several other anticonvulsants have been used to treat bipolar disorder, most notably carbamazepine, but the number of well-designed and convincing clinical trials remains small.
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Can I Borrow With My 401(k) as Collateral?
By: Mark Kennan
••• Jupiterimages/liquidlibrary/Getty Images
Can I Cash Out My 401(k) While I Am Still Employed?
Federal law prohibits you from using your 401(k) as collateral, but that doesn't mean there's no way to get a loan with your 401(k). The Internal Revenue Service permits you to borrow money directly from your account if your 401(k) plan provider permits loans. Those loans must meet certain criteria.
You can borrow up to half your vested account balance or $50,000, whichever is smaller, from your 401(k) plan. But if your 401(k) plan's vest balance is less than $20,000, you can still borrow up to $10,000 if you have at least that much in your account. Your vested account balance refers to the money in your plan that you would get to keep if you left your job. Sometimes, employers make contributions to your 401(k) but require you to give them back if you leave within a few years; those contributions don't count toward boosting your loan limit.
Repayment Terms
You must repay your 401(k) loan within five years and pay interest on it. Many 401(k) plans simply take money out of your paycheck for repayment. If you're borrowing to buy your primary residence, you can have a longer term on your loan. Though you miss out on the investment gains the money would have earned had you left it in your account, the interest you pay is added back to your balance, so you end up paying yourself back.
If you don't pay back your loan according to the terms, the IRS treats you as taking a permanent distribution of the remaining balance on the loan. That means you're hit with income taxes; borrowers under the age of 59 1/2 also have to pay a 10 percent early withdrawal penalty. For example, if you took out a $20,000 loan and had paid it down to $15,000 before you defaulted, that $15,000 counts as a distribution. It get worse if you leave your job before you finish paying off the loan, because the balance becomes due immediately. If you can't pay, it's an early distribution.
Loan Paperwork
Getting a 401(k) loan is relatively straightforward, because you're essentially borrowing your own money. No credit check or minimum credit score is required, as would be the case if you borrowed money from a traditional bank. If you're married, though, getting a 401(k) plan loan requires a little extra paperwork, because you need your spouse to sign off on it, too.
Fox Business: Save 401(k) Hardship Withdrawals for True Emergencies
IRS: Retirement Plans -- FAQs Regarding Loans
IRS: General Distribution Rules
CNN: Early 401(k) Withdrawals and Loans
IRS. "Retirement Topics - Plan Loans." Accessed Nov. 2, 2020.
FINRA. "401(k) Loans, Hardship Withdrawals and Other Important Considerations." Accessed Nov. 2, 2020.
IRS. "Relief for Taxpayers Affected by COVID-19 Who Take Distributions or Loans From Retirement Plans." Accessed Nov. 2, 2020.
Charles Schwab. "The Charles Schwab Guide to Finances After Fifty: Does It Make Sense to Borrow From My 401(k) if I Need Cash?" Accessed Nov. 2, 2020.
Maxwell Locke & Ritter. "Options for Your 401(K) Plan at a Former Employer." Accessed Nov. 2, 2020.
IRS. "Retirement Plans FAQs Regarding Loans." Accessed Nov. 2, 2020.
The Pension Research Council at the Wharton School. "Financial Literacy: Implications for Retirement Security and the Financial Marketplace: Chapter 4: Financial Literacy and 401(k) Loans," Page 71. Accessed Nov. 2, 2020.
IRS. "Retirement Topics - Bankruptcy of Employer." Accessed Nov. 2, 2020.
Based in the Kansas City area, Mike specializes in personal finance and business topics. He has been writing since 2009 and has been published by "Quicken," "TurboTax," and "The Motley Fool."

redpajama_set_name: RedPajamaCommonCrawl


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Post a news Release
January Focus
Hotel Business Review
Hotel Newswire
Features Calendar
Editorial Board Guest Author
Mr. van Santen
Riko van Santen
Vice President Electronic Distribution, Louvre Hotels Group
Riko van Santen graduated with an honours degree in Hospitality Management from Middlesex University, London, and also holds a degree in Japanese business studies and various software administration qualifications. Following experience in various rooms division and revenue management functions at luxury properties, Mr. van Santen joined Pegasus Solutions/Utell in 2000 as Group Revenue Manager. In 2003 he was appointed Director of Electronic Distribution and by 2007 V.P. of Electronic Distribution & ICT for the Golden Tulip TOP Hospitality Group. Currently based at Louvre Hotels Group's headquarters in Paris, Mr. van Santen architects the group's distribution and e-commerce across 6 brands, ranging from 1 star to 5 star properties. The group's Central Reservations System Goldres was among the first hotel reservations system worldwide to achieve full NGS Connectivity, Total Pricing and BAR functionalities. Golden Tulip's award winning website was the first hotel brand website to use RSS technology, Mobile-Device distribution, Facebook API, online guest reviews (UGC) and multi lingual Online Distribution Database usage worldwide. Mr. van Santen specializes in delivering evolving competitive hospitality distribution solutions with fast-to-market, cost effective deployment. Experience also includes the RFP, procuring and deployment of 3rd party cloud based systems such as Revenue Management Systems, Rate Trackers, Commission Processing Systems, multi-chain electronic RFP solutions, POS, ERP and Property Management Systems. Property systems consolidated towards "cloud" solutions include mail Server, payroll Server, POS server, PMS server consolidation as well as cross border VOIP and complex IPVPN rollouts internationally. Mr. van Santen lectures at various hotel schools and global industry events on Distribution trends and Revenue Management, and holds seats on: HTNG Board of Directors (current Vice Presidency), HFTP EHTEC Advisory Council, Pegasus Solutions Customer Advisory Board. A Dutch national, Mr. van Santen was born in Tokyo and having lived over 20 years abroad, currently resides in Paris, France with wife Christel and their two sons.
Mr. van Santen can be contacted at 33-1-42.91-4740 or rvansanten@louvre-hotels.com
Social Media and Reputation Management
By Riko van Santen, Vice President Electronic Distribution, Louvre Hotels Group
Coming up in February 2020...
Social Media: Social Listening Tools
The reach and influence of social media is staggering. Nearly 3 billion people use social media daily, posting a range of messages, selfies, images, and everything in-between. According to HubSpot, almost 4 million posts are uploaded to the major social networks every single minute! That's an astounding amount of content and it is crucial for hotels to skillfully use social media in order to effectively compete. From establishing a suitable brand identity and voice to creating content across all the major networks (Facebook, Twitter, Instagram, Pinterest, etc.), the goal is to actively engage consumers and to eventually convert them to customers. Some hotels are initiating online contests as a way to attract new customers, while others are rewarding customers with discounts who subscribe to the their email lists or follow their social media pages. Another recent strategy is to employ social media listening tools that track what people are posting online about their businesses. These tools allow hotels to monitor - or listen to - what's being said about a brand across the entire social web, and this can prove to be very valuable, unfiltered information. Social listening permits hotels to be aware of people's opinions about their business, industry or competitors, and some of these tools even listen beyond social media platforms. They also monitor publicly available information on blogs, forums, news outlets and websites. Some listening tools are more focused on gathering and analyzing data, while others offer more engagement-oriented features, which allow hotels to interact with people right from the platform. Often the information that is gleaned from these listening tools ends up being the most authentic, unbiased insights a business can get. The February Hotel Business Review will document what some hotels are doing to successfully integrate social media strategies into their operations.
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Agustin Gomez, 85 of Newburgh, entered into rest on Thursday, September 26, 2013.
Son of the late Cirpriano and Carmen Gomez, he was born August 28, 1928 in Mendoza, Argentina.
He is survived by his wife, Crucita Gomez, at home; his children: Maria Rosa Gomez and Agustin Gomez; step children: Miguel, Gerson, Jose Luis and Angel Manuel Cruz; 12 grandchildren: Adri, Agustina, Lemec, Yanira, Jason, Gerson Jr., Maria, Joel, Keisha, Jafet, Ajalet and Erica; and 11 great-grandchildren: Valerie, Crystal, Ayanah, Sarah, Ariana, Cyrus, Naileene, Derrick, Damani, Naiyla and Leilani.
Visitation will be held from 4 to 8 p.m. on Sunday, September 29th at First Spanish Assembly of God Church, 25 William St., Newburgh, where Agustin was a parishioner.


Opportunity is Knocking! Answer the Door and Close in December! Be welcomed by a big, fenced front yard with a pond and a home that sits far back from 35th in a quiet setting. An Urbanites dream location where no car is necessary and a WalkScore of 79. House has plenty of natural light and is ready for you to call it Home! Multiple bus stops within a block, future light rail 2 miles away and a wide array of restaurants, coffee shops, library, shopping, community center and grocery stores are all within blocks. With easy access to UW, Children's Hospital, Northgate, Seattle & Bothell, this ideal location makes a great first time home or the two living areas complete with separate entries and laundry make for a M-I-L or rent the downstairs and subsidize your mortgage, or rental for investor. A one year home warranty is included!