Genetic Propensities for Mental Illness in General
The year 2009 saw the emergence of a network of GWAS (Genome Wide Association Studies) of mental illnesses. Cichon, Craddock, Daly et al. reported that taken together, these GWAS will include 59,000 case studies, 7700 family trios, and more than 40 billion genotypes, all done for the purpose of documenting correlations between diagnosed mental illnesses and specific genetic sequences.
If Mental Illness Makes You Less Fit To Survive, Why Is It that the Numbers of People with Mental Illnesses Does Not Seen to Be Declining Over the Course of Decades & Centuries?
Nesse & Stearns (2009) supply an answer to an age-old dilemma in the intergenerational demographics of mental illnesses: If mental illness puts its patients at such a disadvantage evolutionarily when competing against people without mental illness, why don’t the numbers of the mentally ill in successive generations decline so that people with mental illness become, for lack of a better word, extinct? They argue that our bodies, including our minds which function as part of them, are not optimized over the course of evolution for perfection in all things, but rather, primarily in ways that ensure that whatever else happens to us, or is wrong with us, we persist in striving to reproduce and pass on our genes. As long as persons with genetic propensities towards various mental illnesses are able to have children that survive to their own reproductive age, genes for mental illnesses and inevitably persons with mental illnesses will reappear again and again. This is not, however, a simplistic call for eugenics, since not all persons with such genes, nor their offspring that have these genes, will become mentally ill. And, some people with as yet undiscovered genetic propensities will become mentally ill, despite not having anyone in generations near them with a mental illness. Furthermore, as reported by Sweatt (2009) in the journal Biological Psychiatry it is now undeniable that sometimes, even in adults whose brain structure and function is not thought of as being particularly amenable to remodeling, positive changes in their environments (and yes, even psychotherapy), seem to change their neurochemistry in such a way that the malignant production of adverse proteins or other brain active factors by mental illness genes is offset or silenced, a finding that one would never have found in this journal as recently as ten years ago. As such, mentally ill patients who go even temporarily into recovery, are also available for reproduction, although one cannot guarantee that their offspring will experience a similar mental health improving environment.
Accelerating Findings from Basic Science into Treatment Plans for the Mentally Ill
Insel (2009) announced new initiatives in funding granted by the National Institutes of Mental Health with the idea of translating many, isolated but reliably factual studies from many different disciplines dealing with mental illnesses, into coherent evidence-based protocols which mental health practitioners can apply with some confidence. Ultimately the NIMH hopes, wherever possible, that we try to preempt genetic predisposition to mental illness, or barring that, slow its development or ultimate severity in patients. NIMH funding will also promote the provision of more widely available clinical services so that the mentally ill are in fact, as well as in law, treated in a timely manner and on an equal basis with those with non-mental somatic disorders.
Does the Process of Medical School Education Favor the Development of Empathy in Physicians for their Patients, including the Mentally Ill?
An analysis of the genuine, visceral empathy levels of medical students choosing different medical specialties was measured annually over four years in a class of medical students using a standardized test, the Balanced Emotional Empathy Scale. While overall empathy levels scores trended relentlessly downward compared to class scores at the start of medical school, even among those students who chose psychiatry as their specialty, a field in which empathy is thought to be crucial, it did so to varying degrees of severity. The process of accelerating empathy erosion over the course of medical school seemed to correlate and perhaps even assist students in sorting out which fields were best for them. Not too surprisingly, students who opted for specialties with non-recurring or reduced personal contact with sick patients: most surgeons, radiologists, pathologists, etc., annually typically scored the lowest, while those whose future practices involved a great deal of personal familiarity with their patients, such as pediatricians and primary care providing adult internists generally scored higher. There were some notable gender differences. Most men on entering medical school actually scored well above the norm in empathy on the test, but their empathy levels continued to decline reaching their lowest levels after the third year, while It took women, who generally scored at or only slightly above the norm for empathy upon admission to school, only two years to descend to their empathy nadir.
Schizophrenia: Progression of Impairments, Treatment, & the Question of Remission
A year 2000 study by Green, Kern, Braff et al pointed out that while deficits in secondary verbal memory, immediate memory, executive function, and the overall ability to pay attention for sustained periods to incoming information are characteristic of the long term outcomes of schizophrenics, the ongoing management of schizophrenic patients, has relied on too few tests and measurements, particularly card sorting. These tests do not tell us as much about abilities at onset as about them at endpoint. The authors argued for the incorporation of more recently developed tests of cognitive function and indicate that these may well help measure progression of disease.
A year 2000 paper by Manoach, Gollub Benson et al demonstrated that functional magnetic resonance (fMRI) clearly pointed to aberrant activation of the prefrontal cortex and basal ganglia during the performance of tasks involving working memory, explaining part of the results reviewed by Green, Kern and Braff above. In addition, a 2005 paper by Lewis, Hashimoto and Volk characterized the decline in other cognitive functions in patients with schizophrenia in terms of the failure of TRkB receptors. As receptor function declines, so does the amount of GABA (gamma amino butyric acid) synthesized within the brain. The loss of cognitive function is gradual because other brain cells try to make up for the GABA shortfall, but ultimately fall behind, and a certain synchronicity of neuron firing necessary for learning fails more and more often, leading to progressive cognitive decline.
One of the key problems with the declining physical health of patients with schizophrenia is that taking their prescribed medications leads a significant number of them to gain weight, develop diabetes, incur cardiovascular problems, and often develop drooling, facial ticks, tremors, and eccentric gait. (Unfortunately not taking these medications tends to cause a rebound in their symptoms, particularly in psychosis). It had been hoped that the disadvantages of the first generation antipsychotic drugs (e.g. haloperidol, Haldol™) would be overcome by so-called second generation medications (detailed in the next study). However a 2006 study in Britain by Jones, Barnes, Davies et al. demonstrated that at least at the one year mark, patients randomly assigned either type had similar rates in Quality of Life measures and in rates of compliance in taking their medications. This put the less expensive first-generation drugs at an advantage, particularly in the UK’s National Health system.
Whether the 12 month end point was sufficiently long to determine when American patients typically discontinued taking their schizophrenia mediations , was determined in part by a 2005 study of 1432 patients randomized into taking one of four competing “second generation” medicines, published in the New England Journal of Medicine (Lieberman, Stroup, McEvoy et al). They exhaustively documented what many clinicians already intuitively surmised: 74% of patients quit taking their prescriptions within 18 months, largely because they felt the side effects were intolerable relative to the benefit they received from them. Patients tended to stay with their medication longest with olanzapine (Zyprexa™), followed by perphenazine (Trilafon™), followed by quetiapine (Seroquel™) and then by risperidone (Risperdal™).
A tie breaker in whether or not less expensive first generation drugs should be the first choice was likely exploded by 2005 study by Lieberman, Tollefson, Charles et al. Even after a single course of treatment for a first time outbreak of psychosis, . Haloperidol (Haldol™), the archetypal first generation drug, significantly decreased gray matter volume while olanzapine (Zyprexa™), its second generation counterpart, did not, although a neurochemical pathway that would explain how this shrinkage happened has yet to be discovered..
Along similar lines, it was strongly recommended in 2005 by Glassman that schizophrenia patients be assessed for cardiovascular health before so called “atypical anti-psychotic agents” (e.g. ziprasidone, Geodon™) are prescribed, not because they directly cause torsades de pointes arrhythmias, but because there is an unexplained increase in undiagnosed asymptomatic patients who may have some propensity.
Cross over drugs are becoming far more common in the treatment of schizophrenia. In 2003 Meltzer, Li, Kaneda et al forecast an increase in the use of drugs that dock at multiple categories of receptor sites within the brain (e.g. the so-called 5-HT series in addition to the “D” series) rather than target just one type. A prominent example discussed was Ariprazole (Abilify™) which was initially developed for bipolar disorders, and now has not only cross over use for schizophrenia but also major depression.
In 2005, Andreasen, Carpenter, Kane et al put forward a set of criteria that could be used internationally to standardize the notion of when a patient might be regarded to be in remission from schizophrenia, as a lack of consistency in what constituted remission made it very hard to determine how often it happened and whether or not rates or patterns differed by treatment plans or geographic and demographic groups. This need was reinforced in 2006 in another influential paper by Van Os, Burns, Cavallaro et al.
Schizophrenia: Heritability & Genetic Markers
Arguably the most influential paper of the decade for the systematization of genetic predispositions inclining one towards schizophrenia was by Gottesman and Gould in 2003. They suggested that a number of criteria be met before a characteristic mental illness or important predisposing physiological factor could be truly said to be genetic in nature. The marker or “endophenotype” being characterized must be clear cut, not of itself, some combination of vaguely interacting factors. Ideally, the endophenotype should not be based on an overall impression of the patient, but be measurable and recognizable by multiple raters working independently who were looking for that marker, and would not know whether or not the patients had an active mental illness. The endophenotype should be found readily in other members of the family of a patient with an overt illness whether or not those other family members overtly have the illness, and finally the endophenotype should be significantly more common among persons with the illness and their families than in the general population.
A small scale study of Icelandic families which had members who had schizophrenia seemed to have anticipated the Gottesman and Gould criteria and localized abnormalities in a high proportion of affected family members in the 8p chromosome. This gene regulates NRG1 (neuregulin 1) which controls glutamate receptors whose malfunctioning is thought to be a contributor to schizophrenia. This elegant study included the observation that clozapine, a drug of last resort for severe schizophrenia (owing to cardiovascular and hematological complications) but also a drug possessing a very high degree of effectiveness in the worst cases, specifically works by counteracting malfunctioning glutamate receptors.
One of the largest studies on genetic propensity for schizophrenia was published in 2009 by Lichetenstein, Yip, Bjork et al in The Lancet. Using the exhaustively complete medical records of over 2 million families in Sweden, they were able to trace patients with either schizophrenia or bipolar disorder, and compare their mental health with those of their parents, siblings, and children. The authors were able to chart a direct correlation for the likelihood of developing the disease based on parent-to-child transmission, in the sense that children who had two parents who were both schizophrenic had about double the risk of children who had only one parent so affected, and even this lowered risk was 100 fold the risk in the normal population. This relationship held even when the children were raised apart from their biological parents, negating the notion that environmental factors caused by living in the home with schizophrenic parents are what triggered the child’s schizophrenia. One stunning surprise was that couples with one or both parents having bipolar disorders had about the same high probability of having children with schizophrenia as they did of their developing bipolar disorder, suggesting that the shared genetic predisposition for two diseases thought to be separate entities may indicate that they are closer in molecular and cellular cause than previously thought. This finding was a direct challenge to a 2001 postmortem analysis by Rajowska, Halaris and Selemon, of the brains of persons with bipolar disorder when compared to those of schizophrenics. Bipolar patients have markedly decreased neuronal and glial density when compared to normals, while schizophrenics have markedly increased neuronal and glial density, relative to both groups. In 2006, evidence for a shared genetic propensity for bipolar disorder and schizophrenia grew even stronger according to a review by Craddock, O’Donovan and Owen.
A 2001 paper in the Proceedings of the National Academy of Sciences demonstrated that in a small but significant number of cases, a common functional polymorphism (i.e. genetic variation) termed Va-108/158-Met that regulated dopamine, was a good predictor of those at risk of some familial forms of schizophrenia (Egan, Goldberg, Kolachana et al). A 2005 paper by Harrison and Weinberger suggested that seven other susceptibility genes have also been clearly identified, and that these express proteins that confound the normal cytoarchitecture at the synaptic and other microcircuitry levels.
Schizophrenia: Correlation Between Imaging Studies and Molecular Theories
Three of the very most cited papers of the decade, particularly by schizophrenia researchers, were the 2000 study by Ashburner and Friston, and the 2001 reviews by Liberman, Chakos, Wu et al and Shenton, Dickey, Frumon et al, and the 2008 study by Meisenzahl, Koutsouleris, Gaser et al, in which they reviewed the use of voxel-based morphometry, in which the size of brain structures and volume of gray matter in the brain is rather precisely imaged and calculated, with the idea of comparing the size volumes of living normals with those diagnosed, or thought to be at risk for, major mental disorders.
Nonetheless, the dominant theory of schizophrenia, according to Howes & Kapur (2009) continues to be based on errors of dopamine handling by the brain. They argue that a wide array of analyses of risk factors associated with patients who become schizophrenic, including birth defects and in-utero stresses, a history of traumatic experiences, drug abuse, and genomic studies in which dopamine function is also measured, are now being confirmed by fMRI and PET scans that trace dopamine levels, localization and activation. Ultimately an excess of dopamine activity in the presynaptic striata appears to cause abnormal cognitive salience, or in lay terms, disproportionate and discordant (i.e. exaggerated and odd) fixations in one’s paying attention and processing information flowing before the patient from the world outside.
One of the few causation studies of mental illness that did not emphasize heritability and yet attracted significant attention throughout the decade appeared in 2000 in the American Journal of Psychiatry. There, Kronfol and Remick suggested that while correlations between large molecular weight hormones secreted by specific organs and brain function are increasingly well understood, we have not focused the same attention on brain function and cytokines, lower weight molecular compounds that are produced within cells in many areas of the body (including the brain) and which effect cell-to-cell communication. They note that most studies of cytokines have concerned their role in immune responses to infection or cancer, but that, to date, few researchers have tied the symptoms of mental illness often exhibited by patients who are flooded with cytokines because they are seriously ill with infections or with cancers, with mentally ill people without these infections or cancer but who display the same behaviors and may have similarly high levels of certain cytokines.
Mood disorders: Theories of Causation
A number of new models for the biological basis of depression, anxiety and bipolar disorder were introduced during the decade.
In 2000, Jacobs, Praag and Gage put forward a theory that reduced or absent development of new neurons in the dentate gyrus of the hippocampus may be a cause of depression. Their model correlates with events witnessed in the clinical management of depression. First, stressful episodes in patient’s lives trigger a flood of stress hormones which reduce neurogenesis as well as trigger depression. Second, after successful drug or talk therapy, serotonin levels notably increase and neurogenesis once again resumes.
In 2001, Pariante and Miller put the focus, instead, on glucocorticoid receptors (GRs) . They argued that patients with major depression have demonstrably reduced GR function and note that a number of antidepressants increase GR function, even though this had not been thought of as their primary mode of action.
A 2008 study by Chen, Lawler and Lewis exploded a favored theory: that genetically determined BDNF (Brain-Derived Neurotrophic Factor) levels were the root cause or at least played a significant role in mood disorders, finding no statistically significant correlation. This contradicted at least in part a heavily cited 2003 study suggesting the opposite by Egan, Kojima, Callicott et al, whose study featured some confirmation in fMRIs. And it failed to account for the 2003 observation by Shi and He that antidepressants reverse the low levels of BDNF in patients who recover from their depression.
Mood disorders: The Centrality of Hypervigilance & the Amygdala
Many more studies of mood disorders like depression, anxiety, bipolar, and even PTSD, in this decade however, focused on what might be regarded as the takeover of the brain’s environmental safety assessment by an overactive or dominant amygdala.
In 2000, in a functional magnetic resonance imaging study, Rauch, Whalen Shin et al demonstrated that combat veterans with PTSD patients have markedly higher rates of amygdala arousal to flashed images of fearful faces, than do veterans with similar levels of combat experience without PTSD. In 2001, Shin, Whalen, Pitman et al extended this work to show via fMRI that anterior cingulate function, which serves to dampen down and manage frightful stimuli, is weak in PTSD combat veterans relative to combat veterans without PTSD. In 2001 Sheline, Barch, Donnelly et al extended this fMRI study to patients with major depression, and noted the same exaggerated amygdala stimulation, but these investigators went on to report that after treatment, their levels of amygdala activation to fearful faces matched those of normal patients.
Functional abnormalities in the “affective chronometry” of the amygdala and prefrontal cortex were pinpointed in a 2002 study of anxiety by Davidson. In patients with high anxiety, coming to a faster conclusion based almost solely on what the amygdala “had to say” about potential danger at the expense of further consideration by the prefrontal cortex, yielded disproportionally negative judgments, even if it also served to warn them against real threats sooner. In other words the car far down the road might not stop in time; it may even pick up speed, so let’s not cross the street now and maybe never, because you might get run over.
This over dependence in anxiety-ridden people on part of the amygdala’s warnings at the expense of reasonable risk taking was to receive some confirmation in 2003, when Hariri, Mattay, Tessitore et al, using fMRI were able to observe, by contrast, the normal conscious modulation by the prefrontal and anterior cingulated cortices of patients viewing angry of fearful images after the initial instantaneous unconscious warning firing of the amygdala. In other words, the investigators were able to see the cycle by which we dampen down our initial response to frightful stimuli by subsequent activation of the brain circuits and areas involved in processing information and making judgments.
This two-track theory of visual information capture and processing was also in line with a 2002 study by Haxby, Hoffman and Gobbini, which indicated once again that two different brain circuits were activated for the two roles in processing of human faces, with one circuit attempting to identify the person based on memory, while the other gauges the “state of mind” or mood of the person from noticing facial expressions.
Finally a paper late in the decade (Phillips, Ladoucerur and Drevets, 2008) proposed a similar anatomical theory of bipolar disorder in which two brain circuits, one described as “feedforward” and the other as “feedback” work simultaneously at cross purposes. Findings from fMRI imaging indicate that anatomic regions of automatic emotion processing (dominated by the amygdale but also including certain pleasure centers) override those of voluntary emotion management (prefrontal cortex and related areas).
Mood disorders: Treatment
In 2008, Bandelow, Zohar, Hollander et al proposed a three tiered sequence of drugs of choice for anxiety, obsessive compulsive order and PTSD. Typical serotonin reuptake inhibitors (such as fluoxetine, Prozac™, citalopram, Celexa™, paroxetine Paxil™, sertaline Zoloft™) represent first choices. Next come serotonin norepinephrine uptake inhibitors (such as velafaxine, Effexor™, desvenlafaxine, Pristiq™, and duloxetine, Cymbalta™). Pregabalin (Lyrica™) is used largely in the US to treat fibromyalgia, and sometimes recommended as a third choice. Farther down the road are more traditional tricyclics, benzodiazepines, and others.
New World Federation of Biological Psychiatry guidelines were published in 2007 (Bauer, Bschor Pfennig et al.) Based on a systematic review of treatments for unipolar depressive disorders (i.e. depression) they overwhelming recommend a variety of antidepressants, and in a very small number of sever cases, electroconvulsive therapy, and by contrast in some mild disorders, such as seasonal affective disorder and low intensity depression, light (photo) therapy.
A 2006 study compared two older means of treating patients with major depression with a review to avoiding relapse: an old cocktail of lithium and tricyclics and electroconvulsive therapy (ECT) . Both worked about equally well, although ECT-treated patients who relapsed had longer intervals before relapse.
A definitive 2008 meta-analysis of 23 studies involving 1053 patients by Leichsenring and Rabung documented something that many clinical psychologists and social workers have long advocated, despite serious doubts on the part of many in the neuropsychopharmacology field: Long term talk therapy demonstrably improves the lives and well being of patients with complex mental disorders including chronic anxiety and depression. In addition they showed that brief, short term psychotherapy, often advocated by insurance companies who find it less expensive, simply does not have any way near as good a track record with the worst off patients.
A novel and still not widely used (nor FDA-approved for general use) treatment for depression is repetitive transcranial magnetic stimulation (rTMS). Patients who have not had good results using conventional drug therapy or talk therapy are sometimes referred to centers where an electromagnetic device position on top of the head against the hair and scalp essentially sends pulses which appear to depolarize or otherwise alter certain brain circuits. While most of these devices penetrate only a centime or two, newer models are claimed to get perform this “rebooting” in the deeper limbic system where depression, anxiety, and pleasure centers are thought to be at least partly based. A meta-analysis by Gross, Nakamura, Pascula-Leone & Fregni (2007) discloses that in contrast with earlier evaluative reviews, which showed modest if still somewhat ambiguous improvement in depressive symptoms, more recent studies have shown a larger antidepressant effect, although by no means a decisive one.
Attention Deficit Hyperactivity Disorder
Even before the onset on the 2000s decade, the pharmacology of ADHD in children seemed greatly advanced by the advent of atomoxetine (Strattera™). By 2003, it had been clearly proven by Michaelson, Adler, Spencer et al. efficacious and nonaddictive for adults as well.
Addictions: General Theory
The 2000s were a golden era for the appreciation of addicts as patients more effectively treated based on a better understanding of their altered brain function, than by moral hectoring about losing their souls.
There was absolutely no shortage of authoritative reviews, most sharing many of the same viewpoints.
In 2001, Bechara, Dolan, Denburg et al published a video gambling experiment where alcoholics, speed addicts participated along with two control groups. The first control group were normals but the second, intriguingly, consisted of persons with brain damage from accidents, surgeries, strokes or other causes that excluded addictions, that was known to be centered on their ventromedial prefrontal cortex, an area that governs the ability to foresee adverse consequences of high risk actions. Cards could be drawn from any of four decks, with the object of accumulating the highest total points. The decks differed in their proportions of point-gaining and point-penalizing cards. Normals quickly learned which decks appeared to have the most penalty cards, and not only avoided drawing from them, but even had a measurable increase in physiological indicators of fear or alarm whenever their pointer even got near them on the way towards selecting from the more favorable decks. A significant number of alcoholics and speed addicts, however, performed exactly like those patients whose brain damage had eliminated their aversion to risk. They showed no fear or physiological alarm indicators when going near and/or selecting from, descs that carried the highest rates of negative consequences.
In 2007, Kauer and Malenka, zeroed in on the mesolimbic dopamine system, as a location where at least in new drug abusers, the drugs literally hijack the firing mechanisms of synapses, resulting in memories of pleasure that are so intense that new addicts will do whatever it takes to relive them again. However, as far back as 2001, Drevets, Gautier, Price et al and Volkow and Fowler, and again in 2006, Hyman, Malenka and Nestler, emphasized that long term drug abusers have altered forebrain circuits that processes the experience of drug taking in much the same way that normals process the experience of euphoria upon attaining hard won rewards (such as winning an Olympic medal or getting an 800 on an SAT). They found that even after the ability to obtain a pleasurable experience of getting high or drunk has long been negated through habituation, and even after dire physical illnesses concomitant with long term drug abuse have taken hold, the orbitofrontal cortex circuits that produce the false feeling of having achieved something of consequence continue to function in response to the drugs of abuse and therefore implausibly continue to drive the drug abuse.
Addictions: Cocaine and Methamphetamines
In 2006, Volkow, Wang, Telang et al published one of the more clever tests of cocaine addicted persons to determine who would likely undergo the greatest severity of withdrawal symptoms, and have the highest risk of relapse. It involved showing the patients videos of people using drugs versus videos of persons and scenery not involving drug use, while monitoring them with PET (Positron Emission Spectroscopy) for dopamine activity. Those addicts whose dopamine levels were most radically changed just by viewing the drug use scenes turned out to be those who would have the greatest difficulty kicking their drugs and have the highest relapse rate. This dopamine dependent result is largely in concurrence with observations made back as 2000 by Robinson and Berridge.
Most adolescent users of marijuana do not become schizophrenics or have frequent hallucinations as adults, but a notable subset with a genetic propensity was finally identified in 2005 by Caspi, Moffitt, Cannon et al.
Addictions: Nicotine
The knowledge of the underlying mechanism of nicotine use, largely through smoking, progressed dramatically, and 2008 was a banner year.
In 2008 Benowitz addressed the issue of whether all smokers have the same likelihood of a genetic linkage to their nicotine addiction, or whether there were subgroups of smokers that had a greater or less likelihood of an inherited disposition to smoke. He articulated the notion that situational differences in when a subject is most likely to be smoking and the number of cigarettes smoked at that time are not too surprisingly good predictors of those whose addictions which have the strongest genetic basis. Those who smoke many cigarettes during stressful situations or during the use or withdrawal from other drugs or alcohol have the highest inheritability. Those who smoke fewer cigarettes, usually smoke in the context of upbeat social situations, have the lowest inheritability.
A 2008 study by Gonzales, Rennard, Nides et al. showed that varenicline (Chantix™) was significantly more effective after either a 12 or 24 week course of treatment than placebo or the hitherto standard prescription, buproprion (Wellbutrin™)..
A 2008 meta-analysis by Stead, Perera, Mant et al, reported that all over-the-counter forms of NRT (Nicotine Replacement Therapy) gums, patches, lozenges, inhaler, and nasal spray significantly (50%-70%) reduced rates of quitting smoking.
Finally, Cahill, Stead and Lancaster published a 2008 review which gave a slight advantage for varenicline (Chantix™) over NRT. Interestingly a related drug derived from a number of different plants, cytosine (Tabex™) has some potential in this area but greater concerns have been expressed over potential side-effects.
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