INFLAMMATION AND PSYCHOSIS

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A report by Bloomfield et al. in the January 2016 issue of American Journal of Psychiatry showed further evidence that psychosis is associated with increased inflammatory activity in the brain.  What the researchers did was to use a marker, [11C]PBR28, which binds to activated white blood cells (microglia) in the brain.  None of the subjects had been treated with antipsychotic medications.  The researchers showed that in persons who are at high risk for the development of psychosis and in those in whom psychosis had emerged, there was a greater degree of binding of the marker indicating more activated microglia in the brain.  Moreover, they noted that degree of binding (degree of microglia activation) was correlated with the level of symptoms.

The Bloomfield et al. report fits in well with a larger literature pointing the finger at dysfunction in fast spiking GABA interneurons as the culprit in causing hallucinations and cognitive impairment. (This story is reviewed in chapter 6 in Neuroscience for Psychologists and Other Mental Health Professionals.) Inflammation negatively impacts fast spiking GABA interneurons.  Oxidative stress, a component of inflammation, also impairs the function of NMDA receptors which are the drive on the fast spiking GABA interneurons (Sorce, Schiavone, Tucci et al., 2010; Sullivan & O’Donnell, 2012).  Stressful life experiences can also increase oxidative stress and thus provides a mechanism for how trauma can increase the emergence of psychosis (Cabungcal, Steullet et al., 2013; Jing et al., 2013).  Many persons with psychosis relapse when they incur infections in other parts of the body which than can raise inflammatory factors in brain (see Brian Miller,  2016).

The Impact of Antipsychotic Drugs on Brain Inflammation: Bloomfield et al. (2016) cited two studies using microglia cells in a petri dish which showed that antipsychotics tamed activation of these cells (Bian et al., 2008; Kato et al., 2008).  They also cited a study by Zhu et al. (2014) in live rats which showed that when a molecule of the wall of a bacterium (lipopolysaccharide) is injected into the brain of a rat and subsequently the rat is given a 14 day administration of an antipsychotic the brain’s inflammatory response to the provocation is attenuated.  Bloomfield et al. did not cite the study by Cotel et al. The Cotel et al. study showed that antipsychotic treatment activates inflammation in the brain, the opposite of what the studies cited by Bloomfield et al. showed.  Arguably, the Cotel et al. study is more relevant to the question of how antipsychotic drugs influence inflammation in the brain.  Cotel et al. administered antipsychotics for 8 weeks, much longer than in the other studies.  Moreover, Cotel et al. did not use another activator of an inflammatory response (as was done in the other studies).  Cotel et al. only examined the impact of the antipsychotics in brains which were not exposed to another inflammatory provocation. The Cotel et al. study, which found that antipsychotics create brain inflammation, is important because it might offer an explanation/mechanism for how antipsychotics shrink cortex which was shown in the humans (see Ho et al., 2011) and in the primate studies (Dorph-Petersen et al., 2005). A study by Shao et al. (2013) further confirmed that blocking dopamine receptors, as antipsychotics do, will increase brain inflammation.

The Search for Alternatives to Antipsychotics:   There is a literature on using anti-inflammatories to treat psychosis.  In fact, in a study of children at high risk of converting to psychosis, omega-3s (which are anti-inflammatory) was the only treatment that prevented the emergence of frank psychosis with 27.5% becoming psychotic in the control group versus 4.9% in the omega-3 group at the 12 month follow-up (Amminger et al., 2010).  There is also a literature attesting to the beneficial effects of anti-inflammatories on psychosis.  The anti-inflammatories have included aspirin, minocycline, statins, N-acetylcysteine, and the COX-2 inhibitor, celecoxib (Keller et al., 2013; Sommer et al., 2014).  Sommer et al. concluded that aspirin, estrogen, and N-acetyl-cysteine showed the best effects.  Additionally, social support can also reduce systemic inflammation.  Hopefully, in the future, we’ll have drug trials of anti-inflammatories as the sole pharmacological treatment along with attention to an anti-inflammatory diet and Soteria Project support.  (There is little reason to believe that any chemical anti-inflammatory can eclipse the impact of an inflammatory diet.)  Perhaps the future will offer a better way.

Readers on this website may object to any notion that biology influences human behavior. At risk of offending this audience, I present the findings in these studies because they demonstrate the folly of antipsychotics even for those who believe in physiological explanations for hearing voices.  Since doctors probably won’t ever give up their prescription pads, perhaps they can be coaxed into gentler drugs to prescribe.  I think that for those who are involuntarily committed to the psychiatric hospital, telling the doctor to prescribe “this” instead of “that” and backing up the demand with a study published in a legitimate journal might hold some weight.  If asking for a legitimate alternative does not influence the doctor, it might influence a judge.  In fact, most states have informed consent laws which mandate that physicians discuss all the options available for treating a given condition so that the patient can choose which option they prefer.

Amminger, G. P., Schafer, M. R., Papageorgiou, K. et al. (2010). Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders:  a randomized, placebo-control trial. Archives of General Psychiatry, 67, 146-154.

Bian, Q., Kato, T., Monji, A. et al. (2008). The effect of atypical antipsychotics, perospirone, ziprasidone, and quetiapine on microglia activation induced by interferon-gamma. Progress in Neuropsychophamacology and Biological Psychiatry, 32, 42-48.

Bloomfield, P. S., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D. R., Bloomfield, M.A.P., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V., & Howes, O. D. (2016).  Microglia activity in people at ultra high risk of psychosis and in schizophrenia:  An [11C]PBR28 PET brain imaging study. American Journal of Psychiatry, 173 (1), 44-52.

Cabungcal, J-H., Steullet, P., Morishita, H., Kraftsik, R., Cuenod, M., Hensch, T. K., & Do, K. Q. (2013).  Perineuronal nets protect fast-spiking interneurons against oxidative stress. Proceedings of the National Academy of Sciences, 110(22), 9130-9135.

Chaudhry, I. B. Hallak, J., Husain, N. (2012).  Minocycline benefits negative symptoms in early schizophrenia: a randomized double-blind placebo controlled clinical trial in patients on standard treatment. Journal of Psychopharmacology, 26, 1185-1193.

Cotel, M-C., Lenartowicz, E. M., Natesan, S., Modo, M. M., Cooper, J. D., Willaims, S. C. R., Kapur, S., & Vernon, A. C.  (2015).  Microglia activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses. European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2015.08.004

Dorph-Petersen, K. A., Pierri, J. N., Perel, J. M., Sun, Z., Sampson, A. R., & Lewis, D. A. (2005).  The influence of chronic exposure to anti-psychotic medications on brain size before and after tissue fixation:  A comparison of haloperiodol and olanzapine in macaque monkeys. Neuropsychopharmacology, 30 (9), 1649-1661.

Ho, B. C., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. (2011).  Long-term antipsychotic treatment and brain volumes:  a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68(2), 128-137.

Jiang, Z., Rompala, G. R., Zhang, S., Cowell, R. M., & Nakazawa, K. (2013).  Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. Biological Psychiatry, 73 (10), 1024-1034.

Kato, T., Mizoguchi, Y., Monji, A. et al. (2008).  Inhibitory effects of aripiprazole on interferonγ-induced microglia activation via intracellular Ca2+ regulation in vitro. Journal of Neurochemistry, 106, 815-825.

Keller, W. R., Kum, L. M., Wehring, H. J., Koola, M. M., Buchanan, R. W., & Kelly, D. L. (2013).  A review of anti-inflammatory agents for symptoms of schizophrenia. Journal of Psychopharmacology, 27 (4), 337-342.

Kirkpatrick, N., & Miller, B. J. (2013).  Inflammation and schizophrenia. Schizophrenia Bulletin, 39 (6), 1174-1179.

Miller, B. J. (2016, January 7).  Adjunctive monoclonal antibody immunotherapy in schizophrenia. Psychiatric Times

Miller, B. J., Graham, K. L., Bodenheimer, C. M., Culpepper, N. H., Waller, J. L., & Buckley, P. F. (2013).  A prevalence study of urinary tract infections in acute relapse of schizophrenia. Journal of Clinical Psychiatry, 74(3), 271-277.

Mṻller, N., Riedel, M., Scheppach, C. et al. (2002).  Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. American Journal of Psychiatry, 159, 1029-1034.

Shao, W., Zhang, S.Z., Tang, M., Zhang, X. H., Zhou, Z., Yin, Y.Q., Zhou, Q. B., Hang, Y. Y., Liu, Y. J., Wawrousek, E., Chen, T., Li. S. B., Xu, M., Zhou, J. N., Hu, G., & Zhou, J. W. (2013).  Suppression  of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin.  Nature, 494, (7435), 90-94.

Sorce, S., Schiavone, S., Tucci, P., Colaianna, M., Jaquet, V., Cuomo, V., Dubois-Dauphin, M., Trabace, L., & Krause, K-H. (2010). The NADPH oxidase NOX2 controls glutamate release: a novel mechanism involved in psychosis like ketamine responses. Journal of Neuroscience, 30(34), 11317-11325.

Sommer, I. E., van Westrhenen, R., Begemann, M. J., de Witte, L. D., Leucht, S., & Kahn, R. S. (2014).  Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophrenia Bulletin, 40 (1), 181-191.

Sommer, I. E., de Witte, L., Begemann, M., & Kahn, R. S. (2012). Nonsteroidal anti-inflammatory drugs in schizophrenia:  ready for practice or a good start? Journal of Clinical Psychiatry, 73(4), 414-419.

Sorce, S., Schiavone, S., Tucci, P., (2010). The NADPH oxidase NOX2 controls glutamate release:  a novel mechanism involved in psychosis-like ketamine response. Journal of Neuroscience, 30, 11317-11325.

Sullivan, E. M., & O’Donnell, P. (2012). Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophrenia Bulletin, 38 (3), 373-376.

Zhou, F., Zheng, Y., Ding, Y.Q. et al. (2014). Minocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in rats. PLoS One, 2014, 9:e93966

 

Serotonin Is Still Alive and Well in Psychiatry Land

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In the September 2015 issue of JAMA Psychiatry, a team of Swedish researchers (see Frick et al.) published a study evaluating the serotonin system in persons with social anxiety.  They used Positron Emission Tomography an imaging technique wherein radio-active molecules that will bind in particular places in the brain and then allow for quantification of particular molecules in the brain are employed.  The researchers used two different molecules:  [11C]5-HTP, which is a precursor to the production of serotonin, and 5-hydoxytryptophan labeled with Carbon-11 that will bind to the serotonin transporter.  What the researchers found was an increase in both of these substances in brain areas that are known to be active during the experience of anxiety, viz., the amygdala and the dorsal Anterior Cingulate Gyrus.  The researchers concluded, “Collectively, these findings suggest that extracellular serotonin in the amygdala and dorsal ACC is positively related to severity of social anxiety symptoms” p. 789.  Translated into English, the researcher found that more serotonin release occurs during social anxiety.

Of course, the findings here are in direct contradiction to what the pharmaceutical companies would have us believe: anxiety and depression are caused by deficit levels of serotonin. There was an editorial by Stein and Andrews published in the same issue of JAMA Psychiatry in the “Clinical Review and Education” section which attempted to obfuscate the findings by referencing the heterogeneity in persons who exhibit social anxiety.

Unfortunately, neither Frick et al. article or the editorial referenced the work of neuroscientist Steven Maier on learned helplessness. Neuroscientists have been investigating what happens in the brains of animals that are subjected to uncontrollable shock for the last 30 years.  Given uncontrollable shock, the animals appear depressed and essentially “give-up” failing to make response that could turn off the shock when the opportunity is presented.  It turns out that one of the first areas to be activated by uncontrollable shock contains serotonin neurons in the caudal-dorsal raphe that project to the amygdala.  If these serotonergic neurons are destroyed, then no learned helplessness.  The Frick et al. findings are very consistent with the animal work: serotonin creates anxiety/depression.

While the Frick et al. findings are consistent with data on learned helplessness, Chris Lowry, a colleague of Steven Maier at University of Colorado, has identified multiple serotonin circuits in the raphe. While one of these circuits produces learned helplessness, another circuit turns it off.  Thus, serotonin is just another work-horse neurotransmitter capable of creating opposite effects.  It’s the connections among the neurons, not the particular chemical making the connections, that determines the outcome.  This is another “bad news” story for the pharmaceutical houses because ingesting a chemical such an SSRI, which presumably elevates serotonin in all circuits, will yield unpredictable effects.  There is no way given current technology to target the serotonin neurons you want.

What is clear from the two articles in JAMA Psychiatry is that psychiatrists are still focused on serotonin.  Whatever glib statements psychiatry-spokespersons utter for the general public (“we always knew it was more complicated”), in the psychiatric journals, where psychiatrists talk to each other, they acknowledge having bought the assumption that low serotonin creates anxiety.  Indeed, Stein and Andrews reflect “how do we understand the apparent paradox that potentiated serotonin signaling might underlie increased anxiety-related endophenotypes and the possible predisposition for developing anxiety disorders with the fact that some patients respond to SSRIs, which presumably further increases extracellular serotonin levels?”  As they went through tortured possibilities they could not resolve the paradox.  If they had read the animal literature, it’s far less confusing.

Frick, A., Åhs,F., Engman, J., Jonasson, M., Alaie, I., Bjöekstrand, J., Frans, O., Faria, V., Linnman, C., Appel, L., Wahlstedt, K., Lubberink, M., Fredrikson, M., & Furmark, T. (2015).  Serotonin synthesis and reuptake in social anxiety disorder:  A positron emission tomography study. JAMA Psychiatry, 77 (8), 794-802.

Stein, M. B., & Andrews, A. M. (2015).  Serotonin states and social anxiety. JAMA Psychiatry, 77 (8), 845-847.

 

Will the neurotransmitter of pleasure please stand up

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Over the years a number of neurotransmitters have been described as the neurotransmitter of pleasure. The list includes serotonin, dopamine, endocannabinoids, and endogenous opiates such as endorphin.  In Chapter 2 of Neuroscience for psychologists and other mental health professionals, I discuss particular emotions (fear, sadness, anger) identifying those brain regions that are active when people report the subjective experience of various emotions.  Pleasure, because it comes in so many flavors (excitement, contentment, orgasms, eating delicious food, hugging friends, enjoying music), I speculated that various pleasures may be triggered by activity in several different circuits.  However, a recent wonderful review by Berridge and Kringelbach argues that all forms of pleasure are associated with activity in the pleasure centers of the ventral pallidum in the mid-brain, the subcortical forebrain regions of the Nucleus Accumbens and subregions of the Orbitofrontal cortex.  We’ll look at why serotonin and dopamine can be ruled out as neurotransmitters of pleasure.

Serotonin has been dubbed the neurotransmitter of pleasure by some. This notion may stem from the fact that the Selective Serotonin Reuptake Inhibitors, commonly prescribed antidepressants, selectively prevent serotonin’s uptake into the neuron that released the serotonin.  So, at least initially, the makers of antidepressants might have believed that serotonin is implicated in the experience of pleasure.  At present time, data have accumulated that SSRIs are not efficacious in treating depression.  (Lack of efficacy was the bottom line from the meta-analyses conducted by Irving Kirsch and others.)  Meanwhile, neuroscientists, who can actually selectively activate or destroy specific clusters of neurons, have conducted systematic investigations to identify the functions of various clusters of serotonergic neurons. Chris Lowry, a neuroscientist at the University of Colorado, has done definitive work clarifying the function of various neurons in the raphe, the area in the brain stem containing the neurons which produce serotonin.  Turns out there are multiple circuits that employ serotonin.  One circuit actually is the proximal cause of learned helplessness. (Learned helplessness results from subjecting an animal to uncontrollable shock.  Subsequently, the animal appears depressed and will not turn off the shock when the researcher makes it possible to do so.)  When the “learned-helplessness” serotonergic neurons are destroyed, then an animal will no longer give up after being subjected to uncontrollable shock.  So one major serotonin region causes anxiety and depression.  Another serotonin circuit is involved in taming the learned helplessness circuitry.  This latter circuit is activated by heat.  There are other circuits as well.  For example, a particular circuit induces movement of the projections on the cells lining the fluid-filled cavity in the brain, such that cerebrospinal fluid in the cavity is returned to the blood stream more rapidly.  (A good thing if there is an infection.)  The problem with raising serotonin levels with an antidepressant drug is that it is impossible to know where serotonin is being raised.  The effects of the antidepressants are unpredictable.  Indeed, antidepressants carry a black-box warning for suicidal ideation.

Dopamine is a second neurotransmitter that has enjoyed a reputation as the neurotransmitter of pleasure. Neuroscientists who study addiction noticed that dopamine is released when animals work for various drugs (cocaine, amphetamine, alcohol, opioids), as well as when animals lever press for food and opportunities for copulation.  This led to the initial idea that dopamine was the “pleasure” neurotransmitter.  Then the discrepancies began to emerge.  The idea that dopamine was about pleasure was reevaluated because of  the following observations: (1) dopamine is also released when an animal works to avoid shock as well as when the animal works for a pleasurable outcome; (2) if the dopamine neurons are selectively destroyed, the animal will still display signs of pleasure when force fed, but the animal will no longer work for the food, and (3) when the animal is actually copulating or eating, the time when pleasure should reach its highest point, then dopamine is no long being released; it’s when the animal is working for food that dopamine neurons fire.  The new view is that dopamine is the neurotransmitter of motivation (striving for), rather than pleasure.

Berridge has further explored the areas in the brain which are active when an animal experiences pleasure. The ventral pallidum, which is connected and very near the area where dopamine is released, is activated when the animal experiences pleasure.  Moreover, this area activates in response to a wide range of pleasurable experiences.  Thus, Berridge and Kringelbach argue that many types of pleasurable experiences converge here.  Berridge and Kringelbach also make a distinction between areas which enhance pleasure and areas which are necessary for pleasure.  While stimulation of areas in the Orbitofrontal cortex, the ventral pallidum, the parabrachial can enhance pleasurable responses, most of these areas if removed, don’t erase pleasure.  Only the ventral pallidum, when damaged, turns liking into disgust. The neurotransmitters released in the hedonic hot spots (rostral-dorsal medial shell of the Nucleus Accumbens and ventral pallidum) include opiate type neurotransmitters, orexin, and cannabinoid type neurotransmitters.

All of this parsing of activity in the brain does have implications for how behaviors are viewed.   Dopamine has been recognized as the neurotransmitter most relevant for addiction.  (All drugs that lead to compulsive use induce dopamine release.)  Addiction happens when the motivational system gets captured by a drug.  Although a drug might initially be taken for its impact on mood (the drug either relieves pain or produces pleasure), affective consequences of the drug cannot explain addiction.  Addicts use because they are compelled.  The affective consequences are irrelevant.  The story on how the dopamine system gets captured by a drug and how recovery can be achieved is also pretty interesting.  This story is told in Chapter 8 and will wait for another blog.

Major depression involves both a diminution of motivation and a decrease in pleasure. Being able to distinguish these two components of “depression” anatomically allows researchers to ask whether various environmental manipulations or chemical interventions will have differential effects on each dimension.  In fact, making an animal’s environment less formidable and more predictable enhances the activity of all the pleasure structures, although this manipulation does not affect motivated behavior.  Perhaps, in the future, the distinctions, which are obvious to neuroscientists, will penetrate the thinking of the lay public.

Berridge, K. C., & Kringelbach, M. L. (2015).  Pleasure systems in the brain. Neuron, 86, 646-664.

THE USE OF ANTIPSYCHOTIC MEDICATIONS IN CHILDREN

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Increasing Use of Antipsychotic Medications. Mark Olfson and colleagues have been monitoring the use of antipsychotic medications for the treatment of children over many years. Since the mid-1990s antipsychotic medications have been increasingly prescribed for children, adolescents, and adults (Correll & Blader, 2015; Littrell, 2015). In the most recent report, Olfson, King, and Schoenbaum (2015) find a small reduction in the use of antipsychotics for younger children from 2006 to 2010, but an increase in use for older children from 2006 to 2010. According to the report, “The percentages of young people using antipsychotics in 2006 and 2010, respectively, were 0.14% and 0.11% for younger children, 0.85% and 0.80% for older children, 1.10% and 1.19% for adolescents, and 0.69% and 0.84% for young adults”, p.867.

Antipsychotics Are Primarily Used for Behavioral Control in Young Children. In an editorial discussing the Olfson et al. publication, Correll and Blader (2015) indicated that antipsychotic drugs have only received FDA approval for schizophrenia, bipolar mania, irritability associated with autism, and Tourette syndrome in children. Correll and Blader noted that most of the prescriptions of antipsychotics for children reported by Olfson et al. were for conditions which had not been approved by the FDA (called off-label use). Olfson et al. reported that for younger children those receiving antipsychotic medications most often carried a diagnosis of ADHD with aggression and/or disruptive behavior disorders. For adolescents, most carried a diagnosis of depression. Less than 25% of the children being treated with antipsychotics were receiving any type of talk therapy or family instructions on behavioral control.

Horrendous Side Effects of Antipsychotic Medications.   Antipsychotic drugs all share the property of blocking dopamine receptors. They have very significant side effects. Their use has been questioned for even the conditions for which they were initially designed to treat (see below).

  • Antipsychotic drugs, particularly the second generation antipsychotics such as risperidone, olanzapine, Seroquel cause weight gain that does not plateau. They induce diabetes and increase fats in the blood such that risk of heart disease is greatly increased. Children are much more sensitive to these effects (Correll & Blader, 2015)
  • Antipsychotics induce breast development in boys (references in Chapter 6 of Littrell)
  • Antipsychotics induce hormonal changes associated with osteoporosis (decreased bone strength) (references in Chapter 6 of Littrell)
  • Some second generation antipsychotics induce cardiac arrhythmias that are associated with risk of sudden death (references in Chapter 6 of Littrell)
  • Antipsychotics induce the expression of more dopamine receptors to which dopamine will bind more avidly such that after removal rebound psychosis might ensue (Grace, 2012; Seeman et al., 2005)
  • Antipsychotics induce dystonia or involuntary movement disorders which can make walking and locomotion almost impossible; dystonia occurs immediately upon antipsychotic initiation in about 15.7% of persons (Ballerini, Bellin, Niccolai, Pieroni, Ferrara, 2002); antipsychotics also can induce a second type of motor problem which is similar to the motor problems seen in those with Parkinson’s disease, although second generation antipsychotics are less likely to induce these effects (See Chapter 6 in Littrell, 2015)
  • Antipsychotics have been shown in primates to reduce the volume of the brain by significant amounts (Dorph-Petersen et al., 2005; Konopaske et al., 2007). Brain volume reduction has also been shown in people as well (Fusar-Poli et al., 2013; Ho, Andreasen, Ziebell, Pierson, & Magnotta, 2011). In terms of mechanism through which antipsychotics might reduce brain volume, recent research suggests that these drugs induce activation of white blood cells in the cortex (Cotel et al., 2015).

Concurrent Use of Antipsychotics with Other Medications. According to the Olfson et al. (2015) report, many children prescribed antipsychotic medications were concurrently prescribed other classes of medication in addition to their antipsychotics. For small children, 58.7% were also receiving stimulants; for older children 68.7% were receiving concurrent stimulants; for older adolescents, 59.1% were receiving concurrent antidepressants. Poly-pharmacy is alarming because drugs are evaluated for safety individually. Little information is available regarding the safety of various drug combinations.

Not only is poly-pharmacy an adventure into the land of the unknown with regard to safety, but knowledge regarding the mechanism of action of various drugs introduces wonderment over the rationale for the combinations being used in the treatment of children. Stimulants increase the release of dopamine, while antipsychotics block dopamine receptors that will receive the dopamine or serotonin message. The purported mechanism of action of antidepressants is increasing the availability of serotonin, which will be countered by the action of the atypical antipsychotic, which block serotonin receptor (Loy et al., 2012). It makes no sense to increase a neurotransmitter and then block its action.

Rather than having a theoretical basis for the use of antipsychotics, the current use of antipsychotics is based on the limited findings from 8 studies that they decrease aggressive behavior. The Cochrane Review (Loy et al., 2012) concluded that “there was some evidence of limited efficacy of risperidone in reducing aggression and conduct problems in children and youths (aged 5 to 18 years) with disruptive behavior disorders in the short term (four to 10 weeks) from a small number of studies in which there was some risk of bias of overestimating the true intervention effect” p. 19.

Irony that Antipsychotics Are Being Questioned for Use in Those Who Have Psychosis.  Antipsychotics are able to significantly reduce auditory hallucinations in those with psychosis. However, even for those with psychosis, antipsychotic use is being questioned. Long term studies find that those who are not medicated have better long term functional recovery (employment and social relationships) than those who are medicated (Harrow, Jobe, & Faull, 2012; Wunderink et al., 2013, see discussion in Chapter 6 of Littrell, 2015). It’s ironic that while antipsychotics are being questioned for the population for which they were initially named, they are being extended for use in new populations.

Alternatives to Antipsychotics for the Treatment of Aggression/Disruptive Behavior in Children. Physicians may feel compelled to prescribe antipsychotics for children because they are motivated to decrease the distress in families who are raising difficult children. However, alternatives to antipsychotics, without the horrendous side-effects, are available. Omega-3s have been shown to improve aggressive behavior in children (Raine, Portnoy, Liu, Mahoomed, & Hibbein, 2015). With regard to the older children treated for depression with antipsychotics, omega-3s, exercise, meditation all ameliorate depression (see Chapter 4 in Littrell, 2015). Perhaps, today’s physicians need to remember the admonition to “first, do no harm”?

Ballerini, M., Bellin, S., Niccolai, C., Pieroni, V., & Ferrara, M. (2002). Neuroleptic-induced dystonia: incidence and risk factors. European Psychiatry, 17 (6), 366-368.

Correll, C. U., & Blader, J. C. (2015). Antipsychotic use in youth without psychosis: a double-edged sword. JAMA Psychiatry, 72(9), 859-860.

Cotel, M-C., Lenartowicz, E. M., Natesan, S., Modo, M. M., Cooper, J. D., Williams, S. C. R., Kapur, S., & Vernon, A. C. (2015). Microglial activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses. European Neuropsychopharmacology, http://dx.doi.org/10.1016/j.euroneuro.2015.08.004.

Dorph-Petersen, K. A., Pierri, J. N., Perel, J. M., Sun, Z., Sampson, A. R., & Lewis, D. A. (2005). The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: A comparison of haloperidol and olanzapine in macaque monkeys. Neuropsychophramacology, 30(9), 1649=1661.

Fusar-Poli, P., Smieskova, R., Kempton, M. J., Ho, B. C., Andeasen, N. C. & Borgwardt, S. (2013). Progressive brain changes in schizophrenia related to antipsychotic treatment: A meta-analysis of longitudinal MRI studies. Neuroscience and Biobehavioral Reviews, 37(8), 1680-1691.

Grace, A. A. (2012). Dopamine dysregulation by the hippocampus: implications for the pathophysiology and treatment of schizophrenia. American Journal of Psychiatry, 161(9), 1750-1780.

Harrow, M., Jobe, T. H., Faull, R. N. (2012). Do all schizophrenia patients need antipsychotic treatment continuously throughout their lifetime? A 20-year longitudinal study. Psychological Medicine, 42(10), 2145-2155.

Ho, B. C., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. (2011). Long-term antipsychotic treatment and brain volume: a longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68 (2), 128-137.

Konopaske, G. T., Dorph-Petersen, K. A., Pierri, J. N., Wu, Q., Sampson, A. R., & Lewis, D. A. (2007). Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys. Neuropsychopharmacology, 32 (6), 1216-1223.

Littrell, J. (2015).  Neuroscience for psychologists and other mental health professionals: promoting well-being and treating mental illness.  New York:  Springer.

Loy, J. H., Merry, S. N., Hetrick, S. E., & Stasiak, K. (2012). Atypical antipsychotics for disruptive behavior disorders in children and youths. Cochrane Database System Review, doi: 10.1002/14651858.CD008559.pub.2.

Olfson, M., King, M., & Schoenbaum, M. (2015). Treatment of young people with antipsychotic medications in the United States. JAMA Psychiatry, 72 (9), 867-874.

Raine, A., Portnoy, J., Liu, J., Mahoomed, T., & Hibbeln, J. R. (2015). Reduction in behavior problems with omega-3 supplementation in children aged 8-16 years: a randomized, double-blind, placebo-controlled, stratified, parallel-group trial. Journal of Child Psychology and Psychiatry, 56 (5), 509-520.

Seeman, P., Weinshenker, D., Quirion, R., Srivastava, L. K., Bhardwaj, S. K., Grandy, D. K., . .. Tallercio, T. (2005). Dopamine supersensitivity correlates with D2high states, implying many paths to psychosis. Proceedings of the National Academy of Sciences, 102(9), 3513-3518.

Wunderink, L., N., Nieboer, R. M., Wiersma, D., Sytema, S. & Nienhuis, F. J. (2013). Recovery in remitted first-episode psychosis at 7 years of follow-up of an early dose reduction/discontinuation or maintenance treatment strategy: long-term follow-up of a 2-year randomized clinical trial. JAMA Psychiatry, 70 (9), 913-920.

Does the System for Training Physicians Need to Change?

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The lofty goal of evidence-based medicine: Evidence-based medicine became the mantra following the introduction of the term by David M. Eddy during the 1990s in publications in New England Journal of Medicine and Health Affairs. The idea is that research evidence rather than clinical hunch should guide the behavior of physicians. Guidelines for treating particular conditions have been developed based on the available findings from published studies. Medical schools base their training on guidelines and published studies.

Unfortunately, the term “evidence-based medicine” has become a mechanism for reassuring physicians that they are doing the right thing. The problem is that the edifice of the evidence is rigged to allow cheating. A variety of factors aggregate to create a system which ensures that the “evidence” should not be believed.

Believing the Positive Findings While Ignoring the Negative: In teaching research and statistics, an initial lesson includes a discussion of Type 1 Errors. In any test of statistical significance, researchers know how many times they will be wrong in concluding that a particular treatment was effective. The current standard is accepting wrong conclusions 5% of the time. (That is, in believing the results of your statistically significant test, you will be making a Type 1 error, 5% of the time.) The researcher knows that if a research study involves examining multiple measures, then that “willingness to be wrong 5% of the time” does not accurately describe the probabilities. One has to set a much tougher standard (a “p” value much smaller than 0.05) when making multiple tests of significance. We call this correcting for alpha-inflation. The problem with the current system for approving drugs is set up to make Type 1 errors. In approving drugs in psychiatry, the FDA does not aggregate across studies submitted by a drug company. The FDA bases approval on two positive trials. They ignore all the negative trials. When Irving Kirsch used the Freedom of Information Act to obtain all the trials on antidepressants from the FDA, he found that only for the very severely depressed do the drugs work better than a placebo. In the US, the bulk of antidepressants are prescribed for the less-severely depressed: the group for which the drugs are no better than placebo. Thus, in the US, we are spending a lot of money for placebos and more problematically, these placebos have plenty of very negative side effects (see Chapter 4 in Neuroscience for Psychologists and Other Mental Health Professionals for full details.)

The Medical Journals Are Also Set Up to Make Type 1 Errors: Erick Turner and Ben Goldacre, among others, have drawn attention to the fact that positive studies are much more likely to be published than negative studies. Indeed, the results of positive studies are often published multiple times, while the studies not supporting efficacy are buried. Thus, reading the literature, the source of information for most doctors, will yield a very biased perception of reality. Sometimes big meta-analyses reviewing all the published studies are conducted. But, again, when access to all the data is not available, including unpublished studies, there is little reason to believe aggregated findings. Unfortunately, pharmaceutical houses, which fund most of the trials of drugs in the US, are under no obligation to publish negative findings. There is no law against suppressing the truth.

The Ways to Put Lipstick on a Pig. Erick Turner, in the video “How publication bias corrupts the evidence base for psychiatric drugs” available through madinamerica.com, discusses the ways in which pharmaceutical trials can make negative trials of a drug look like support for drug efficacy. (Erick Turner knows where of he speaks. He was employed at the FDA but now teaches ethics at Oregon Health and Sciences University.) Basically, the ways of “putting lipstick on a pig” are variations on the theme of scan the data after the study to find the Type 1 errors, or, stated alternatively, see where you can capitalize on chance findings. The following strategies are popular favorites:

  • if the outcome is not supported at the planned study ending, scan for a point in time when the outcome supported drug efficacy and publish a study making it appear that the drug-favorable time point had been the planned time point for evaluating the outcome
  • If the planned outcome is not supportive, look for a minor measure that might be supportive and talk about this finding as if it were the planned major variable
  • slice the subjects into subgroups and see if there is some subgroup for which the drug worked
  • if four study sites were included in the study, see if things look better at a particular study site and only discuss the site which was positive
  • everyone knows that antidepressants and antipsychotics have rather severe withdrawal phenomenon, so in your study of drug efficacy, use subjects who had been medicated and then are pulled off the drug; when you resupply subjects with the drug, you will relieve withdrawal symptoms and the drug will appear efficacious
  • only count those subjects who have completed the trial and ignore all those subjects who left the trial because the drug wasn’t working

In the video “How publication bias corrupts the evidence base for psychiatric drugs” Erick Turner compares findings as reported to the FDA with the findings from the same studies published in journals. By using the clever strategies, the negative studies as reported to the FDA suddenly appear to support drug efficacy once the drug companies massage the data. In the publications, the source for educating physicians, it looks like the evidence in support of the drug is strong. 

Registration of Clinical Trials. As Erick Turner points out the proper way to evaluate the findings from a study is to know the specific hypothesis that is being tested. The outcome which is expected to be changed by the drug at a particular time point must be agreed upon before the study begins. Scanning the data after the fact for anything that might support the general hypothesis is capitalizing on chance. In 2007, the FDA began requiring drug companies to register their trials of various drugs for which approval applications had been made to the FDA. The International Committee of Medical Journal Editors pledged to only publish those studies that had been properly registered. The process of registration requires that the protocol for the study be provided. With specification of which measures will be evaluated at which points in time, a way to check whether a researcher is guilty of capitalizing on chance is available. It is possible for interested people to go to the FDA website to determine the design of the trial. Presumably the findings from the study are to be provided to the FDA within a year following completion and are to be publicly available. Any doctor can then go to the Clinicaltrials.gov website and access the information to do his/her own evaluation of the drug’s efficacy. (Turner has published directions for doctors on how to navigate the ClinicalTrials website.) However, the FDA is reluctant to provide the raw data making it difficult for interested persons to analyze the raw data themselves.

Compliance with Clinical Trials Registration: While the Clinical Trials web site is a very important step in the right direction, it won’t help everything. Post drug approval studies on a drug are not registered. The data from studies before the change in policy are not available. Moreover, Scott, Rucklidge, and Mulder (2015) evaluated the degree of compliance by journal editors with the new mandates. Only 33.1% of published studies were prospectively registered with clearly defined outcomes. Ben Goldacre in his book and Tedtalks also concludes that medical journal compliance with commitments to publish only the results of registered studies has not been good. While capitalizing on chance has been particularly widespread in psychiatry, McGauran et al. (2010) note that the lack of truth telling is not limited to psychiatry but occurs throughout various areas of medicine.

Questions Not Asked by the FDA. The FDA’s function is to evaluate drugs for safety and efficacy. When procedures and standards were promulgated at the FDA years ago, most of the available drugs were assumed to be taken like antibiotics: use them for a short period of time until the condition resolves and then stop. Times have changed. Many Americans take medications daily for years at a time. For psychotropic drugs, people take the drugs for decades. The FDA evaluates psychotropic medications for 8 weeks. They don’t collect data on efficacy after 8 weeks. While doctors are supposed to report adverse events (side effects), it is estimated that only 1-10% of adverse events are actually reported (See Chapter 3 of Neuroscience for Psychologist and Mental Health Professionals). Particularly for drugs that are taken daily for extended periods, the long term impact on the body is not known at the time of drug approval. Moreover, no evaluation of the difficulty of withdrawing from a drug is required by the FDA. (Withdrawal process from antidepressant medications is rather severe.) Certainly, information about long term efficacy, about the long-term impact on the body, and about the difficulty of drug discontinuation might be very important pieces of information to have for both physicians and patients when deciding whether to initiate drug use. This information is just not available when drugs are released onto the market. 

Effective System Change? Given the current system, I wonder how the broken system in medicine in the US will ever be fixed. Evidence-based medicine is a good thing, but that is not the system we have. Speilmans and Parry (2010) suggest that our current system is marketing-based medicine, not evidence- based medicine. Erick Turner suggests that individual doctors can go to the clinical trials web site to evaluate drugs for themselves. Perhaps some will. We can wait for someone like Irving Kirsch to evaluate all the FDA data to evaluate efficacy. But Kirsch is then fighting against all the “noise” in the literature on the published studies. I wonder whether America’s escalating medical costs and the fact that medical care consumes more of GDP in the US than in any other country in the world might be a force for demanding a more truthful system. Surely those who worry about the National Debt will want to ensure that their dollars are not being wasted. Perhaps it will be the states, which have to balance their budgets, whose Medicaid/medicare panels might demand honest evaluations of which treatments are safe and effective. I have faith that in the long run, the truth will win. However, as John Maynard Keynes said, “in the long run, we’re all dead.”

Ghaemi, S. N. (2009). The failure to know what isn’t known: negative publication bias with lamotrigine and a glimpse inside peer review. Evidence Based Mental Health, 12, (3), 65-68.

Goldacre, B. (2012). Bad pharma: how drug companies mislead doctors and harm patients. New York: Faber & Faber.

Kirsch, I. (2010). The emperor’s new drugs: exploding the antidepressant myth.   New York, NY: Basic Books.

McGauran, N., Wieseler, B., Kreis, J. Schuler, Y-B., Kolsch, H., & Kaiser, T. (2010). Reporting bias in medical research—a narrative review. Trials, 11, 37.

Melander, H., Ahlqvist-Rastad, J., Meijer, G., & Beermann, B. (2003). Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. British Medical Journal, 326, 1171.

Scott, A., Rucklidge, J. J., & Mulder, R. T. (2015). Is mandatory prospective trial registration working to prevent publication of unregistered trials and selective outcome reporting? An observational study of five psychiatry journals that mandate prospective clinical trial registration. PLoS One, DOI: 10.1371/journal.pone.0133718.

Spielmans, G. I., & Parry, P. I. (2010). From evidence-based medicine to marketing-based medicine: evidence from internal industry documents. Biomedical Inquiry, DOI 10.1007/s11673-010-9208-8

Turner, E. H. (2013). How to access and process FDA drug approval packages for use in research. British Medical Journal, 347, 15992.

Turner, E. H., Matthews, A. M., Lindardatos, E., Tell, R. A., & Rosenthal, R. (2008). Selective publication of antidepressant trials and its influence on apparent efficacy. New England Journal of Medicine, 358 (3), 252-260.

 

STRESS INCREASES INFLAMMATION BUT ALSO DECREASES THE IMMUNE SYSTEM’S CAPACITY FOR FIGHTING VIRUSES AND CANCER

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Stress does increase inflammation throughout the body. This conclusion is supported by correlational research and manipulated variable research. It is known that caregivers of patients with Alzheimer’s disease display elevations in markers of systemic inflammation.   Persons experiencing stress at work display elevations on inflammatory markers. When researchers induce stress in individuals by having them talk about embarrassing events in front of a scowling audience, inflammatory markers in the blood spike. (See the post on depression is inflammation for references.)

Systemic inflammation is a causal factor in the development of cardiovascular disease and type 2 diabetes.   Systematic inflammation is a marker of an activated immune system. However, the mystery is that stress impairs the body’s capacity for fighting cancer, fighting viruses, and mounting an immune response after vaccination. A new study sheds light on how the immune system can be both activated in some ways but depressed in other ways. The explanation focuses on a recently discovered class of white blood cells called Myeloid-Derived Suppressor Cells.

Myeloid-Derived Suppressor Cells have been the focus in research on tumors. Myeloid-Derived Suppressor Cells get recruited into cancerous tumors where they prevent the attack of the killer T cells, the cells which would otherwise kill cancerous cells.   Advancements have been made in the treatment of cancer. Antibodies to molecules expressed by tumors which turn off killer T cells can be blocked by antibody treatment.   Many cancers can be cured with these antibodies. However, solid tumors often fail to respond to the antibody treatment. The efficacy of the antibody treatment is impaired because of the second obstacle preventing the killer T cells from eliminating the tumor: Myeloid-Derived Suppressor Cells. The ways in which Myeloid-Derived Suppressor Cells prevent killer T cells from doing their job have been identified. In the future, ways to subvert the Myeloid-Derived Suppressor Cells will be forthcoming so that the immune system will be able to eradicate cancer.

Besides influencing the cancer outcomes, Myeloid-Derived Suppressor Cells can impair the immune system in other ways as well. They decrease the capacity of killer T cells to kill cells infected with virus. A recent study by Jin et al. showed that stressing animals by restricting their movement increased the number of Myeloid-Derived Suppressor Cells in circulation. This study demonstrated that psychological stress does increase the population of Myeloid-Derived Suppressor Cells.   Assuming this finding applies to many diverse types of psychological stressors it clears up the mystery of how stress can increase inflammation while weakening the immune system’s capacity for responding to cancer and viral infected cells.

As discussed in Neuroscience for Psychologist and Other Mental Health Professionals in Chapter 2, the arms of the immune system can be divided into the innate system and the adaptive immune system. The innate system responds non-specifically to any molecule that looks foreign. The adaptive immune system responds to a very specific foreign protein. The adaptive immune system is recruited by vaccination. Cells responding to the proteins in the vaccine are increased. These cells will only attack when they once again see the same protein that was in the vaccine. The Myeloid-Derived Suppressor Cells seem to primarily impair the function of the adaptive system, the system needed to fight cancer and viruses. Thus, Myeloid-Derived Suppressor Cells may be a critical link for how stress increases cancer risk and impairs the body’s capacity of eradicating viruses.

Jin, J., Wang, X., Wang, Q., Guo, X., Cao, J., Zhang, X., Zhu, T., Zhang, D., Wang, W., Wang, J., Shen, B., Gao, X., Shi, Y., & Zhang, J. (2013). Chronic psychological stress induces the accumulation of myeloid-derived suppressor cells in mice. PLoS One, 8 (9), e74497.

Thoughts on the Nature of Emotions

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I recently finished reading Joseph LeDoux’s wonderful book Anxious: Using the Brain to Understand and Treat Fear and Anxiety. LeDoux has been working on fear for many decades now. LeDoux has written numerous books and articles. His style is very accessible and he makes neuroanatomy and neuroscience easy to understand. LeDoux does study the brain, but readers of this site should know that he is rather dubious about drugs being the answer to ameliorate anxiety or fear. He also raises questions regarding what domains of behavior belong to brain and which domains belong to mind. A little background on Joe LeDoux is appropriate for those who have not followed his work.

Split Brain Research. LeDoux’s doctoral mentor was Michael Gazzaniga. Under Gazzaniga, LeDoux worked with split brain patients. Persons with intractable epilepsy sometimes have the axons connecting the two sides of cortex severed so that seizure activity can no longer spread from one side of the brain to the other. For most functions of daily life these patients are fine. However, the fact that the right brain does not know what the left is doing leads to some interesting phenomena. In fact, language, that is the ability to comment on what one is doing, is housed in the left side of the brain, in most of us. Information from the right field of vision goes to the left brain where it can be commented on. Information from the left field of vision goes to the right side of the brain, where it can be acted upon but not commented on. (It is possible to set up screens so that visual information only goes to one side of the cortex.)  Numerous experiments have been conducted in which stimuli presented to the right brain induces some action and then the left side of the brain is asked “why did you do this?” LeDoux and Gazzaniga reflect that no one is ever puzzled by the question. Rather, the left brain just comes up with some plausible explanation for the motivation driving the behavior, which people apparently believe. (Of course, LeDoux knows that the left brains explanation is not correct because LeDoux knows what the right brain saw.) For Gazzaniga and LeDoux these findings raise the issue about whether anyone ever really knows why he/she did anything. People for Gazzaniga and LeDoux are effectively almost in the position of being observers of their own behavior just like another person observes our behavior and guesses at our motivation. In some cases, we can only guess about why we did what did in the same manner that others might guess about the motivation driving a behavior. It should be noted that Gazzaniga and LeDoux were not the first psychologists to discover this. Gazzaniga and LeDoux basically confirmed what social psychologists Nisbett and Wilson came up with years preceding their work: under particular circumstances, none of us can definitely know why we behave as we do. We can only piece together some plausible explanation based on observation of what we have done in the context of a particular environmental contingencies which we have consciously processed.

More About LeDoux and Fear Conditioning. After establishing an independent career in the 1980s, LeDoux embarked on the study of where in the brain fear conditioning occurs. (Fear conditioning means the organism comes to react to environmental stimuli associated with a harmful stimulus in the same manner as the actual harmful stimulus.)   LeDoux identified those neurons in the amygdala where information about the co-occurrence of a light (the conditioned stimulus) with shock (the unconditioned stimulus) enters the amygdala and then the parts of the brain to which the amygdala sends the output. Given a danger associated stimulus, the output from the amygdala increases cortisol levels in the blood (the stress hormone), induces an increase in heart rate and respiration, and the animal freezes (think: deer in headlights). (For the anatomical details, the reader should consult LeDoux’s book.)

Emotion Entails a Conceptual Narrative. What will interest visitors to this web site is that LeDoux argues that the animal’s freezing, the increase in blood pressure, and the rise in stress hormones is not anxiety. LeDoux characterizes freezing, an increase in stress hormones, and increased heart rates as hard-wired defensive programs. When under attack, we all have hard wired “defensive programs” which will be elicited. According to LeDoux, these defensive programs are not emotion. Emotions in general, and in particular here, anxiety, are defined by subjective, self-report.   Self-report of emotions (feelings) are concepts: stories that people tell themselves. To state it alternatively, when deciding how you feel you are constructing a narrative that integrates physical sensations and your concept of yourself responding to your environment. Thus, self-reports of emotion are, in part, a statement about one’s self-concept.

This of course returns us to the old debate between William James and Walter Cannon in the early 1900s. Walter Cannon argued that I’m scared so I run from the bear.   William James argued, I see myself running from the bear, so I decide I’m scared. In fact, a lot of data support William James’ position. Emotions are as much a product of self-observation as they are of awareness of internal events. If people are induced to behave consistent with a particular emotion or their facial expressions are manipulated by the experimenter to be consistent with a particular emotional expression, their self-report of emotion is greatly enhanced. When discussing these rather novel ideas with my students, I always ask the mothers in the class, “who did your two-year old look at after falling down to decide whether he/she should cry?”   Most little kids look to see whether mom is horrified before they decide if they’re hurt.

The idea that emotions are constructs raises issues about self-reports of depression. In an earlier post, I presented the data supporting the case that depression involves systemic inflammation and inflammatory hormones in the brain. Since a virus or bacteria will induce an equivalent physical state to one induced by stressful circumstances, it’s equally valid for persons with systemic inflammation to decide they are depressed as to decide they harbor a virus. The question is which explanation enables a faster recovery.

Caveats Regarding Trauma-Informed Psychotherapy. Assuming that self-report of emotion entails a conceptual narrative carries implications for talk therapy. Currently, trauma informed care and screening for trauma is in vogue. A problem with this approach is the implication is that if I have experienced a trauma, I should be traumatized. “Traumatized” is a concept. It’s a narrative incorporating the concept of who the person is in relationship to an event. Unfortunately, it’s not a narrative of resilience. Just as psychiatrists look at physical manifestations (e.g., low threshold for a startle reflex) and decide it’s evidence of a brain disease (PTSD), are those who screen for experience of traumatic events in the past making an analogous mistake of finding evidence of an unfortunate event in the past (my mother was very shaming) and deciding that the client is “traumatized”. Saying my diseased brain caused my current distress or my past caused my current distress leaves no room for personal choice. Could we instead be screening for evidence of strength in the client and helping them to find a narrative of resilience. (Yea, mom was shaming, but that was about her and not about me.   I’ll write my own narrative.)

With the emphasis on trauma-informed-care these days, I’m wondering if anyone remembers the last time we collectively went down that path. In the 1980s, everyone was searching for repressed memories of child sexual abuse. If a child was shy, many therapists asked who might have abused them. Therapists frequently defined themselves as doing a good job, when a client came up with another memory. Competent women who recalled their traumatic pasts would be hospitalized for extended periods of time with the diagnosis of borderline personality or multiple personality disorder. Treatment consisted of processing the memories. This all ended rather abruptly when a prominent psychiatrist lost his license and insurance companies began prosecuting for insurance fraud, a felony offense. The history of this trauma centered approach is recounted in Mistakes were made but not by me authored by Caroll Travis and Eliot Aronson. (Yea, talk therapy can do a lot of damage too.)

Are “How Questions” More Important Than “Why Questions” ? My social work students all want to explore why a client comes in with a particular problem. Perhaps it’s human nature to ask “why?” Those of us with a physiology bent ask about diagnosis and evidence of heredity. The social science people ask about “what happened to you?” These days some of us might ask about diet (see my last post). What I try to impress on my students is that in any particular case, we will actually never know “why”. There are just too many potential causes. In line with the late Jay Haley suggestion, “define the problem in such a way that you can solve it” perhaps the more important question is “how do we get from where we are now, to where we want to be?” Often times, how one got there has little to do with how one moves on.

Donovan, L. (December 8, 1999). Controversial psychiatrist suspended: recovered memory case spurs state move. Chicago Tribune

Gut Microbiota and Mental Health

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Brain-Gut-Microbiota Axis: There are approximately 1013-1014 microbes in the human being. Microbial cells are 10 times more numerous than human cells in the human body such that 90% of the cells in the human body are microbes.  Approximately 500-1000 microbial species occupy the human gut. The microbes perform vital functions for the human host. Without these microbes, the gut immune system fails to develop. Harmless bacteria (called commensal bacteria) are needed to compete with harmful bacteria for space and nutrients. Commensal bacteria degrade dietary fiber into short-chain-fatty-acids which then can be absorbed. Commensals are required for the absorption of vitamin K and B (Bailey et al., 2011; Dinan &Cryan, 2012).

The composition of the microbiota community is important because some species are highly inflammatory whereas other species are anti-inflammatory. In almost all human cells there are pattern recognition receptors that recognize “foreign” molecules. Some foreign molecules belonging to bad bacteria will result in inflammation which gets communicated by the vagus nerve to the brain resulting in negative moods (anxiety and depression as discussed in the next section). Other foreign molecules associated with good commensal bacteria activate alternative pattern recognition receptors that lead to the release of white-blood-cell hormones (such as interleukin-10) that counter inflammation (Dinan, Stanton, & Cryan, 2013: Smits, et al., 2005), although the mechanism for how this is accomplished are still being worked out (Geuking, McCoy, & Macpherson, 2011). The IL-10 (white-blood cell hormone) protects the human gut from any aggressive inflammatory response that might be evoked by a bad bacteria.

The Composition of the Gut Microbiota Influences Behavior. Biologists who work with mice know that there are major strain differences in innate anxiety levels. Some mice strains are very wary of the novel and readily freeze. The skittish strains are prone to trepidations and rarely venture forth. Other strains are fearless and outgoing. While a good guess might have been that the mice differ in some aspect of the nervous system, turns out that what accounted for the difference between the species was the bacteria that they harbor in their guts. When researchers transferred the bacteria of the skittish mice into the intrepid mice, the intrepid mice exhibited anxious behavior and showed a decrease in BDNF, a protein required for optimal brain health, in their hippocampi. When researchers did the reverse fecal transplant experiment, transferring the intrepid mice microbiota into the skittish mice, the skittish mice became daring and showed an increase in BDNF in their hippocampi (Collins, Kassam, & Bercik, 2013). There were genetic differences between the skittish and intrepid mice driving behavioral differences.   But, the genes had to do with differences in the immune systems not the neurotransmitters. Immune system differences can determine which bacterial species are eliminated and which are invited to stick around.

The composition of the gut microbiota determines more than depression and anxiety levels. Gut microbiota influence appetite, obesity levels, insulin resistance (type 2 diabetes), and memory. In a dramatic demonstration, researchers transferred the gut microbiota from the obese mice to the thin mice. The thin mice then got fat, even though they had not increased their calorie consumption (Turnbaugh et al., 2006).

Factors that Influence the Composition of the Microbiota. Not surprisingly antibiotics can drastically alter the composition of the microbial community in the gut. When antibiotics are used to eradicate pathogens in some part of the body, the friendly gut bacteria who keep the nasty bacteria in check are wiped out. A relatively common occurrence these days is that after a course of antibiotic treatment, Clostridium difficile, a really nasty bacteria, takes over in digestive tract; it’s hard to get rid of. These days, fecal transplants from a healthy donor are sometimes provided. The other two major influences on microbiota composition are stress and diet.

Stress Can Alter Microbiota Composition and Behavior.

Stressors will increase the release of stress hormones in the gut which will then alter the microbial colonies which will then provoke systemic inflammation (Bailey et al., 2011; Bangsgaard Bendtsen et al., 2012). (Systemic inflammation means that inflammatory, white-blood-cell hormones are increased in blood.) Beyond changing the colonies of microbiota in the gut, stress will also alter the tight connections between the cells lining the gut so the lining becomes more permeable to pathogens and to secretions from these pathogens, further contributing to systemic inflammation (Kiliaan et al., 1998).

Diet Is a Major Factor for Determining Microbiota Composition.  Eating fermented foods such as sour kraut and yogurt is good strategy for encouraging the colonization of good microbes in the gut. Fermented food substance are called probiotics.   Fermented foods contain the good bacteria. For increasing good bacteria in gut, there’s also the prebiotic strategy (which will be referred to later in reference to why eating apples is good). Rather than consuming beneficial bacteria directly, prebiotics is about consuming dietary nutrients that will promote the survival of beneficial microbes.

A number of studies have found that administration of the species of bacteria found in yogurt decrease anxiety and depressive behaviors (Bravo et al. 2011; Messaoudi et al., 2011). In animals, probiotics are also protective against the development of anxiety in responses to stressors (Cryan & O’Mahoney, 2011). In humans, probiotics narrowed the differences between high and low anxious subjects on stress hormones in the urine (Martin et al., 2009) and decreased anxiety and depression and reduced levels of the stress hormone cortisol in blood (Benton, Williams, & Brown, 2007; Messaoudi et al., 2011; Rao, et al., 2009). Consumption of probiotics decreased social anxiety in those scoring high on a measure of neuroticism (Hilimire, DeVylder, & Forestell, 2015). Additionally, Tillisch et al. (2013) showed that consumption of probiotics resulted in a reduction in activity in the insula while viewing emotionally evocative pictures and resulted in an increase in regulatory control over areas of the brain that respond to emotion.

While probiotics and prebiotics can potentially influence microbiota composition so that distress (anxiety and depressive behaviors) is reduced, other dietary factors will probably reverse the effect. Consequently attending to the entire diet is necessary if a positive effect is to be achieved.

Encouraging the wrong type of microbes. Generally, high saturated fat and refined sugar promote inflammatory microbes in the gut (Magnusson, Hauck, Jeffrey, Elias, Humphrey, Nath, Perrone, & Bermudez, 2015; Ohland et al., 2015; Trunbaugh et al., 2009).  However, the bottom line is likely to be more nuanced than merely saying that a particular molecule is good or bad. Spreadbury (2012) suggests that it is not just saturated fats or carbohydrate molecules that should be considered but rather whether these molecules are consumed in the context of high fiber. Thus, carbohydrates consumed in plant fiber might have a different impact than pure glucose. In fact, consumption of high fiber foods (apples) change microbiota composition in animal studies (Koutsos, Tuohy, Lovegrove, 2015).   Various bacteria live on fiber and thus eating fruit with fiber is a prebiotic strategy for increasing good bacteria.

Artificial sweeteners have also been shown to alter gut microbial communities in undesirable ways (Suez et al., 2014). Atypical antipsychotics also alter the microbiota in negative ways (Dinan, Stanton, & Cryan, 2010).

Chemicals that extend the shelf-life of foods. The food industry adds detergent-emulsifiers to many processed foods. (Most ice creams are loaded.) Several of these common emulsifiers (carboxymethylcellulose and polysorbate-80) were tested on mice in research conducted by Chassaing et al. (2015). The emulsifiers changed the composition of microbiota to less friendly species. With the change in microbiota composition, the protective mucus layer lining the gut was eroded, bacteria clung to the cells lining the gut, and the gut lining allowed invasion into the blood stream. Of course, the immune system rapidly responded to the presence of the bacteria and bacterial products. The results were low grade systemic inflammation, more insulin insensitivity, and weight gain. The authors of the study speculated that common food additives may be contributing to the rise in inflammatory bowel disease, diabetes, and obesity. The authors did not measure changes in behavior, but given the research cited here, it’s a good bet that behavioral changes might have been found.

The serotonergic, anti-panic neurons connection. The “old-friends” hypothesis has been in the literature for a while now. The idea is that formerly common dietary bacteria such as Mycobacterium vaccae (common in human feces used as fertilizer in some parts of the world) induce the production of anti-inflammatory hormones (IL-10). IL-10 tames inflammation such that allergies and inflammatory bowel diseases are less likely (Rook & Lowry, 2008). Additionally, M. vaccae induces a cluster of serotonergic neurons, in the interfasicular part of the dorsal raphe, which are anti-panic neurons (Lowry et al., 2007). Lowry et al. placed M. vaccae under the skin or into the lungs and showed that mice displayed less anxiety.   Administering M. vaccae orally also decreases anxiety associated behaviors and improves memory (Matthews & Jenks, 2013). Recently, Lowry et al. (2015) fed mice M. vaccae and then exposed them to a larger, more aggressive animal. Rather than succumbing to the aggressor, the M. vaccae pretreated mice fought back. In another test of the anti-anxiety impact of M. vaccae, Lowry showed that fearful responses are unlearned (extinguished) much more readily in mice treated with M. vaccae. Feeding with M. vaccae has been characterized as a way to vaccinate against PTSD (Reardon, 2015).

It should be noted here, that M. vaccae is an aerobic (oxygen requiring) microbe and thus could not live for very long in the gut. However, its cell membrane contains molecules that are recognized by the “pattern recognition receptors”. Signaling through the pattern recognition receptor is the mechanism for the increase in the anti-inflammatory hormone, IL-10.

Clarification on Serotonin. It is important to recognize that serotonin is just another neurotransmitter in the brain. It is used in both anxiety inducing and anxiety reducing circuits. (There are distinct sets of connecting neurons.) Thus, the above should not be interpreted to imply that increasing serotonin is necessarily good or bad, as is sometimes implied by the simplistic story that serotonin deficiency creates depression.   (The story on serotonin is reviewed in Chapter 2 of Neuroscience for Psychologists and Other Mental Health Professionals.)

The Microbiota Research Is Just Beginning. The importance of the gut microbiota for physical health, mood, and perhaps cognitive capacity is a recent discovery. There are still plenty of unknowns. Given that so much of the American diet is based on processed foods, each food addictive needs to be interrogated to determine its impact on the microbes in the gut, general inflammation, and mood and behavior. Also each probiotic in fermented foods needs to be evaluated. Preliminary research suggests they are not all the same. However, the implications of this research are apparent. In the future, those with depression might conceivably be treated with fecal transplants from happy people. But then, it just might be easier to eat lots of nut, fruits and vegetables and avoid the processed foods and artificial sweeteners and start enjoying yogurt (the stuff without the high fructose corn syrup).

Bailey, M. T., Dowd, S. E., Galley, J. D., Hufnagle, A. R., Allen, R. G., & Lyte, M. (2011). Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain, Behavior, & Immunity, 25(3), 397-407.

Bangsgaard, Bendtsen, K. M., Krych, L., Sorsen, D. B. et al. (2012). Gut microbiota composition is correlated to grid floor induced stress and behavior in the BALB/c mouse. PLoS One, 7, e46231.

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IDENTIFYING AN OPTIMAL POLICY WITH REGARD TO OPIATES

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History of Opiates in the US.  I wrote my last post on buprenorphine and methadone with some ambivalence.  I’m not against methadone maintenance clinics.  Generally, limiting access to any drug has proven to be a bad idea.  We all remember prohibition.  When there is demand for a substance, making it illegal merely empowers the gangsters, although the numbers dependent on the substance remain about the same.  (Before the drug laws in 1914, about 1/400=.25% of Americans were addicted to opiates; in 2006, 1.6% of Americans reported having used heroin, Hart, Ksir, Ray, 2009, p.63 & p. 318).  In my class on substance abuse, we review the history of the drug laws in the US.  In fact, when all drugs were legal before the Harrison Act of 1914, there was not much of a problem with drugs in this country.  (However, in the late 1800s, there were reports of infants dying from paregoric, an opiate-based treatment for diarrhea, in the emerging pharmacy literature.)

Why Was Heroin Made Illegal?  The impetus for the Harrison Act was foreign policy.  After the Spanish American War, the US acquired the Philippines.  Given a US presence in the Pacific, Teddy Roosevelt wanted to trade with the Chinese.  But the Chinese did not trust the westerners who ran opiate concessions/parlors all along the coasts.  (The Chinese emperor did not succeed in his attempt to throw out the “foreign devil” in the Boxer Rebellion.)  Roosevelt believed he could ingratiate the US with the Chinese by regulating the world traffic in opiates.  However, the US itself had no domestic policy.  To avoid a charge of hypocrisy when telling the Europeans to clean up their act, America needed to regulate opiates. In order to promote making drugs illegal in the US, the government realized that opposition would emerge from the South to any attempt to legislate morality.  (What’s next, Jim Crow?)  So, drug policies were sold with racist propaganda.  Given that the federal income tax had recently been established in 1913, the government believed that regulating drugs through taxation would be the path of least resistance.  The Harrison Act of 1914 taxed opiates and cocaine, but omitted marijuana.  Enforcement was through the Treasury Department (IRS).  The war on drugs, at least before the recent change in metaphors, has/d been vigorous.  Michele Alexander’s book, The New Jim Crow, argues that US drug laws have effectively been an excuse to disenfranchise African Americans, who are over-represented in prison largely by dint of commission of drug-related crimes.

Why is heroin so devastating:  the drug or the drug-policy?  In talking about opiate addiction so much propaganda has surrounded the topic that it’s hard to discern the truth.  The stereotype is that of the desperate addict devoting all his/her time in pursuit of a drug which compromises values and demands the sacrifice of what one would otherwise hold dear.  There is support for the stereotype but is this stereotype attributable to the opiate drug or America’s drug policy?  In terms of addictive liability, nicotine is touted as one of the most addictive chemicals in the formulary.  Yet, no one neglects his/her children or steals to obtain a cigarette.  Cigarettes are relatively cheap and available.  Cigarettes have devastating long term effects on health, but they don’t impair ability to work or start bar room fights.  So, maybe the desperate efforts to seek an addictive drug (in this case, opiates) at any cost are a function of the government’s restriction.  If opiates were widely available, would many of the social problems evaporate?

The next question is “to what extent do opiates impair job performance?”  Although there are not many data on this issue, I remember the story of William Halsted.  Halsted was a physician at Johns Hopkins during the 1900s.  He is credited with being the father of modern surgery and the physician who came up with sterile procedures.  Halstead was maintained on morphine by his friends throughout his career.  In the modern era, we also have data on methadone maintenance clients.  The justification for the harm reduction approach of methadone maintenance is that it restores peoples’ ability to work.  The data are pretty consistent with this claim.  People in methadone maintenance clinics do return to productive employment.  Methadone is about equivalent to heroin in terms of potency at a mu receptor.  So extrapolating to other opiates from methadone, opiates probably will not rob anyone’s capacity for productive behavior, although taken in excessive doses people will fall asleep.

Then there’s the issue of long term effects on health.  Perhaps surprisingly, opiates are probably the least harmful drug on the body of just about any drug in the formulary.  They don’t damage any organ system.  They do cause immune system suppression, although Sacerdote, the expert on this topic, claims that with long term exposure to opiates cells compensate becoming tolerant to this effect.  Opiates do suppress testosterone levels and sexual function, which might result in muscle and bone wasting, although again some argue that tolerance develops here too.  Whereas withdrawal from alcohol, benzodiazepines, and barbiturates can be lethal, unless an individual is otherwise in poor health, opiate withdrawal is not life threatening.

The big problem with opiates is that they are very dangerous drugs.  They block the function of the baroreceptors (which detect a lack of oxygen) so that breathing centers don’t operate properly.  Addicts using illicit drugs and pain patients treated with OxyContin regularly die from overdoses.  Additionally, methadone (but not heroin) is associated with cardiac arrhythmias (Qtc prolongation) which can be potentiated when combined with antidepressants and antipsychotics.

What concerns me about the federal government’s response to the current opiate epidemic is that they are advocating for more opiates in the form of methadone and buprenorphine.  Although physician-prescribed buprenorphine and methadone are certainly safer than street heroin, they aren’t safe.  After clients show some trustworthiness in the methadone maintenance clinic, clinics are allowed to provide clients with take-home methadone and buprenorphine.  Once this happens, accidents are more likely to occur.  We’ll probably see more accidental poisonings with little kids.  The future should inform regarding whether OD rates decline or increase once more Americans are in “Medication Assisted Treatment.”

Can another drug cure drug addiction?  Over the years, I’ve gone to many a seminar on finding a drug to treat addiction.  I remember the NIDA researcher who came up with a drug to block a cannabinoid receptor.  There was even a guy who thought amphetamines might be the way to treat cocaine addiction.  (Works in the monkeys.)  The problem here is that for most drugs of abuse, they operate on receptors for natural chemicals in the body.  The brain releases endocannabinoids which then operate on cannabinoid receptors and decrease anxiety signaling in the amygdala.  Endorphins and enkephalins are the body’s neurotransmitters at mu and delta opiate receptors.  They function in circuits for pleasure and for energizing behavior.  Do we really want to find some chemical that blocks opiates or cannabinoid receptors?  Although some magic chemical might make it so that the drug of abuse won’t work, the body’s natural chemicals won’t work either.  The cure is often more devastating than the disease.

What is addiction anyway?  There is a lot of confusion in professional journals and in lay publications on what accounts for the compulsion to find and use drugs of abuse, the now generally accepted definition of addiction.  I’ve been convinced by the work of Peter Kalivas and Kent Berridge, among others, that compulsion to use cocaine, alcohol, and opiates has little to do with seeking pleasure or avoiding the pain of withdrawal.  Rather, it’s a story about capturing the brain’s motivational system, which operates independently from seeking pleasure or avoiding pain.  (I review this story in Chapters 2 and 8 of Neuroscience for Psychologists and Other Mental Health Professionals.)  There are ways to take back the brain’s motivational system that don’t involve more chemicals.  But, it’s tricky and knowing when someone is vulnerable to relapse is important.    This story raises the question of whether anyone has free will and ways in which free will might operate.  It’s a very interesting story.  With clarity on what accounts for compulsion to use, a more targeted picture of when people are vulnerable to relapse emerges.

Barceloux, D. G.  (2012).  Medical Toxicology of Drug Abuse. New York:  John Wiley & Sons.

Courtwright, D. T.  (1982; 2001).  Dark Paradise: A History of Opiate Addiction in America.  Cambridge, MA: Harvard University Press.

Hart, C. L., Ksir, C., & Ray, O.  (2009).  Drugs, Society & Human Behavior.  New York:  McGraw Hill.

Musto, D. F.  (1973).  The American Disease:  Origins of Narcotic Control.  New York:  Oxford University Press.

Sacerdote, P., Franchi, S., Gerra, G., Leccese, V., Panerai, A. E., Somaini, L. (2008).  Buprenorphine and methadone maintenance treatment for heroin addicts preserves immune function.  Brain, Behavior, & Immunity, 22(4), 606-613.