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,

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

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

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.


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,

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/

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.

Thoughts on the Nature of Emotions

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

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).

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