Affective Disorders: Qatar Clinical Neuroscience Conference

Journal Articles

Affective disorders: a neurodevelopmental problem?

Anastasia A, Deinhardt K, Chao MV, et al. Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun. 2013;4:2490.

Benedetti F, Mayberg HS, Wager TD, et al. Neurobiological mechanisms of the placebo effect. J Neurosci. 2005;25(45):10390-402.

Fox AS, Oler JA, Shelton SE, et al. Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proc Natl Acad Sci U S A. 2012;09(44):18108-13.

Fox AS, Shelton SE, Oakes TR, et al. Trait-like brain activity during adolescence predicts anxious temperament in primates. PloS One. 2008;3(7):e2570.

Oler JA, Fox AS, Shelton SE, et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature. 2010;466(7308):864-8.

Pattwell SS, Duhoux S, Hartley CA, et al. Altered fear learning across development in both mouse and human. Proc Natl Acad Sci U S A. 2012;109(40):16318-23.

Peciña M, Azhar H, Love TM, et al. Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology. 2013;38(4):639-46.

Soliman F, Glatt CE, Bath KG, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327(5967):863-6.

Tottenham N, Hare TA, Millner A, et al. Elevated amygdala response to faces following early deprivation. Dev Sci. 2011;14(2):190-204.

Translational medicine: new insights in the biology of mood disorder

Binder EB, Bradley RG, Liu W, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA. 2008;299(11):1291-305.

Craddock N, Sklar P. Genetics of bipolar disorder. Lancet. 2013;381(9878):1654-62.

Fani N, Gutman D, Tone EB, et al. FKBP5 and attention bias for threat: associations with hippocampal function and shape. JAMA Psychiatry. 2013;70(4):392-400.

Felger JC, Mun J, Kimmel HL, et al. Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates. Neuropsychopharmacology. 2013;38(11):2179-87.

Glassman AH, O'Connor CM, Califf RM, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288(6):701-9.

Grozeva D, Kirov G, Ivanov D, et al. Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry. 2010;67(4):318-27.

Klengel T, Mehta D, Anacker C, et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci. 2013;16(1):33-41.

Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-42.

Murrough JW, Perez AM, Pillemer S, et al. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013;74(4):250-6.

Purcell SM, Wray NR, Stone JL, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460(7256):748-52.

Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41.

Clinical approaches to affective disorders

Blasey CM, Block TS, Belanoff JK, Roe RL. Efficacy and safety of mifepristone for the treatment of psychotic depression. J Clin Psychopharmacol. 2011;31(4):436-40.

Hajcak G, Anderson BS, Arana A, et al. Dorsolateral prefrontal cortex stimulation modulates electrocortical measures of visual attention: evidence from direct bilateral epidural cortical stimulation in treatment-resistant mood disorder. Neuroscience. 2010;170(1):281-8.

Nahas Z, Short B, Burns C, et al. A feasibility study of a new method for electrically producing seizures in man: focal electrically administered seizure therapy [FEAST]. Brain Stimul. 2013;6(3):403-8.

Nahas Z. The frontiers in brain imaging and neuromodulation: a new challenge. Front Psychiatry. 2010;1:25.

Wollmer MA, de Boer C, Kalak N. Facing depression with botulinum toxin: a randomized controlled trial. J Psychiatr Res. 2012;46(5):574-81.

Websites

American Academy of Neurology

American Association for Geriatric Psychiatry

American Board of Psychiatry and Neurology

American Psychiatric Association

American Foundation for Suicide Prevention

Asian Federation of Psychiatric Associations

Brain & Behavior Research Foundation

Department of Defense. Congressionally Directed Medical Research Programs: Psychological Health and Traumatic Brain Injury (PH/TBI) Research Program.

Depression and Bipolar Support Alliance

National Institute of Mental Health. Mental Health Information.

Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS): A Partnership Between NIMH and the U.S. Army

World Psychiatric Association

Sponsors

Presented by

Affective disorders are highly variable and heterogeneous but tend to be labeled broadly, and current treatments follow a one-size-fits-all model. Precision medicine holds great promise for improving the diagnosis and treatment of these disorders, but many scientific and practical challenges remain.

It is inherently difficult to study affective disorders because mood and affect are hard to define, quantify, and model, as Huda Akil of the University of Michigan pointed out in her opening keynote address. Compounding the challenge, disorders like depression and anxiety have a wide range of causes and manifestations. Neurobiological research on psychiatric disorders has generally focused on neural signaling, but scientists are now considering the roles of other factors, including immune responses, growth factors, and hormones.

Some of our ideas about mood disorders may have led us astray. Depression is not one disease but many: "We're dealing with depressions and bipolar illnesses," John F. Greden explained. Our current conceptual frameworks do not reflect the evolving and dynamic nature of these disorders, which have lifelong courses of remission and relapse and typically become more severe over time. Our models capture only some of the brain changes involved in depression and do not reflect the 30% of cases that are treatment-resistant. We do not yet have good biomarkers that could reveal the pathophysiology of the disorders and predict treatment responses.

Research in clinical neuroscience is, however, generating new ideas about how affective disorders emerge and change over time. Several lines of evidence suggest that anxiety and depression involve dysfunctions in neurodevelopment. Research on the role neuroplasticity plays in affective disorders provides a new perspective that can generate leads in the search for causes and treatments. The link between affective disorders and other biological changes is also increasingly evident. Charles B. Nemeroff presented compelling evidence that depression is a risk factor for cardiovascular disease, and Andrew Miller outlined the role of inflammation in depression.

Molecular genetics is providing a more sophisticated understanding of vulnerability to mood disorders. Many gene variants increase the risk for all psychiatric illnesses, undermining the traditional view that psychotic disorders are biologically distinct from mood disorders, as Nicholas Craddock observed. Several of these variants modify the function of ion channels, consistent with other research pointing to dysregulated neuronal excitability in psychiatric disorders. At the same time, as Dan V. Iosifescu described, the surprising success of ketamine in treatment-resistant depression has attracted new attention to the glutamate signaling system.

In practice, drug therapy for depression has not changed much in the past few decades. Several promising candidates have recently failed in clinical trials, but treatment options may soon change. Alan Schatzberg described ongoing trials of compounds with novel mechanisms of action, such as the melatonin receptor agonist agomelatine and the glucocorticoid receptor antagonist mifepristone. Ziad H. Nahas previewed techniques for brain stimulation that are more precise and specific than older techniques and could provide the same benefits with fewer side effects. The complexity of affective disorders may be daunting, but research revealing their diversity and pervasiveness also offers the promise of a new era of precision medicine, prevention, and treatment.

Speakers:
Francis Lee, Weill Cornell Medical College
BJ Casey, Weill Cornell Medical College
Ned H. Kalin, University of Wisconsin School of Medicine and Public Health
Jon-Kar Zubieta, University of Michigan

Highlights

• Anxiety may be a neurodevelopmental disorder.
• Early life stress leads to early and persistent alterations in amygdala function in humans and mice.
• Fear extinction is impaired during adolescence in humans and mice.
• Strong placebo response is tied to increased release of dopamine and opioids in basal ganglia.

A mouse model for anxiety: a new view of BDNF

Parallel studies in humans and animal models can shed light on the biology of affective disorders in humans. A mouse model for mood disorders developed by Francis Lee of Weill Cornell Medical College is inspiring a new understanding of the role of neurodevelopment in the risk for affective disorders.

Using gene knock-in technology, researchers can introduce genes that may be involved in multiple mood disorders into mice models and explore the circuitry and behavioral phenotype of that gene or gene variant. Brain-derived neurotrophic factor (BDNF) is a neural growth factor and so-called master molecule that may influence many affective disorders. Knocking out BDNF in mice leads to anxiety and depression-like phenotypes and impairs fear-learning extinction, the ability to learn that a cue that previously signaled an adverse outcome no longer does. The BDNF polymorphism val66met, present only in humans, is found in about 25% of the U.S. population. Knocking the SNP into mice increases anxiety-related behaviors and impairs fear extinction. BJ Casey, also at Weill Cornell, has found that humans with the Met allele also have impaired fear extinction. One important implication is that cognitive behavioral therapy (CBT), which involves unlearning fearful associations and is the only evidence-based technique to treat anxiety, may be an inefficient therapy for such people.

Surprisingly, fear extinction is normal in heterozygous BDNF knockout mice, which have 50% less BDNF. They are capable of learning new associations to previously frightening stimuli at a normal rate. Efforts to understand why heterozygote knockouts differ from mice with one Met allele led Lee's group to a discovery: while the mature BDNF protein sustains and encourages neural growth, the BNDF Met prodomain causes neurons to stop growing and shrink in vitro. The SNP had been thought to result in a loss of function (to impair the function of BDNF), but Lee's finding suggests it instead causes a gain in function by downregulating neuronal growth. The SNP may alter the development of circuits that link the prefrontal cortex (PFC) and hippocampus, in turn altering how fear memories are modified: "humans who have this [SNP] have the Met prodomain running around in the brain, potentially suppressing the circuitry during a specific point in development," Lee said.

The implication is that simply increasing BDNF in the brains of people with this polymorphism might be deleterious, if the Met prodomain is also upregulated. "You'll have to come up with a much more elegant strategy of increasing one and decreasing the other," Lee said.

Adolescence and anxiety

Related work by BJ Casey at Weill Cornell Medical College suggests that adolescence is a critical period for the onset of anxiety. During this stage, brain development is uneven: subcortical limbic regions that subserve affect develop quickly, but projections from the prefrontal regions involved in emotional regulation mature more slowly. In anxious people, this prefrontal–limbic circuitry functions differently in response to images of faces with fearful expressions.

After repeated presentations of faces with fearful expressions, the amygdala stops responding in people who rate themselves as low-anxiety (blue regions), but continues to respond (yellow) in people who rate themselves as high-anxiety. (Image courtesy of BJ Casey)

Early life experience shapes the risk for anxiety. Behavioral and neuroimaging studies of children who spent their first months or years in an orphanage revealed heightened amygdala response to fearful faces, correlated with less-frequent eye contact with an adoptive parent. In a parallel study in mice, pups reared by stressed and inattentive mothers had heightened amygdala response and were rated high in a measure of anxiety that tested willingness to search for a sweet food reward in an exposed, brightly lit cage.

In both mice and humans, fear extinction is impaired during adolescence in comparison to preadolescence and adulthood. CBT is also less effective at this age. "There may be a developmental window in which cognitive behavioral therapy shows a diminished effect for treatment," Casey said. Better treatment for anxiety in adolescence might involve techniques that do not place demands on the underdeveloped PFC. One promising option is reconsolidation, which might be used to modify memories while they are reactivated. Considering nuances such as age, genetics, and environment in tailoring treatment is another step toward precision medicine.

Anxious temperament in rhesus macaques and humans

The behavior and neural circuitry of non-human primates makes these animals good models for human affective disorders. Ned H. Kalin of the University of Wisconsin School of Medicine and Public Health is working on parallel studies in humans and a rhesus macaque colony on Cayo Santiago to explore the developmental origins of inhibited or anxious temperament—an extreme behavioral inhibition to novel situations or individuals at a young age. In humans, this temperament increases the later risk of social anxiety disorders by 7-fold.

Intruder tests measure the responses of children and young monkeys when confronted by a stranger, testing behavioral inhibition in humans and its analog, freezing, in young animals. Using this technique, Kalin's group has determined that anxious temperament (AT) is 30%–40% heritable in both monkeys and humans.

PET scans of hundreds of young monkeys indicate individual differences in anxiety are reflected in differences in the metabolism of the central nucleus of the amygdala and anterior hippocampus—but only differences in the hippocampus show a heritable pattern. In AT animals, many distinctive changes in gene expression are related to neuroplasticity. Higher levels of AT were associated with reduced expression of neuroplasticity genes. Using viral vectors to influence gene expression in specific brain regions, Kalin found that introducing the CRH gene increased anxious behavior (CRH, corticotropin-releasing hormone, is secreted by the hypothalamus in response to stress).

Other regions, including the orbital frontal cortex and the periaqueductal gray, are also affected in AT. "We're not just talking about one brain region, but a whole network that seems to be overactive in individuals with this disposition," Kalin said. Functional connectivity analysis with resting fMRI and metabolic analysis in PET point to reduced coupling between the dorsolateral PFC and the amygdala in both anxious animals and human children. This pattern, similar to that seen in Casey's research, suggests the PFC regulates anxiety, with metabolism in dorsal regions of the central nucleus of the amygdala as an intermediary.

Anxious temperament involves a whole network, Kalin found in neuroimaging almost 600 young rhesus macaques. Changes are found in amygdala, anterior hippocampus, orbital frontal cortex (red regions at far left and right), periaqueductal gray, and anterior hippocampus. (Image courtesy of Ned H. Kalin)

Placebo and depression

The placebo effect is not just a vexing confounder in clinical trials; it is a potentially useful signal. Jon-Kar Zubieta of the University of Michigan explained: "This noise in the signal of antidepressants has a biological meaning that has the potential to point to new targets for medication discovery or treatments." Placebo responses in drug trials for affective disorders might result from spontaneous recovery or be caused by the Hawthorne effect, in which symptoms improve when patients are closely observed. But a placebo effect is not merely a subjective impression, Zubieta cautioned: naloxone, which blocks opioid analgesia, also blocks placebo in pain studies.

In a PET study of volunteers subjected to pain and given a placebo, endogenous opioid release increased 12%–34%, with marked individual variation. Opioid release correlated with pain relief and with changes in brain regions such as the subgenual cingulate that are involved in the affective experience of pain. Analgesia also correlated with increased dopamine release in the basal ganglia, and variations in dopamine release accounted for about one-fourth of the variation in placebo response. Similarly, a neuroimaging exploration of participants who reported a "nocebo" effect (the converse phenomenon, when an inactive substance causes side effects or illness) showed a similar but opposite brain circuitry response, with reduced endogenous opioids and dopamine in the basal ganglia.

But placebo is not merely a dopamine effect. Agreeableness, neuroticism, and a variable called "ego resiliency" explain 28% of the variance in placebo analgesia and are associated with opioid system activation and cortisol suppression. Placebo response also interacts with polymorphisms in genes for mu-opioid receptors, for BDNF, and for the FAAH enzyme, which is involved in metabolizing endocannabinoids.

Given the overlap in pain circuitry and emotional circuitry, pain placebo mechanisms may generalize to depression. A 2-week randomized placebo study in depression revealed inter-individual variability in mood responses, but the greatest improvements in mood were associated with a high release of endogenous opioids in regions involved in mood regulation such as the nucleus accumbens, amygdala, and medial thalamus. In a 10-week open study of placebo and antidepressant, placebo responders showed higher opioid release in those regions, greater mood improvement, and higher remission compared to nonresponders. Those who responded strongly to placebo also responded to the antidepressant, suggesting a common mechanism.

Speakers:
Charles B. Nemeroff, Leonard M. Miller School of Medicine, University of Miami
Kerry Ressler, Emory University; Howard Hughes Medical Institute
Nicholas Craddock, Cardiff University, UK
Dan V. Iosifescu, Icahn School of Medicine at Mount Sinai
Andrew H. Miller, Emory University School of Medicine

Highlights

• Depression increases heart disease risk as strongly as does cigarette smoking.
• Antidepressants may improve outcomes in heart disease.
• In victims of early childhood abuse, FKBP5 genotype (involved in cortisol receptor regulation) predicts risk of post-traumatic stress disorder in adulthood.
• The diagnostic distinction between psychotic and mood disorders may not be valid.
• Ketamine has rapid effects and an up to 70% response rate in treatment-resistant depression.

Depression and the heart

Depression is now considered an official risk factor for heart disease and for a poor prognosis in several cardiac diseases. Charles B. Nemeroff of the University of Miami explained the history of this classification. In the 1990s, epidemiological studies documented links between depressed affect and ischemic heart disease, as well as a 4-fold increase in mortality in depressed patients following myocardial infarction. Further observational studies established that cardiac mortality worsens as depression becomes more severe. The cardiac risk of depression is equal to better-known risk factors such as cigarette smoking and elevated blood lipids.

Depressed patients (top line) have an almost 4-fold increase in mortality during the 6 months following a heart attack compared to non-depressed patients (bottom line). (Image courtesy of Charles B. Nemeroff)

Given this strong relationship, Nemeroff argued, it makes sense both to intervene to treat depression before the onset of cardiac diseases and to treat aggressively. "It highlights the importance of treating patients to remission," he said. Some argue that this phenomenon is primarily artifact, since depressed patients exercise less, have poorer nutrition, and are less likely to adhere to medications or stop smoking. But some biological changes in depressed people point to intermediary factors such as changes in platelet function, which can lead to thrombosis or clotting. Depressed patients have abnormal platelet function, exaggerated platelet reactivity, and accelerated conversion of prothrombin to thrombin, the first step in platelet aggregation. Treatment with selective serotonin reuptake inhibitors (SSRI) partly normalizes platelet function. Two other heart disease risk factors, inflammation and heart rate variability (changes in heart rate in response to increased demand), are also abnormal in depressed patients.

A study of the SSRI sertraline for major depression in patients with acute myocardial infarction or unstable angina found statistically non-significant reductions in death and a slight reduction in myocardial infarction. Nemeroff proposed a Framingham-like study to test the efficacy of treating cardiac patients with very low doses of SSRIs, which he predicts would have a more powerful effect than low-dose aspirin on platelet function.

The biology of PTSD: genes, epigenetics, and early life experience

Post-traumatic stress disorder (PTSD), marked by hypervigilance, flashbacks, and difficulty inhibiting fear, is difficult to predict. Genetic and epigenetic factors influence risk, explained Kerry Ressler of Emory University and the Howard Hughes Medical Institute, as does the interaction between early life experience and genetics.

The fear circuitry that is dysfunctional in PTSD is conserved in mammals and therefore particularly suitable for studies in animal models. The amygdala is the essential node in the circuit, modulated by activity in the hippocampus, prefrontal cortex, insula, and cingulate cortex. This circuitry underlies hard-wired fear responses and fear conditioning—learned associations between aversive and neutral stimuli.

A consortium study of genetic variation and PTSD is now scaling up to a goal of 20 000 cases. Polymorphisms in the OPRL1 gene in the nociceptin pathway are associated with differential risk for PTSD. An agonist in this pathway blocks memory consolidation of fear conditioning, suggesting that PTSD could one day be prevented with a drug that would block the formation of a fearful memory after a traumatic incident. Neuromodulators such as D-cycloserine might also enhance plasticity to potentiate the effects of exposure therapy, which is currently ineffective in many cases.

Dysregulated feedback in the hypothalamic–pituitary–adrenal (HPA) axis is a well-replicated finding in PTSD. Ressler's group determined that variants of FKBP5, which regulates the sensitivity of the glucocorticoid receptor, interact with adverse childhood experiences to influence risk for the disorder. The risk allele genotype is also associated with unusual hippocampal connectivity.

Experiences of trauma in childhood (but not adulthood) are associated with demethylation and enhanced transcription of the risk allele of FKBP5. The finding suggests a critical period for emotional development and PTSD risk, in which the amygdala is modulated during development by cortisol so that the risk allele interacts with early life stress to change lifelong sensitivity to stressful events. Epigenetic effects may persist into subsequent generations; Ressler is exploring mechanisms of transgenerational trauma transmission with a model based on fear learning and the rodent olfactory system.

The genetics of bipolar disorder

Unlike many other affective disorders, bipolar disorder, which involves episodes of mania and depression, is highly heritable. Nicholas Craddock of Cardiff University pointed to studies in molecular genetics that suggest the longstanding distinction between bipolar disorder and schizophrenia may not be clear cut. A major population registry of 2 million Swedish families revealed significant overlap in genetic susceptibility between schizophrenia and bipolar disorder.

Schizophrenia (left) and bipolar disorder (right) have remarkable overlap. Dark red shows the nonspecific genetic contribution to develop either disorder; pink reflects genetic effects specific to the disorder. (Image courtesy of Nicholas Craddock)

In recent years, large genome-wide association studies (GWAS) identified replicable risk genes in bipolar, coding proteins such as ANK3, a scaffold that tethers proteins such as sodium channels in position across the neuronal membrane, and a variant in CACNA1C, a subunit of the voltage-gated calcium channel. Both variants influence neuronal excitability, and there is evidence that other episodic neurological disorders such as forms of epilepsy and migraine may also be due to ion channelopathies. So far, 12 genes have been strongly implicated by GWAS for bipolar disorder. However, copy number variations, which increase the risk for developmental disorders and some neuropsychiatric disorders, do not seem to play a significant role here.

Most candidate risk genes identified by GWAS, including CACNA1C, have nonspecific effects, potentiating the risk of both mood disorders and psychosis. "This has all the hallmarks of something not specific to bipolar disorder, but a general increase in susceptibility," Craddock said.

Hundreds of common variants with small effects on susceptibility have been identified. Each alone increases risk on the order of 1.3-fold, but the small risks summed together can accurately differentiate people with a psychiatric diagnosis on a group level.

The ketamine mystery

The serendipitous discovery that the anesthetic ketamine rapidly lifts depressive symptoms is inspiring an effort to identify compounds that work the same way but are more suitable as treatments. Dan V. Iosifescu of the Icahn School of Medicine at Mount Sinai discussed studies aiming to identify how the drug works. At the doses used in studies of mood disorder, ketamine induces a potent antidepressant effect within 24 hours. At higher doses, the drug can cause hallucinations, which is why it is also used recreationally.

In a study comparing ketamine to the benzodiazepine midazolam in patients who had failed more than five treatments on average, 64% responded to ketamine, with an average improvement on a depression scale of nearly 8 points, about twice the effect of most antidepressants. Those who responded had relief for 23 days on average. "This is definitely not a cure, but a very exciting method for a single intervention," Iosifescu said. Ketamine may also rapidly reduce suicidal ideation.

A large study (green bar at right) reported a response rate of 63.8% for ketamine in treatment-resistant depression, a result in line with earlier, smaller studies. (Image courtesy of Dan V. Iosifescu)

Results from several trials suggest that ketamine does not cause psychotic side effects at the lower doses used in depression. Some patients experienced dissociation that resolved within 2 hours of infusion. The drug also increased blood pressure and heart rate: 10%–15% of participants in the most recent study needed a beta blocker. While heavy recreational use of ketamine may cause cognitive deficits, single infusions do not seem to pose this risk.

Multiple lines of evidence suggest glutamatergic signaling is abnormal in depression; ketamine is known to act on NMDA receptors in this system. Ketamine may upregulate BDNF release, which is often associated with response to depression treatment. Many antidepressant candidates with targets in the glutamatergic pathway are now in early clinical trials. Iosifescu's group is exploring minocycline, an antibiotic that may also have antidepressant efficacy.

Intranasal ketamine administration is controversial. This method is an effective and convenient way to deliver the drug but may encourage abuse, a concern raised by many discussants in the conversation following Iosifescu's presentation. Ketamine is not yet understood well enough to be suitable as a treatment, Iosifescu agreed. Nonetheless, given the potential of the drug to help desperate patients, he added, "it pains me that we're not doing the follow-up studies" more quickly.

Inflammation and depression

The inflammatory activity of the innate immune system plays a role in many common diseases, from cancer to cardiovascular disease, and it is increasingly clear that inflammation also plays a role in depression. Inflammatory proteins such as cytokines are increased in roughly 20%–30% of depressed patients.

Andrew H. Miller of Emory University is studying interferon-α (IFN-α), which induces other cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and causes depressive symptoms in humans and non-human primates. PET studies show IFN-α decreases activity in PFC and increases activity in parts of the basal ganglia such as the putamen and globus pallidus. IFN-α reduces the basal ganglia response to reward and increases activity in the dorsal anterior cingulate cortex, the "neural alarm system" active in anxiety disorders. In non-human primates, 4 weeks of IFN-α administration caused extracellular dopamine in the caudate nucleus to plummet, as measured by microdialysis.

The monoclonal antibody infliximab, a TNF-α antagonist with highly specific action, improves depressed mood in patients with inflammatory disorders and cancer. A double-blind randomized study in treatment-resistant depression showed no effect overall but found a clinically significant effect in the 35% of participants with the highest levels of C-reactive protein, a measure of inflammation. Symptoms related to motivation and psychomotor retardation, which recruit the basal ganglia, particularly improved, consistent with the idea that cytokines target these regions.

Although TNF-α-inhibitor treatment was no more effective than placebo in the group overall (right panel), a subgroup of patients with high C-reactive protein, an indicator of high inflammatory activity, showed a significant response to anti-inflammatory treatment (left panel, >5 mg/L red bar). (Image courtesy of Andrew H. Miller)

Speakers:
Ziad Kronfol, Weill Cornell Medical College in Qatar
John F. Greden, University of Michigan
Alan F. Schatzberg, Stanford University
Ziad H. Nahas, American University of Beirut, Lebanon

Highlights

• Bipolar disorder in Arab populations is characterized by higher rates of psychosis and medical co-morbidity and lower rates of psychiatric co-morbidity.
• Approaching depression as a deficit in cognitive flexibility offers new perspectives and ideas for therapy.
• Location and frequency are essential parameters in treating depression with brain stimulation.

Bipolar disorder in the Arab world

The unique characteristics of bipolar disorder in the Arab world are not yet well understood. Most genomic studies in psychiatry have been conducted on European populations. Ziad Kronfol of the Weill Medical College in Qatar described an effort to study bipolar disorder among Qataris and Lebanese, which aims to establish an Arab repository for biological samples and identify genetic variants unique to this population. Genomic studies in the Arab world are advantaged by a high rate of consanguinity—some estimates hold that 25%–50% of marriages are between cousins or distant cousins. This study includes 30 consanguineous families.

Preliminary results from 166 subjects suggested a high frequency of psychotic symptoms and a much lower rate of alcohol and drug use among this sample as compared to studies on European and American populations. Medical comorbidity in bipolar patients was higher, particularly with diabetes and hypertension. Preliminary analysis of genome sequencing of 62 bipolar type 1 participants identified three significant associations and a novel loss-of-function SNP in a psychiatric target gene, AUTS2, that has not previously been identified in European and American data sets.

Treatment-resistant depression: a serious challenge

A paradigm shift will be required to tackle treatment-resistant depression, which is disabling, destructive, and common, explained John F. Greden of the University of Michigan. Although affective disorders have many causes and take different forms, current practice is to prescribe the same agents to all patients. "We frankly do not have any way to match patients with the right treatments," Greden said. The biggest real-world study of major depression, Star-D, revealed that only 37% of patients improve with a first-line intervention, and with each subsequent treatment failure remission rates decrease and relapse rates increase. Treatment-resistant depression may develop as a result of inadequate or inappropriate treatment.

Longitudinal studies in depression are essential because it is a recurrent, lifelong disorder that tends to worsen with age. Yellow blocks here represent episodes of depression, which become more frequent in adulthood, even without precipitating stressors. (Image courtesy of John F. Greden)

Biomarkers, longitudinal studies, and big data sets that include samples in the thousands will be required to improve outcomes. The National Network of Depression Centers has coordinated one registry, providing a rich source of data, but such efforts need to be larger and better coordinated.

New antidepressant agents like ketamine and scopolamine could be valuable tools to examine who responds and to probe mechanisms of treatment response. Prospects for biomarkers include cortisol measurements, BDNF dynamics, inflammatory cytokines, serotonin receptor gene variants, and structural and functional imaging. Preliminary research has identified potential markers, as several discussants in the conversation that followed mentioned, but the field as a whole has not come together to evaluate promising biomarker candidates.

New ideas in antidepressant therapy

On one hand, the future of antidepressant therapy looks bright: therapies with entirely new modes of action are being developed and tested. But on the other, the future looks tenuous: recent negative results in clinical trials for deep brain stimulation (DBS) and drug augmentation are disappointing and many pharmaceutical companies are exiting this research space. Challenges for antidepressant trials include high placebo response, inadequate understanding of therapeutic dosage, and difficulty defining "depression," a biologically inexact term.

Clinical psychopharmacologist Alan Schatzberg of Stanford University explained that the success of ketamine may be hard to build upon: although ketamine is an NMDA antagonist, some evidence suggests its antidepressant effects may be due to its influence on other neurotransmitters such as glycine or mu-opioids. Other NMDA antagonists such as memantine and lamotrigine do not have antidepressant effects. In a clinical trial, an AstraZeneca drug that acts like an NMDA antagonist without inducing depersonalization or psychosis was no more effective than placebo. However, GLYX-13, a glycine partial agonist and NMDA agonist, showed efficacy and a "reasonable" effect size in an early-stage clinical trial. Augmenting with high-dose d-cycloserine in treatment-resistant depression also showed some effect in a small randomized trial.

Ketamine is not the only surprise in antidepressant therapy; several unconventional compounds are now being evaluated for depression. Injections of botulinum toxin (Botox) in the brow improved mood in about half of subjects in a study with 74 participants. Given known links between brow furrowing and emotional regulation, it is possible that the injection serves as a signal to change emotional regulation.

The glucocorticoid receptor antagonist mifepristone (approved as an abortifacent) is now in phase III trials for psychotic major depression, which is linked to excessive activity in the HPA axis. In earlier tests, the drug reduced psychotic symptoms in 44% of participants after one week of treatment, which is somewhat better than placebo. The melatonin-1 and melatonin-2 agonist agomelatine, approved in Europe, is now in phase III studies in the U.S.

Altering the circuitry of depression

Chronic depression could be thought of as a systems problem, suggested Ziad H. Nahas of the American University of Beirut. The mind and brain are trapped in one pattern of response and resist transitioning. "For me, the opposite of depression is mental flexibility," he said. Neurostimulation technologies that improve plasticity or modify neuronal function may be effective in restoring that flexibility. Brain stimulation technologies for depression include electroconvulsive therapy (ECT), DBS, vagal nerve simulation (VNS), and transcranial magnetic stimulation (TMS), as well as newer techniques such as focal electrically-administered seizure therapy (FEAST) and bilateral epidural prefrontal cortical stimulation (EpCS).

Location, frequency, and stimulation are important features of neurostimulation technologies. Applying TMS to anterior and lateral regions of the dorsolateral PFC in unmedicated depressed patients improves outcomes; stimulation applied to the wrong areas can cause acute depression. Nahas suggested weak results in DBS studies might be due to poor targeting. In technologies like TMS, stimulation frequency influences response, as does the time course of vagus nerve stimulation. Concurrent brain activity also modifies response, suggesting that pairing psychotherapy or medication with stimulation might offer added benefits.

To illustrate scientists' evolving understanding of brain circuitry involved in depression, Nahas cited an aphorism from mathematics: "All models are false, but some are useful." Brain stimulation does not merely affect one hub or node, but an entire network or set of networks. Along with sadness and emotional pain, people suffering from depression have motivational problems and become socially isolated. Within the PFC, the more lateral portion of the middle frontal gyrus is more involved in attending to the outside environment, while the frontal pole is more engaged in attending to the internal environment, control of emotion, and motivation.

Depression makes people isolated and impairs empathy; depressed people (red) activate different brain regions than controls (blue) when asked to do a mental attribution task of analyzing what another person is feeling. (Image courtesy of Ziad H. Nahas)

New stimulation technologies

By targeting stimulation more precisely, FEAST may produce some of the antidepressant effects of ECT without side effects such as memory loss and cognitive impairment. EpCS, in which stimulating electrode leads are placed on the surface of the cortex, is a simpler and less-invasive procedure than DBS. In a small trial, EpCS led to remission in 3 of 5 severely depressed patients over a period of more than 5 years.

Stimulating technologies can also be used to better understand brain circuitry. In one patient with a long and well-documented history of depression, frontopolar PFC activation via EpCS increased activation in circuitry related to empathy, while dorsolateral activation influenced attention and emotional arousal, as measured by the late positive potential response to negative stimuli. This procedure provided the first direct demonstration of how the lateral circuit influences negative affect. EpCS technology is promising and should be tested in a randomized trial, Nahas noted.

Developing new therapies for affective disorders is essential, since these conditions are chronic and marked by frequent relapses. Better treatments will arise from a fuller understanding of the heterogeneity of these disorders, improvements in individualized therapy, and the ability to precisely tailor the treatment to the particular genetics, biology, and life history of the patient. But in the discussion that followed the session on new therapeutics, Schatzberg also emphasized the role of serendipity. The discovery that ketamine can rapidly relieve depressive symptoms is one example; the recent suggestion that a Botox injection in the corrugator muscles of the brows might improve depression is another: "We need to keep our minds open," he concluded.

Why is the val66met SNP so common in some human populations?

What factors predict the risk of developing anxiety?

What factors predict treatment response for anxiety?

How should the more than half of people who do not respond to cognitive behavioral therapy for anxiety be treated?

How does early anxious temperament predispose children to later develop social anxiety disorder and depression?

How are deficits in neural plasticity related to anxiety?

What is the biological mechanism behind the placebo effect?

Could individual variability in placebo response be useful in predicting vulnerability to depression?

Why does anxiety or depression spontaneously remit?

Can treating depression improve outcomes in cardiovascular disease?

How does childhood trauma interact with genetic risk factors and epigenetic mechanisms to account for adult risk of disorders like PTSD?

Why do many genes increase risk of both bipolar and schizophrenia?

How can we advance our classification of psychiatric disease to reflect what we know about the biology?

Given its rapid effects, could ketamine be used to treat suicidal ideation in depressed patients?

Why does ketamine work quickly in treatment-resistant depression, while most therapies require at least 6 weeks?

How do cytokines and other inflammatory molecules contribute to depression?

Can some patients with treatment-resistant depression be helped by anti-inflammatory therapies?

What are distinctive features of mood disorders in Arab populations?

What are the best potential biomarkers in treatment-resistant depression?

How can we move toward an era of personalized or precision treatment for depression?

What is the mechanism by which ketamine rapidly relieves depressive symptoms?

Can electroconvulsive therapy be made more precise, with fewer side effects?