Präsentation zum Thema: "Neurobiologie Angst Josef Marksteiner"— Präsentation transkript:
1 Neurobiologie Angst Josef Marksteiner Abteilung für Psychiatrie und PsychotherapieLKH Klagenfurt
2 „Der Schmerz der Seele ist schlimmer als der Schmerz des Körpers.” Publius Syrius, 42 n. Chr.ILLUSTRATION BY MATT MAHURIN FOR NEWSWEEK
3 1. REGEL: Ich muss Angst vermeiden Ich weiß: ich werde sie bekämpfen. Ich muß sie los werden.AngstIch weiß: ich werde sie bekämpfen.It can get worse. Modern culture seems to have an unwritten rule that suffering is bad, and the absence of suffering is good, and that if something is bad, you should try to get rid of it by acting on it directly. Although it is sometimes possible to get rid of negative things in the world by acting on them directly, this does not seem to be a successful technique when applied to painful thoughts and feelings. We are so deeply programmed into trying to get rid of bad stuff that the struggle against negative psychological content can seem automatic. We live by the rule, ‘I must avoid my painful feelings.’ Do you think you have been successful in your life in getting rid of unwanted thoughts and emotions?
4 Angst „alte Angsterfahrung“ + Es funktioniert nicht: es wird schlimmer. Es ist schrecklich. Ich muß noch stärker dagegen ankämpfen.Es wird schlimmer. Es ist eine Katastrophe. Was, wenn es noch schlimmer wird? Reiß dich zusammen – kämpfe – ich werde vernichtet.AngstThis is what happens if experience brings you anxious thoughts and feelings, and you struggle to get rid of them. You end up with the original anxiety, plus new anxiety caused by the failed attempt to get rid of it.„alte Angsterfahrung“+„neue Angsterfahrung“: Ich bin wieder gescheitert.
5 Diskussionspunkte - Angsterkrankungen HäufigkeitNeuroanatomie – welche Hirnregionen sind betroffen?Neurotransmitter – welche sind am wichtigsten?Neue Therapieverfahren – welche Ansätze gibt es?
6 Anspannung und Leistungs-Niveau Yerkes, R.M. & Dodson, J.D. (1908). The Relationship of Strength of Stimulus to Rapidity of Habit Formation. Journal of Comparative Neurology and Psychology., 18,
7 Prävalenz von Angsterkrankungen 2724211815Lebenszeit Prävalenz12963IrgendeineAngstErkrankungSozialPhobiePTSDGeneralisierteAngstErkrankungPanikStörungKessler et al. Arch Gen Psychiatry. 1995;52:1048.Kessler et al. Arch Gen Psychiatry. 1994;51:8.
8 Prevalence of GAD compared with other psychiatric disorders DysthymiaBipolar disorderMDDOCDPTSDSocial phobiaSpecific phobiaAgoraphobia*Panic disorderIn the NCS replication survey (n=9282), conducted by face-to-face interviews between 2001 and 2003, the lifetime prevalence of GAD was estimated to be 5.7%. This compares with estimated lifetime prevalence rates of 28.8%, 20.8% and 14.6% for any anxiety disorder (including panic disorder, social phobia, GAD, post-traumatic stress disorder [PTSD] and obsessive-compulsive disorder [OCD]), mood disorder (major depressive disorder [MDD], dysthymia, bipolar I and II) or substance abuse/dependence, respectively .Reference1. Kessler RC et al. Arch Gen Psychiatry 2005; 62:Substance abuseLifetime prevalence (%)*Without panic n=9282Kessler et al 2005
9 Der „erweiterte“ Angstkreis AuslöserIntroversion„Grübeln“Sozialer RückzugVermeidungs-verhaltenAngstErwartungsangst
10 Amygdala (Mandelkern) Evolutionsgeschichtlich sehr altTeil des limbischen SystemsErkennen und Ausdruck von Emotionen, besonders FurchtSehr enge Verschaltungen mit Hippocampus und Thalamus und HPA-Achse
13 Keine Bedrohung Keine Gefahr Gewöhnlicher Stimulus SO, LET’S TRANSLATE THIS TO THE WORLD OF THE RAPE VICTIM.HERE’S A STIMULUS THAT ORDINARILY WOULD NOT TRIGGER A FEAR RESPONSE.THE BRAIN PROCESSES THE STIMULUS ALMOST EXCLUSIVELY THROUGH THE CORTEX, AND NO FEAR RESPONSE IS TRIGGERED.Keine GefahrGewöhnlicher Stimulus
14 Bedrohung!!BUT AFTER A RAPE, THAT ORDINARY STIMULUS IS NOW RECOGNIZED BY THIS BRAIN AS A FEAR STIMULUS.WHY? BECAUSE A PAIR OF HANDS WERE USED TO HOLD HER DOWN DURING THE RAPE.SO NOW, A PAIR OF HANDS ARE NO LONGER A MUNDANE STIMULUS.WHEN THEY ARE PERCEIVED, THE INFORMATION IS FED DIRECTLY TO THE AMYGDALA, BYPASSING THE CORTEX, AND A FULL-FLEDGED FIGHT OR FLIGHT RESPONSE IS TRIGGERED.THE CORTEX EITHER CANNOT INHIBIT THIS FROM HAPPENING, BECAUSE IT HAPPENS BEFORE THE CORTEX CAN INTERVENE.OR, THE CORTEX MAY ACTUALLY AMPLIFY THE SIGNALS, IN EFFECT, AGREEING WITH THE INITIAL INTERPRETATION OF THREAT.Gefahr!!Post-Trauma Verarbeitung eines “gewöhnlichen Stimulus”
15 Trauma verursacht anatomische und funktionelle Veränderungen im Gehirn THIS IS THE ANATOMICAL CHANGE THAT IS RESPONSIBLE FOR THIS PERSON’S REACTION TO THE PAIR OF HANDS.THE RAPE CREATED A PERMANENT NETWORK OF NEURAL CONNECTIONS IN THE AMYGDALA.THIS NETWORK DOES 2 THINGS:1) IT IS HYPERSENSITIVE TO ANY INCOMING STIMULI THAT RESEMBLE ANY OF THE STIMULI THAT WERE PRESENT DURING THE RAPE.2) WHEN ANY SIMILAR STIMULI ARE PERCEIVED, IT REACTS WITH HYPER-SPEED, IMMEDIATELY TRIGGERING A FIGHT OR FLIGHT RESPONSE.Post-Trauma und Amygdala
16 Herry, C. , S. Ciocchi, et al. (2008) Herry, C., S. Ciocchi, et al. (2008). "Switching on and off fear by distinct neuronal circuits." Nature 454(7204):Likhtik, E., D. Popa, et al. (2008). "Amygdala intercalated neurons are required for expression of fear extinction." Nature 454(7204):Jungling, K., T. Seidenbecher, et al. (2008). "Neuropeptide S-mediated control of fear expression and extinction: role of intercalated GABAergic neurons in the amygdala." Neuron 59(2):
17 Hippocampal Volume Reduction in PTSD NORMAL PTSDBremner et al., Am. J. Psychiatry 1995; 152: Bremner et al., Biol. Psychiatry 1997; 41: Gurvits et al., Biol Psychiatry 1996;40: Stein et al., Psychol Med 1997;27: DeBellis 1999-no change in children with PTSD
18 Effect Size Estimates for Hippocampal Volume in Adults with Chronic PTSD Versus Healthy Subjects Pooled meta-analysis demonstrates smaller hippocampal volume in PTSDP<0.05P<0.05Left HippocampusRight HippocampusEffect size (black square) and 95% confidence interval (red line) measured with Hedges GU
20 Effekte von GC:Stimulation der Glukoneogenese & der Glykogensynthese,Erhöhung der Konzentration von Glukose, Aminosäuren, freien Fettsäuren im Blut,Suppression d. zellvermittelten Immunität,Antiproliferative & anti-inflammatorische Wirkung,Wirkungen auf Hämatopoese, Muskel-, Wasser-, Elektrolyt- & Proteinstoffwechsel.
21 Selye explains STRESS – induced activation of HPA axis Nature, July 4, 1936.A Syndrome produced by Diverse Nocuous Agents“…. a typical response appears, the symptoms of which areindependent of the nature of the damaging agent…and represent rather a response to damage as such”H. Selye
22 Corticosteroid receptors Lower sensitivity ofCorticosteroid receptorsImpaired feed-backCRH-Hypersekretion in theHypothalamus↑ ACTH and cortisol release
23 Stress Hippocampus CA3 normal Glucocorticoide BDNF normales Wachstum und ÜberlebenStressGlucocorticoideBDNFAtrophieDuman et al., 1997; Jacobs et al., 2000
24 Angst und Neurotransmitter Verstärkte Freisetzung von Neurotransmittern und HormonenAdrenalinNACRHACTHKortisolProlaktinWachstumshormone
27 Serotonin (5-HT)5-HT ist für viele physiologische Funktionen sehr wichtigkognitive Funktionen z.B: Lernen; AufmerksamkeitEmotionen; Stimmung; AntriebGestörte Serotonin Funktion findet sich beiDepression SERT, 5-HT1APanik Attacken 5-HT1AImpulskontrollverlust 5-HT2AAlkoholkrankheit SERTSchizophrenie Zwangserkrankung, Autismus SERTAngsterkrankungen SERT
28 SSRIs - Angsterkrankungen 20406080100CGIresponse rate (%)n=12n=30n=187n=290Fluvoxamine 150 mg/dayPlaceboSeroxat/Paxil (20-60 mg/day)Sertraline ( mg/day)Double-blind treatments:van Vliet et al 1993; Katzelnick et al 1995; Stein et al 199832
29 Efectin ER in der Langzeittherapie der Generalisierten Angststörung 26Placebo (n=123)24Venlafaxin ER 75–225 mg (n=115)2220*18HAM-A total score (adjusted mean)16‡14‡*12‡‡*‡‡‡‡10BL1234681216202428Week*P0.007 vs Placebo‡ P<0.001 vs PlaceboGelenberg AJ et al. JAMA 2000;283:3082
32 The short (S) 5-HTTLPR variant (purple) of the 5-HTT gene (SLC6A4) produces significantly less 5-HTT mRNA and protein, as indicated by the green arrow, than the long (L) variant (red), leading to higher concentrations of serotonin in the synaptic cleft. The short variant is associated with anxiety-related personality traits such as neuroticism, which are risk factors for affective spectrum disorders. MAOA, monoamine oxidase A; SSRI, selective serotonin reuptake inhibitor.Lesch et al. 2008
33 Avshalom Caspi and Terrie E. Moffitt Influence of exposure to early stress (peer rearing) on subsequent exaggerated responses of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) responses to stress is conditioned by serotonin transporter gene promoter variation (rh-5HTTLPR) in rhesus macaques. When exposed to stress later in life, peer-reared animals with the short/long genotype had higher ACTH levels than animals with the long/long genotype. There were no differences between genotypes among animals reared with their mothers (data from Ref. 105).Avshalom Caspi and Terrie E. MoffittNature Reviews Neuroscience 7,
35 Knock-out von 5HT1A Wild-type control 5HT1A receptor knockout Noradrenergic, GABAergic glutamatergic, and peptidergic neurocircuits5HT1A5HTT5HT1B5HTT5HT5HTAnxiety-related and antidepressant-like behavior5HT1A5HT2C
36 The GABA receptorThis is a image of the GABA receptor, showing it’s receptor sites for GABA, along with alcohol, barbiturates and the compounds I intend to study: benzodiazepines.
38 GABAA receptor composition and location of GABA/benzodiazepine-binding sites Biochemical Society Transactions Biochem. Soc. Trans. (2006) 34,
39 Fig. 1. Immunohistochemical distribution of diazepam-sensitive GABA(a) receptor subtypes. Diazepamsensitive receptor subtypes (α1-, α2-, α3- and α5-containing receptors) are attributed to largely distinct neuronal circuits, as demonstrated by the localization of the corresponding α-subunit variants in parasagittal sections of mouse brain. False color coding indicates different levels of α-subunit expression: white (high expression) > yellow > red > purple (low expression) > blue (no expression). The α1-containing GABA(a) receptors are most prevalent, particularly in the cerebral and cerebellar cortex*. The α2-containing receptors are largely expressed in the hippocampus, amygdala (not visible) and striatum, whereas the monoaminergic and serotonergic neurons of the brain stem*, basal forebrain cholinergic neurons and the reticular nucleus of the thalamus express exclusively the a3-containing receptors*. The α5-containing receptors are largely restricted to the hippocampus. All four receptor subtypes are expressed in the olfactory bulb*). *) Fritschy, J.M. and Möhler, H. GABA(a)-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194 (1995)Fritschy, J.M. and Möhler, H. J. Comp. Neurol. 359, 154–194 (1995) GABA(a)-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits.
41 Freisetzung und Wiederaufnahme von GABA Normal release and reuptake of GABAAfter GABA is released into the synapse, its synaptic action is normally terminated by diffusion and reuptake into nerve terminals and astrocytic processes.1Reference1. Meldrum BS, Chapman AG. Basic mechanisms of Gabitril (tiagabine) and future potential developments. Epilepsia. 1999;35(Suppl 9):S2-S6.
42 GABA Wiederaufnahme Hemmer GABA TransporterActivity of tiagabine at the GAT-1 transporterTiagabine acts by selectively blocking the reuptake of GABA at the GAT-1 GABA transporter. As a result, available GABA is increased without increasing the total amount of GABA in the central nervous system. By blocking the reuptake of extracellular GABA via the GAT-1 transporter, tiagabine enhances its normal inhibitory function. With an SGRI, therefore, GABA remains under normal physiologic control. Several commentators have speculated that this mode of action may reduce the potential for adverse effects, since enhancement of GABA-mediated function is limited by the total amount of GABA released.1,21. Schmidt D, Gram L, Brodie M, et al. Tiagabine in the treatment of epilepsy –– a clinical review with a guide for the prescribing physician. Epilepsy Res. 2000;41: Schmitt U, Hiemke C. Effects of GABA-transporter (GAT) inhibitors on rat behavior in open-field and elevated plus-maze. Behavioral Pharmacol. 1999;10:
44 Pregabalin bindet mit hoher Affinität an die alpha-2-delta Untereinheit, einem Protein. Neben Pregabalin binden nur Substanzen mit ähnlicher Struktur (z.B. Gababentin) an diese Bindungsstelle. Kein anderes verfügbares Antiepileptikum bindet an diese alpha-2-delta Untereinheit. Die Bindung von Pregabalin an die alpha-2-delta Untereinheit reduziert den Einstrom von Kalziumionen aus dem synaptischen Spalt in die präsynaptische Nervenendigung, was eine verminderte Freisetzung der Neurotransmitter Noradrenalin, Glutamat und Substanz P zur Folge hat. Hieraus resultiert eine verringerte Stimulation postsynaptischer Rezeptoren durch diese Neurotransmitter. Man geht davon aus, dass diese verminderte Erregung postsynaptischer Rezeptoren die analgetischen, anxiolytischen und antiepileptischen Eigenschaften von Pregabalin vermittelt. Gee NS et al. J Biol Chem 1996;271(10): ; Fink K et al. Neuropharmacology. 2002; 42(2): ; Dooley DJ et al. Neurosci Lett. 2000: 280: ; Dooley DJ et al. J Pharmacol Exp Ther. 2000; 295: ; Maneuf YP et al. Pain. 2001; 93: ; Bialer M et al. Epilepsy Res. 1999; 34: 141; Welty D et al. Epilepsia. 1997;38 (Suppl 8):35. Abstract
46 Local injection of CB1 agonists of the mPFC reduced fear-potentiated Role for prefrontal cortex CB1 receptors in the extinction of fear memory.Role in Synaptic PlasticityCannabinoids are increasingly being regarded as important receptors in synaptic plasticity. Because of CB1’s inhibitory response and localization on the presynaptic end of synapses, it is believed that cannabinoids function as local retrograde modulators. Essentially, they are believed to help maintain homeostasis in the brain and keep neurons from over-exciting themselves. Neurons that over exert themselves can suffer from excitotoxicity which is fatal. In one study, mice were altered to lack the expression of CB1 and then stimulated with kainic acid, a excitotoxin. These mice suffered seizures. In vitro, neurons lacking CB1 showed a lowered threshold for kainic acid induced excitability. In wildtype mice, kainic acid administration raised anandamide (cannabinoid agonist) concentrations and triggered various neuronal protective mechanisms. These protective mechanisms were not triggered in mice lacking CB1, showing that CB1 is clearly used to help protect neurons from over-exciting themselves.One of the interesting aspects of the endocannabinoid system is that it is mainly a retrograde system. Cannabinoid receptors are located presynaptically. Activation of classic post synaptic receptors releases cannabinoid compounds that move backwards across the synaptic cleft. Once bound to the receptor, the the presynaptic cell is inhibited or even prevented from releasing more post-synaptic bound transmitters. This type of plasticity has been shown to be both long term and short term, as well as occurring at both inhibitory and excitory synapse junctions.CB receptors play an obvious role in fear and anxiety. CB-knockout mice have provided some excellent data on CB’s role in anxiety. CB-KO mice demonstrate increased anxiety at all times, especially in high stress environments. Knockout mice also appear to receive decreased benefits from anti-anxiety medication such as bromazepam and buspirone, indication that CB receptors play a crucial role in the action of anxiolytic medication. Mice administered with CB1 antagonists showed similar anxiety results. Administration of CB1 agonists, however, completely reversed anxiety-induced behavior. Interestingly, the anxiolytic benefits of the CB1 agonist were only seen in mice habituated to the test environment. Mice performing the test for the first time (running a maze) showed normal signs of stress. It was only after they had become familiar with the environment did the anti-anxiety effects of the CB1 agonist kick in. Clearly, CB receptors play a crucial role in the regulation of mood and anxiety in mammals.Local injection of CB1 agonists of the mPFC reduced fear-potentiatedstartle
47 annabinoids are the psychoactive compound of marijuana annabinoids are the psychoactive compound of marijuana. They have been used as medicines for thousands of years to treat diseases. The cannabinoid receptors has recently emerged as an important player in the regulation of emotionality, including fear extinction learning. Cannabinoid receptor type1 (CB1 receptor)-deficient mice were strongly impaired in extinction of cue-conditioned fear. Importantly, the initial acquisition of fear during CS-US pairings as well as the subsequent consolidation process was unchanged in CB1 receptor-deficient mice compared with wild-type littermate control subjects. This phenotype was mimicked by systemic injections of the specific CB1 receptor antagonist, SR141716, either before conditioning or before the extinction trial. As with the knock-out mice, only extinction was impaired in this pharmacological experiment, whereas the acquisition and consolidation of fear memory were unaffected. This result strongly indicates that the endocannabinoid system is activated during the extinction trial and is required specifically during that period of time. Indeed, elevated endocannabinoid levels were measured during the extinction trial in the BLA. This observation, together with the presence of CB1 receptor mRNA and protein in BLA, strongly suggests that the amygdala plays a crucial role in the process of CB1 receptor-mediated fear extinction. We showed that infusion of CB1 receptor antagonist into the mPFC retarded CS-alone trials (extinction training)-induced reduction of fear-potentiated startle. Conversely, CB1 agonists mimicked extinction training causing a reduction of startle potentiation in a dose-dependent manner. The effect of CB1 agonists was mimicked by the endocannabinoid uptake inhibitor or fatty acid amidehydrolase inhibitor, and could be blocked by a specific CB1 receptor antagonist. CB1 agonist activated extracellular signal-regulated kinases (ERKs), reduced inhibitory postsynaptic potentials (IPSPs) and facilitated excitatory synaptic transmission in the mPFC slices. CB1 agonist-treated animals similar to those receiving extinction training exhibited shock-induced reinstatement and spontaneous recovery of fear. Furthermore, treatment with CB1 agonist did not alter baseline startle or shock reactivity. Taken together, these results suggest that extinction training may release endocannabinoids in the mPFC. Activation of CB1 receptors in the mPFC decreases GABAergic inhibition and activates ERKs, resulting in the inhibition of amygdala-mediated expression of conditioned fear. Understanding the mechanism of how fear memory can be extinguished provides potential therapeutic strategy for the treatment of post-traumatic stress disorders. In rodents, some of this evidence comes from the infusion of drugs directly into the amygdala. In vivo electrophysiology has identified cellular correlates of extinction learning and memory in the amygdala. In addition, some studies have directly identified changes in molecular constituents of the basolateral amygdala. Together these experiments strongly indicate that the basolateral amygdala plays a crucial role in extinction learning. Finally, we also suggest that CB1 receptor in the mPFC is critically involved in the extinction of fear.
48 Image courtesy of University of Michigan Health System) Right now, about half of all people who take medicine for an anxiety disorder don't get much help from it. And doctors have no definitive way to predict who will, and who won't, benefit from each anti-anxiety prescription they write.See also: Health & MedicinePsychology ResearchControlled SubstancesBrain TumorMind & BrainAnxietyDisorders and SyndromesPsychiatryReferenceSeparation anxiety disorderGeneral anxiety disorderPanic attackPMSBut a University of Michigan Medical School researcher and his team are working to bring more certainty to how doctors and patients choose anxiety treatments, by probing the connection between brain activity, genetics and medication.K. Luan Phan, M.D., and his former University of Chicago colleagues recently reported intriguing findings from a brain imaging study in occasional, non-dependent, marijuana users in the Journal of Neuroscience.In a placebo-controlled design, they made the findings after giving the volunteers delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana, and exposing them to photographs of emotional faces, which served as signals of social communication. The study results, which showed that THC reduces the response to threat in a brain region called the amygdala, allowed the researchers to zero in on an area of the brain that might serve as a good target for new anti-anxiety drugs.Now, with a new clinical trial that is currently seeking participants, Phan is searching for more clues as to how anxiety treatment could be tailored to the individual patient, to give the best chance that a treatment will work for him or her.The new study will test a generic form of the drug Zoloft (sertraline), a selective serotonin reuptake inhibitor (SSRI) approved by the U.S. Food and Drug Administration for social anxiety disorder and other anxiety disorders. Both people with social anxiety disorder and a comparison group of people without anxiety are needed for brain scanning and genetic testing.The idea is to see whether variations in the genes for certain brain receptors and transporters are linked with variations in how a person's brain reacts to pictures of emotional faces, and variations in how they respond to the anti-anxiety drug. This information could lead to an individualized or personalized approach to medical care."These two studies are trying to get to the same goal: to find better treatments for anxiety disorders that affect millions of Americans and seriously interfere with their functioning," says Phan, an assistant professor of psychiatry at U-M and the VA Ann Arbor Healthcare System. "The cannabis study highlights a new avenue that we need to explore further as we try to develop novel medications, while the sertraline study will try to find out if we can tell which patients might or might not respond well, and by what mechanism, to an already existing medication known to have some efficacy in treating anxiety disorders."Phan led the cannabis study at the University of Chicago, collaborating with Harriet deWit, Ph.D., the director of the Human Behavioral Pharmacology Laboratory in the Department of Psychiatry there. Their results are based on brain scans of 16 recreational marijuana users who agreed to undergo functional magnetic resonance imaging, or fMRI.The researchers chose fMRI because it allows them to see in real time which areas of the brain are most active while a volunteer is performing a certain task -- for example, viewing a picture of a human face that is expressing anger or fear, or performing a decision-making exercise.This composite image from the 16 study volunteers' brains shows that the amygdala was the site of the largest difference in brain response to emotional images after volunteers received either THC or placebo. (Credit:Image courtesy of University of Michigan Health System)
49 Oxcytocin Oxcytocin Placebo Functional magnetic resonance imaging data (red) superimposed on structural MRI scans. Frightful faces triggered a dramatic reduction in amygdala activity in subjects who had sniffed oxytocin, suggesting that oxytocin mediates social fear and trust via the amygdala and related circuitry. Source: NIMH Genes, Cognition and Psychosis Program.Placebo
51 Kognitive Verhaltenstherpie - mehrere Komponenten Informationsvermittlung/PsychoedukationKonfrontation mit angstauslösenden SitutationenTherapeutisches Gespräch über angstbezogene GedankenTherapeutische Hausaufgaben
52 Odds ratios and statistical tests of the acute treatment response to CBT versus placebo for the identified studies
53 COGNITIVE-BEHAVIORAL THERAPY FOR ADULT ANXIETY DISORDERS: A META-ANALYSIS OF RANDOMIZED PLACEBO-CONTROLLED TRIALSStefan G. Hofmann, Ph.D.1 and Jasper A. J. Smits, Ph.D.2Average effect size estimates (Hedges’ g) and corresponding 95% confidence intervals of the acute treatment efficacy of CBT as compared to placebo on the various anxiety disorders for the primary continuous anxiety measures (red bars) and depression measures (green bars)