PSYC 383 Lecture 10 PDF

PSYC 383 Psychopharmacology: Lecture 10 – Psychotherapeutics for Anxiety & Affective Disorders  What is Anxiety? “Discomfort avoidance is the common thread that binds all anxiety problems together” John Forsyth & Georg Eifert “Most of our te...

PSYC 383 Psychopharmacology: Lecture 10 – Psychotherapeutics for Anxiety & Affective Disorders  What is Anxiety? “Discomfort avoidance is the common thread that binds all anxiety problems together” John Forsyth & Georg Eifert “Most of our tensions and frustrations stem from compulsive needs to act the role of someone we are not” Hans Selye “It is no measure of health to be well adjusted to a profoundly sick society” Jiddu Krishnamurti “Pain that is not transformed will be transmitted” Brené Brown/Richard Rohr What is Anxiety? Anxiety is a future-oriented emotional state and a set of unsettling feelings of concern or worry that are expressed through: facial expressions (cranial nerves) muscle tension (somatic) sympathetic hyperactivity (in the direction of ‘fight-or-flight’) avoidance behaviours cognitive impairment: concentration, working memory, attention, negative thoughts, sleep irritability Acute stress is important for versatility, adaptability (when appropriately deployed) Chronic anxiety, like chronic pain, is maladaptive and detrimental Humans may be more prone to vicious cycles of anxiety than other animals due to shortcuts through memory (e.g., language) and metacognition (e.g. theory of mind, self-reflection) Anxiety about anxiety must almost certainly be uniquely human What is Anxiety? What is Anxiety? Anxiety Disorders Generalized Anxiety Disorder (GAD) Panic Disorders Specific Phobias Social Anxiety Disorder Obsessive-Compulsive Disorders (OCD) Trauma-related anxiety; Post-traumatic Stress Disorder (PTSD) Generalized Anxiety Disorder Chronic anxiety is spontaneously generated by many sources, and it is often difficult to determine the ultimate cause One of the more common anxiety disorders, ~5% of the general population suffer from GAD GAD tends to run in families, but twin studies do not support high genetic heritability - therefore “heritability” is likely in exposure to environmental risk factors Patients have increased amygdala volume and amygdala/insula activity in response to acute stressors Significant reduction in temporal cortex GABAA receptor density Panic Attacks and Panic Disorder Instead of constant worry that is seen in GAD, panic disorder presents as maladaptive intense bursts of fear (fight-or-flight-or-freeze) Symptoms such as hyper-sympathetic activation can be triggered by either environmental cues (e.g., cues of trauma) or pseudo-randomly Panic disorder usually begins in the late 20’s includes both proneness to panic attacks and anxiety about panic itself Higher genetic heritability than other anxiety disorders Characterized by small white matter lesions in the temporal lobes, enlargement of the lateral ventricles, reduced amygdala volume  Phobia Fear of Specific Phobias Acrophobia* Heights Aichmophobia Sharp, pointed objects; knives Ailurophobia Cats Algophobia Pain Irrational fear responses to specific Astraphobia* Storms, thunder, environmental cues lightning Claustrophobia* Tight enclosures Specific cues can be either individually Hematophobia* Blood or even culturally significant Monophobia* Being alone Nyctophobia Darkness, night Effective treatments are available such Ochlophobia Crowds as behavioural desensitization: Pyrophobia Fire retraining the individual to remain relaxed during presentation of the conditioned cue Thanatophobia* Death Xenophobia* Strangers Social Anxiety Disorder Characterized by extreme fear of being evaluated/criticized by others Anxiety causes avoidance of social interactions, which leads to a vicious cycle Early onset: most develop symptoms by 11 Slightly more common in women than men Common disorder: ~12% lifetime prevalence Increased activity in response to social cues: Amygdala (social threat detection) Insula (monitoring body states) Anterior cingulate cortex (social conflict monitoring) Decreased activity in response to social cues: Prefrontal cortex (impaired regulation of fear responses and cognitive control) Ventral striatum (less positive social reinforcement) Obsessive-Compulsive Disorder Recurring, persistent, intrusive thoughts (obsessions) that cause anxiety, guilt, and shame, seen with alleviation rituals (compulsions), similar to superstitious ritual behaviours Remember Skinner’s pigeons Lifetime prevalence is about 2%-3% Often classified as motor disorder of species typical behaviours Neurological model includes abnormalities in a loop connecting the frontal lobe (OFC), basal ganglia, thalamus, and anterior cingulate (ACC) Circuit disruption alleviates some symptoms  Post-Traumatic Stress Disorder (PTSD) Development of more genetically heritable chronic anxiety in response to intense trauma, from many possible sources: war, natural disasters assault, major accident Fear and helplessness that can also trigger panic attacks Emotional numbing is typical Lower hippocampal volume is a susceptibility factor in PTSD Neurobiology of Anxiety The amygdala is a crucial structure in the processing of fear, located adjacent to the hippocampus with strong input to both dorsal and ventral parts Therefore, input influences spatial memory and fear conditioning Neurobiology of Anxiety Neurobiology of Anxiety Loss and risk aversion increase when we are anxious: Amygdala activity positively correlated with vmPFC when emotion drives loss/risk aversion Amygdala activity negatively correlated with dACC when analytic decisions override anxiety Damage to input areas to the lateral amygdala extinguish specific components of anxiety (perceptual, affective, or cognitive cues) Damage to the central nucleus itself extinguishes most aspects of anxiety Central nucleus plays roles in fear response to distinct threatening stimuli (common pathway) BNST (bed nucleus of the stria terminalis) responds to more ambiguously threatening stimuli, produces more prolonged response (to hypothalamus) Chronic stress increases dendritic length, branching, and volume of the BNST Neurobiology of Anxiety Neurobiology of Anxiety Neurobiology of Anxiety - CRF Corticotropin-releasing factor: Initiates HPA-axis functions Modulates autonomic response Widespread cognitive modulation Corticosteroid release prepares the organism for increased stress and utilization of energy stores (glucose) Negative feedback inhibits several limbic and telencephalic structures, but notably chronically high cortisol will induce a decrease in hippocampal volume Neurobiology of Anxiety - CRF Increased heart rate and hormonal adrenaline after CRF administration CRF receptors are located in several places throughout the forebrain: High density especially in the amygdala Most symptoms of anxiety are reduced by CRF antagonists CRF neurons project to the locus coeruleus, increase NE cell firing rates CRF levels are higher in PTSD sufferers Neurobiology of Anxiety - NE Locus coeruleus has reciprocal connections with the amygdala: arousal and orientation to threats LC shows increased firing to novel threat or reward (general novelty) Yohimbine (α2 antagonist) induces hypervigilance, signs of panic Clonidine (α2 agonist) has opposite effects: anxiolytic Neurobiology of Anxiety - NE Norepinephrine is also the transmitter released by the sympathetic system NE improves memory formation for emotional events β-receptor agonists in the amygdala increase likelihood of consolidation β-receptor antagonists likewise impair it Propranolol (β-blocker) can disrupt already consolidated fear cues to trauma (retrieval) Many anxiolytic drugs affect LC directly or indirectly through other transmitters  Neurobiology of Anxiety - GABA Benzodiazepines still have anxiolytic effects when the amygdala is destroyed, therefore must have some effects elsewhere as well Normal variance in amount and density of BDZ sites is related to typical variance in animal emotional responses Patients with panic disorder have fewer BDZ binding sites, especially in: mPFC, orbitofrontal cortex (OFC), insula, and limbic structures Neurobiology of Anxiety - GABA Neurosteroids are elevated during physiological stressors & are anxiolytic Higher levels are seen in those with panic disorder, may be compensatory However, lower levels of neurosteroids are seen in patients of other disorders such as GAD and social phobia Therefore, they may be a distinguishing feature between specific anxiety disorders GAD perhaps causes a type of exhaustion Risk Factors: Early Life Stress & ACEs Traumatic insults have the most impact on specific brain areas during specific developmental periods Earlier “insults” (including neglect) produce greater effects Prenatal white noise exposure in rhesus macaques produces behavioural signs that replicate symptoms of anxiety disorders hypertension reduced exploration (novelty seeking) increased HPA response greater preference for alcohol impaired learning capacity Effects are mediated by early chronic exposure to corticosteroids Risk Factors: Early Life Stress & ACEs Drugs for Treating Anxiety Anxiolytics are drugs that ‘kill’ anxiety - many are sedative-hypnotic, which are in turn part of a larger class of CNS depressants: barbiturates benzodiazepines alcohol (poor therapeutic index) These drugs relieve anxiety signs and produce calm relaxation, drowsiness, and mental cloudiness Primary action is through GABAA co- agonism, amplifying inhibition  Drugs for Treating Anxiety - Barbiturates First barbiturate employed was sodium amytal (Wada test) Many others have since been developed, but clinically they have been replaced by the benzodiazepines Small molecular differences account for lipid solubility variance Ultashort-acting: highly lipid soluble, fast sleep induction Short/intermediate-acting: sleep induced in ~30 min Long-acting: onset of an hour or more, prolonged sleep induction  Drugs forLipid Duration of action Treating Anxiety solubility Onset Duration - Barbiturates Use Ultrashort High 10–20 s 20–30 min IV anesthesia Thiopental (Pentothal) Methohexital (Brevital) Short/intermediate Moderate 20–40 min 5–8 h Surgical anesthesia and sleep induction Amobarbital (Amytal) Secobarbital (Seconal) Pentobarbital (Nembutal) Long Low Over 1 h 10–12 h Prolonged sedation and seizure control Phenobarbital (Luminal) Mephobarbital (Mebaral)  Drugs for Treating Anxiety - Barbiturates “Side” Effects: Barbiturates induce sleep but reduce the amount of REM - therefore sleep not as restorative; some rebound afterwards Impaired cognitive functions: lower memory capacity, slower reaction times, jumbled speech at high doses Upregulation of liver enzymes: tolerance to the drug and cross-tolerance to other pharmacotherapies Produces physical dependence, are prone to abuse  Drugs for Treating Anxiety - Benzodiazepines Common molecular structure that targets the BDZ binding site of GABAA receptors much safer therapeutic index than barbiturates Differences in effect duration are largely dependent on method of biotransformation and depot binding Long-acting BDZs can have half-lives longer than 60 hours and/or have multi-step metabolism with bioactive metabolites Short-acting BDZs are metabolized in a single step Drugs for Treating Anxiety In the absence of GABA, benzodiazepines have no effect on the GABAA receptor GABA antagonists have a more pronounced counter-BDZ activity than BDZ antagonists themselves Competitive antagonists on the BDZ site block the effects of benzodiazepines There is a positive correlation between the ability of a ligand to displace diazepam and the clinical effect of relieving anxiety Drugs for Treating Anxiety - Benzodiazepines BDZs can have sedative-hypnotic and memory impairing effects Clinically useful for relief of worry and physiological (sympathetic) signs of anxiety with little to no tolerance for anxiolytic effects Advantages: high therapeutic index lethal overdose is very rare no liver enzyme increases lower dependence/abuse Research continues for more selectivity in subunit binding Drugs for Treating Anxiety Chemicals that have different structure/ binding pattern than BDZs Buspirone - partial 5-HT1A agonist less effective in relieving the physical signs of anxiety, but strong effect on reducing worry Advantages: also treats accompanying depression lower sedation and mental cloudiness no enhancement of other depressants almost no recreational use no rebound withdrawal symptoms However, onset of effectiveness quite long  Drugs for Treating Anxiety Drug class Trade name Anxiety disorders BZDs Valium, Xanax GAD, panic disorder, OCD, social phobia, alcohol withdrawal, acute situational anxiety Tricyclic antidepressants Tofranil, Aventil Panic disorder, GAD, OCD, PTSD MAOIs Nardil, Parnate Social phobia, panic disorder SSRIs Prozac, Zoloft, Paxil Social phobia, panic disorder, OCD, PTSD Buspirone BuSpar GAD, panic disorder  Drugs for Treating Anxiety SSRIs are somewhat effective in treating some symptoms of OCD and other anxiety disorders Opioids are anxiolytic, but not prescribed for anxiety (abuse potential) Ketamine has shown initial success in treating OCD and PTSD symptoms LSD and psilocybin demonstrate long- term value for anxiety treatment MDMA assisted psychotherapy is highly effective for treating PTSD 15 Minute Break Affective Disorders Two principal types of affective disorders: Major depressive disorder recurring episodes of emotional dysphoria, negative thinking, and impaired functioning Bipolar disorder (I and II) mood swings from major depression to manic episodes Both characterized by extreme exaggeration of mood, not reflecting a realistic appraisal of the environment With anxiety and impulse control disorders, they are among the most common forms of mental illness today Major Depressive Disorder Distinguished from reactive depression or grief by persistence in the absence of an obvious identifiable external cause for the depression Characterized by loss of interest in normal activities, and anhedonia Often coincides with sense of hopelessness, worthlessness, sadness, guilt, or desperation, insomnia, anorexia, fatigue, asexuality Suicidal ideation and attempts are much more frequent for those with MDD There is extensive comorbidity between depression and anxiety disorders Most untreated episodes last ~6-9 months, but can recur later in life Major Depressive Disorder – Three Types SSRIs are ineffective for at least 30% of depressive patients An fMRI comparison of 67 depressive vs. 67 control subjects revealed three subtypes based on angular gyrus functional connectivity CATS = childhood abuse & trauma scale Takuda et al., 2018 Subjects high in both AG-FC & CATS scores were resistant to SSRI treatment Bipolar Disorder Unlike unipolar depression, the incidence is the same between sexes Mania: burst of psychological energy characterized by elation, feelings of grandiosity, euphoria, impulsivity Manic states can involve high-risk activities but can also be effectively channeled into productive/creative outlets Onset is typically between 20 and 30 years of age, can continue throughout the lifespan Risk Factors for Mood Disorders – Heredity Adoption and twin studies are used to estimate the degree of genetic heritability of mood disorders, but can be plagued by confounds Highest mood disorder concordance rate between monozygotic twins is for bipolar disorder; major depression is low Linkage studies try to identify specific genes that confer susceptibility no single gene yet stands out as significantly more contributive genes that regulate 5-HT and BDNF are candidates being investigated Risk Factors for Mood Disorders - Stress Locus of control; strong overlap between anxiety and depression - many symptoms of anxiety accompany clinical depression Elevated cortisol levels, enlarged adrenals/pituitary in depression HPA-axis (excessive CRF release in depression) is regulated by NE, ACh, and GABA inputs to hypothalamus trauma alters early set points Abnormal circadian cortisol release & agonist response Risk Factors – Biological Rhythms Altered sleep rhythms is one a characteristic trait of depression Long onset before sleep, decrease in slow- wave sleep, early REM onset seen more frequent/vigorous eye movements 5-HT and NE activity show circadian patterns; contribute to the dysregulation of emotion in depression Manic episodes in bipolar disorder are characterized by a lack of sleep (insomnia) direction of relationship is unclear Risk Factors – Biological Rhythms  Enteric Contributions The enteric nervous system has hundreds of millions of neurons, many 5-HTergic “Second brain” (actually the first, phylogenetically) On average humans have ~1000 species of mutualist bacteria that comprise our bodies We are more of an ecosystem than “individuals” Mice lacking gut bacteria have heightened responses to stress via the HPA-axis The microbiome composition has been linked to several psychiatric disorders, including depression Probiotics can increase system robustness Fecal transplants from anxious/depressed rats can induce symptoms in recipient Animal Models of Affective Disorders Animals models are insufficient for studying certain depressive signs like guilt and feelings of worthlessness, but are extremely useful for probing the neurobiology of physiological and behavioural signs Reveral of reserpine-induced sedation (psychomotor slowing) is useful for determining the efficacy of many antidepressant drugs Forced swim test/tail suspension test induce behaviours resembling learned helplessness (conditioned failure to act in one’s benefit) Other antidepressant use targets the consequences of chronic mild unpredictable stress, chronic social defeat, maternal separation, or sleep deprivation Animal Models of Affective Disorders Earliest explanatory attempt: the monoamine hypothesis based on observations of the effects of reserpine (VMAT antagonist) Two early medications, MAOIs and tricyclics, found to reduce signs of depression and reverse reserpine-induced effects Both 5-HT and NE play a role in depression Hypothesis is overly simplistic: there is a time disparity between NTs and depressive symptoms Neural Correlates of Depression Brain imaging (fMRI and PET) have demonstrated increased metabolism in the mOFC and amygdala in patients with unipolar depression Amygdala activity correlated with severity mOFC activity reflects emotional control attempts Default-mode network (DMN) regional activity is more strongly correlated in depressed patients compared to controls Increased rumination Anticorrelated with salience (“task-on”) network Reduced baseline coupling and activity after prolonged mindfulness meditation practice Neural Correlates of Depression Serotonin 5-HT metabolite 5-HIAA and precursor tryptophan are lower in depressed patients tryptophan depletion can cause relapses SERT allele (long vs short) is implicated in response to stress (amygdala activity) Brains of depressed patients have higher compensatory 5-HT2A receptor densities antidepressants down-regulate receptor 5-HT receptors are less sensitive in patients with depression, seen in challenge studies Norepinephrine NE contributes to depression through its role in neuroendocrine regulation, reward, attention, arousal, and stress response Metabolite MHPG levels have been inconsistent, but increased during antidepressant treatment Down-regulation of β-receptors and α2 after chronic treatment with antidepressants Down-regulation time (7-21 days) corresponds to clinical efficacy Tyrosine depletion (NE (but also DA) precursor) can induce relapse in depressive symptoms 5-HT & NE Interactions Serotonin-norepinephrine hypothesis of depression: Reciprocal connections exist between the locus coeruleus and the raphe nuclei Destruction of 5-HT axon terminals prevents down-regulation of β-receptors during treatment with antidepressants 5-HT agonists can indirectly stimulate NE neurons, causing β-receptor down-regulation, which in turn may increase raphe activity Neurobiological Models of Depression Glucocorticoid hypothesis: PFC and hippocampal neural populations damaged by chronic high cortisol - less inhibition reduced neurogenesis - BDNF antidepressants reverse both effects Neurotrophic hypothesis: low BDNF may cause low neurogenesis and reduced dendritic branching chronic stress reduces BDNF antidepressant use both reverses and prevents BDNF loss Stabilization of Highs and Lows Lithium carbonate: has no effect on neurotypical individuals, but has powerful stabilizing effects on manic episodes, reduces suicide rate not as effective at treating depressive symptoms elevates tryptophan & 5-HT, affects neurotrophic factors therapeutic index is low, toxic effects can be severe Valproate: simple fatty acid, actions similar to lithium, but it increases GABA levels and influences DA & Glu Carbamazepine: resembles TCA, inhibits NE reuptake, blocks & up-regulates adenosine receptors Therapies for Affective Disorders Three major classes of antidepressant drugs: monoamine oxidase inhibitors (MAOIs) tricyclic antidepressants second-generation antidepressants SSRIs are a part of this group A fourth class called atypical antidepressants Non-drug related therapies include: electroconvulsive shock therapy transcranial magnetic stimulation transcranial direct current stimulation  Monoamine Oxidase Inhibitors (MAO-I) Earliest effective drug treatment for depression (1950s), but resulted in many undesirable “side” effects including: changes in blood pressure sleep disturbance (insomnia) hyperphagia (especially carbohydrates) and weight gain MAOIs have an immediate effect on DA, NE, and 5-HT synapses, but antidepressant effects are likely the result of receptor regulation over the course of several weeks Tricyclic Antidepressants Non-selective monoamine reuptake inhibitors (on DAT, NET, and SERT) ratio of actions differs by specific drug Like the antidepressant effects of MAOIs they are likely due to long term regulation Unlike MAOIs, they also block ACh, histamine, and α2 NE receptors “Side” effects: sedation, fatigue, autonomic nervous system effects Second Generation Antidepressants Not more effective than MAOIs or tricyclics, but result in fewer undesired effects (more selective) Selective serotonin reuptake inhibitors (SSRIs): familiar drugs such as fluoxetine (Prozac) and sertraline (Zoloft) mechanism of action is in the name, but recall that 5-HT is complex Some undesirable effects come with saturation of every 5-HT synapse in the brain: anxiety & restlessness nausea, headache, insomnia, and sexual dysfunction serotonin syndrome at very high doses dependence and withdrawal with prolonged use and abstinence Atypical Antidepressants Intravenous ketamine: ~65-70% of treatment resistant patients get reduced symptoms increased ACC activity, possibly reflecting increased AMPA activity some antidepressant effects can be blocked by AMPA antagonists Tianeptine: Structurally a tricyclic, but its action is in phosphorylating mGluRs (& other kinases), which in turn potentiate AMPA receptors Drug name Norepinephrine Serotonin TCAs Desipramine (Norpramine) +++ + Protriptyline (Vivactil) +++ + Amitriptyline (Vanatrip) ++ ++ Imipramine (Tofranil) ++ ++ Clomipramine (Anafranil) ++ ++++ SSRIs Fluoxetine (Prozac) 0 ++++ Sertraline (Zoloft) 0 ++++ Paroxetine (Paxil) + ++++ SNRIs Reboxetine (Edronax) ++++ 0 Atomoxetine (Strattera) ++++ 0