Introduction to Psychiatry - Anxiety and Anxiety-Related Disorders PDF

Introduction to Psychiatry – Anxiety and Anxiety-related Disorders BMS 150 Week 6 Objectives Compare general anxiety disorder, phobia disorders, agoraphobia, social anxiety disorder and panic disorder in terms of: Signs and symptoms required for diagnosis T...

Introduction to Psychiatry – Anxiety and Anxiety-related Disorders BMS 150 Week 6 Objectives Compare general anxiety disorder, phobia disorders, agoraphobia, social anxiety disorder and panic disorder in terms of: Signs and symptoms required for diagnosis Time course of illness required for diagnosis Describe the clinical features of post-traumatic stress disorder, including: Types of exposures that render a person at risk for development of PTSD The general categories of signs and symptoms that characterize PTSD Typical signs and symptoms that correspond to each category Time course of illness required for diagnosis Objectives Describe the clinical features of obsessive compulsive disorder, including: The major features of obsessions and compulsions Signs and symptoms required for diagnosis Time course of illness required for diagnosis Describe the clinical features of eating disorders, including: Risk factors for their development Signs and symptoms required for diagnosis Important complications that accompany eating disorders Briefly describe the general neurobiological mechanisms underlying anxiety and obsessive compulsive disorders Objectives Differentiate between the use of BDZ as anxiolytics vs hypnotics, and provide examples of each type Outline the therapeutic mechanism of action of BDZ and flumazenil Discuss the adverse effects of BDZ, especially wrt hangover effects, rebound insomnia, tolerance and dependence Describe BDZ withdrawal symptoms from high vs low doses, and relate prescription length to the likelihood of developing withdrawal symptoms Discuss the warnings associated with use of BDZ for insomnia Provide therapeutic uses for flumazenil, and recognize the potential dangers of using it in a multi-drug overdose Anxiety A wide range of symptoms and signs, which everyone is familiar with because everyone has experienced it to some degree ▪ Can you name some? When is fear “pathologic”? ▪ Fear is out of proportion to risk/severity of threat ▪ Response lasts beyond the duration of the threat ▪ Response becomes generalized to other situations (similar or dis-similar) ▪ Social or occupational functioning is impaired Wide range of anxiety disorders ▪ 17% of adults report a lifetime history of one of the major anxiety disorders Anxiety Disorders “True” anxiety disorders: Panic disorder Agoraphobia Specific phobia Generalized anxiety disorder “Anxiety-like” disorders (no longer strictly considered as part of the anxiety disorder spectrum) Obsessive-compulsive disorder Post-traumatic stress disorder Panic disorder A type of anxiety disorder ▪ 1 - 2% prevalence Characterized by recurrent panic attacks ▪ What’s a panic attack? ▪ To be diagnosed with panic disorder, need to have periods in between attacks where patient a) fears another attack or b) does maladaptive things to avoid another attack Need at least 1 month history of avoidance or fear of another panic attack ▪ The panic can’t be due to a particular phobia or another anxiety-related disorder ▪ The panic symptoms cannot be due to an underlying medical disorder Panic Attacks - Features Four or more of the following: ▪ Palpitations, pounding heart, or accelerated heart rate ▪ Sweating ▪ Trembling or shaking ▪ Sensations of shortness of breath or smothering ▪ Feelings of choking ▪ Chest pain or discomfort ▪ Nausea or abdominal distress ▪ Feeling dizzy, unsteady, light-headed, or faint ▪ Chills or heat sensations ▪ Paresthesias (numbness or tingling sensations) ▪ Derealization (feelings of unreality) or depersonalization (being detached from oneself) ▪ Fear of losing control or “going crazy.” ▪ Fear of dying Generalized anxiety disorder GAD – generalized worry that occurs more days than not that is disproportionate to the severity of the event that is feared ▪ Common, prevalence is 3 – 8% ▪ Can be difficult to treat Often anxiety reduces with age Diagnostic criteria: ▪ Excessive anxiety for more days than not for 6 months ▪ Individual has difficulty controlling the anxiety ▪ Is accompanied by typical symptoms (see next slide) Generalized Anxiety Disorder - Symptoms 3 of 6 of the following must be present for diagnosis ▪ Restlessness or feeling “keyed up” or on edge ▪ Being easily fatigued ▪ Difficulty concentrating or mind going blank ▪ Irritability ▪ Muscle tension ▪ Sleep disturbance As with all psychiatric diagnoses, the anxiety, worry, or physical symptoms must: ▪ Cause clinically significant distress OR ▪ Impairment in social, occupational, or other important areas of function Agoraphobia In general, unreasonable fear of being out-of- doors or being in a crowd or being in a place where they can’t escape from or may suffer embarrassment ▪ The anxiety and its symptoms are typically present almost all of the time… even when the patient is somewhere comfortable to them ▪ Avoidance is prominent Very common disease, but again has a good prognosis if well-treated ▪ Rough estimate – about 1% of the population Agoraphobia – Symptoms Examples of situations that cause worry or fear in agoraphobia: ▪ Using public transportation ▪ Being in open spaces… or enclosed spaces ▪ Standing in line, being in a crowd, or being in other social situations ▪ Being outside of the home These situations should almost always provoke fear or anxiety ▪ Usually the patient fears that he/she cannot escape from the situation/environment or that they will experience a panic attack or other embarrassing symptom The fear or anxiety needs to be present for > 6 months and needs to cause significant distress or impairment in social or occupational function Specific Phobias fears of specific objects or situations that go beyond the true threat of the stimulus and cause avoidance and functional impairment ▪ Spiders, blood, clowns, etc. Surprisingly common – 12 - 16% Diagnostic criteria: ▪ exposure to stimulus provokes an immediate fear/anxiety response; may present as a panic attack ▪ phobic object/situation is actively avoided or endured with intense anxiety. ▪ fear/anxiety out of proportion to actual danger/sociocultural context ▪ person recognizes fear as excessive or unreasonable ▪ significant distress or impact on daily routine, occupational/ social functioning and/or marked distress ▪ Must be present > 6 months Social Anxiety Disorder marked and persistent (>6 mo) fear of social or performance situations in which: ▪ One is exposed to unfamiliar people or to possible scrutiny by others ▪ One is afraid that fearing he/she will act in a way that maybe humiliating or embarrassing e.g. public speaking, initiating or maintaining conversation, dating eating in public ▪ Out-of-proportion fear that they will be harshly judged by their interpersonal interactions ▪ Very common, 2 - 7% Post-traumatic stress disorder When does it happen? ▪ Exposure to actual death, threatened death, physical or sexual violence, serious injury Could have witnessed or received the violent act Can occur in people that are repetitively exposed to disturbing or violent events (i.e. police officer repeatedly exposed to details of an abuse situation) Often the sufferer feels helpless during the event ▪ In men, frequently associated with combat ▪ In women, abuse is frequently the causative factor ▪ First responders, healthcare personnel, law enforcement are a growing demographic affected by this disorder ▪ Lifetime prevalence estimated to be ~ 8% ▪ Diagnostic criteria and symptomatology are complex and specific – see next 3 slides Post-traumatic stress disorder Many different manifestations Symptoms divided into general categories: ▪ Intrusion symptoms Intrusive, distressing memories, flashbacks, dreams ▪ Avoidance behaviour Avoidance of situations or events that are associated with the inciting trauma Can also involve avoiding people, places, or conversations that arouse memories or feelings associated with the event ▪ Cognitive and mood symptoms Memory deficits, negative emotions, guilt, shame Detachment from others, loss of interest in people or activities ▪ Arousal and reactivity symptoms Difficulty sleeping, exaggerated startle responses Anger, irritability, increased risk-seeking behaviour Post-traumatic stress disorder - Symptoms Intrusion symptoms – examples ▪ Recurrent, involuntary distressing memories or dreams of a traumatic event (they “intrude” on the sufferer’s mind) ▪ Dissociative reactions where the individual feels as if the event was occurring Known as a flashback – different than a memory ▪ Marked physiological reactions or distress at exposure to cues that resemble the traumatic event Alterations in arousal and reactivity – examples ▪ Irritable behaviour or angry outbursts with little or no provocation ▪ Hypervigilance or exaggerated startle responses to everyday stimuli ▪ Sleep disturbances or difficulty concentrating ▪ Reckless or self-destructive behaviour Post-traumatic stress disorder - Symptoms Negative alterations in cognitions or mood – examples ▪ Inability to remember important aspects of the traumatic event ▪ Negative beliefs about oneself or the world in general These could be linked to or independent from self- blame about the traumatic incident ▪ Persistent inability to experience positive emotions ▪ Diminished interest or participation in general day-to-day, essential activities ▪ Detachment or estrangement from other people Time criteria: > 1 month for symptoms The disturbance must cause significant distress or impairment in social, occupational, or other important areas of function Obsessive-Compulsive disorder What is an obsession? A compulsion? Surprisingly difficult to treat ▪ Often refractory, a lot of work needs to be done by both patient and psychotherapist to get better Lifetime prevalence of 2-3% ▪ Subclinical OCD thought to be more prevalent, but few epidemiologic studies conducted  Obsessive Compulsive Disorder Obsession: intrusive and unwanted repetitive thoughts, urges, or impulses that lead to a marked increase in anxiety or distress Compulsion: repeated behaviors or mental acts that are done in response to obsessions, or in a rigid rule-bound way (i.e. ritual) ▪ Act may attempt to “suppress” the obsession Usually both are present Obsession Compulsion Fear of contamination Cleaning or washing rituals Pathological doubt (i.e. something was Repetitive checking missed leading to catastrophic consequences) Fear of causing harm to others Repetitive checking Need for symmetry or exactness Ordering, rearranging objects Superstitious obsessions (can include Superstitious rituals (i.e. repeating things religious obsessions) a certain number of times) Obsessive Compulsive Disorder Additional criteria ▪ Obsessions and compulsions must take > 1 hour/day or cause significant distress or impairment in social, occupational, or other areas of function Patients are usually aware that obsessions and compulsions are illogical and not based in fact ▪ This is known as insight ▪ Most patients with delusions and hallucinations have poor insight Other disorders may share a similar neurobiology with OCD, including: ▪ Hoarding disorder ▪ Skin-picking or trichitomania (hair-pulling/plucking) disorders ▪ Body dysmorphic disorder patient focuses on appearance in a negative way to the extent that it impairs social functioning  Neurobiology of Anxiety Disorders General concepts in fear and anxiety: Fear response: activation of the locus coeruleus (LC), a midbrain nucleus that contains neurons that release norepinephrine (NE) at the presynaptic terminal Activation of the LC ! release of norepinephrine (NE) ! ▪ Activation of the amygdala – emotional “fear” responses The amygdala is a prominent area that attaches an emotional weight to situations – this “weighting” can help prioritize and enhance learning ▪ Activation of the hypothalamus – activation of the sympathetic nervous system and cortisol release ▪ Activation of the reticular activating system in the brainstem – increased arousal Neurobiology of Anxiety Disorders The networks involved in anxiety-type disorders are complex ▪ i.e. ! in response to a fear-causing stimulus, the perception is sensed by the cortex ! communication to the amygdala via the thalamus ▪ The hippocampus can be “activated” or involved as part of the process of learning about the cause of the fear and how it can be avoided ▪ The pre-frontal cortex can exert a “top-down” control over how a patient (or any of us) regulates our cognitive responses or behaviours to a potential fear-causing stimulus ▪ The serotonin-releasing nucleus in the brainstem (the raphe nucleus) can also have a more “global” modulatory effect on mood, memory, and also fear + stress responses The noradrenergic, serotonergic and dopaminergic pathways all have important nuclei in the brainstem and all of them “cross-talk” to each other Noradrenergic Pathway Review Neurotransmitter: Noradrenaline (also known as norepinephrine) Origin: The cell bodies of noradrenergic neurons are located in the locus coeruleus in the brainstem. Function: Plays a key role in regulating mood, attention, arousal, and stress response. It is involved in the "fight or flight" response. Clinical Significance: Dysregulation of noradrenergic pathways is implicated in various psychiatric disorders such as depression, anxiety disorders, and attention deficit hyperactivity disorder (ADHD). Serotonergic Pathway Review Neurotransmitter: Serotonin (also known as 5- hydroxytryptamine or 5-HT) Origin: The cell bodies of serotonergic neurons are located in the raphe nuclei in the brainstem. Function: Regulates mood, emotion, appetite, sleep, and various cognitive functions. It is involved in modulating anxiety, aggression, and impulsivity. Clinical Significance: Imbalances in serotonin levels are associated with mood disorders such as depression and anxiety, as well as obsessive-compulsive disorder (OCD) and eating disorders. Dopaminergic Pathway Review Neurotransmitter: Dopamine Origin: Dopaminergic neurons have several nuclei in the brain, including the substantia nigra and the ventral tegmental area (VTA). Function: Plays a crucial role in reward, motivation, pleasure, movement, and reinforcement learning. Dopamine is involved in regulating mood, attention, and executive functions. Clinical Significance: Dysregulation of dopamine pathways is implicated in various psychiatric disorders such as schizophrenia, addiction, and Parkinson's disease.  Dopaminergic Neurobiology of Anxiety Disorders Noradrenergic, Dopaminergic, Serotonergic Pathways ! Brainstem Nuclei Serotonergic Noradrenergic Neurobiology of Anxiety Disorders A generalized model may be: Prolonged stress or genetic factors lead to a transition between “normal” anxiety and fear responses and “abnormal”, excessive anxiety and fear responses ▪ “Normal” – areas activated include the locus coeruleus, amygdala ! activation of the sympathetic nervous system and temporary increased release of cortisol Helps us deal with threats – the prefrontal cortex is able to regulate mood, negative cognition, and general worry Neurobiology of Anxiety Disorders A generalized model may be: Prolonged stress or genetic factors lead to a transition between “normal” anxiety and fear responses and “abnormal”, excessive anxiety and fear responses ▪ “Abnormal” – areas activated OR inactivated include an area close to the amygdala (stria terminalis) and other midbrain nuclei like the dorsal raphe nucleus as well as the locus coeruleus Poorer regulation of mood, fear/worry by the prefrontal cortex Excessive long-term activation of cortisol release by activation of the hypothalamic pituitary axis as well as excessive chronic activation of the sympathetic nervous system Obsessive Compulsive Disorder - Neurobiology OCD likely has a pathogenesis that is distinct from that of the anxiety disorders ▪ It likely involves circuits that involve the basal ganglia Remember the direct and indirect pathways as part of the extrapyramidal motor system? ▪ Research suggests that over-activation of the direct pathway and poor activation of the indirect pathway as they modulate activity of the orbitofrontal cortex Inhibitory dopaminergic transmission transmission (D2 receptors) may be implicated NOTE: this is a very simplified generalization for a disorder that has many different types of behaviour that are likely moderated by a range of different circuits ▪ The most effective medications are higher-dose SSRIs It is unclear how they mediate their positive impact on these circuits Recall - Nuclei of the basal ganglia General function Specific Nucleus Nucleus Function Input nuclei Putamen Control of limb and trunk (striatum) movements Caudate Cognition and eye movement control Nucleus accumbens Emotional regulation Associated nuclei Globus pallidus externa All are involved with limb/ Substantia nigra pars trunk movements, eye compacta movements, and Subthalamic nucleus emotional regulation Output nuclei Globus pallidus interna More involved with the putamen functions Substantia nigra pars More involved with the reticulata caudate functions Recall - Nuclei of the basal ganglia Frontal Input Output Thalamus lobe nucleus nucleus S.N.c. Ass. Nuclei Ass. Nuclei GPe STN Components of the direct and indirect pathway are illustrated here in a general fashion RED arrow = excitatory input BLUE arrow = inhibitory input Basics of eating disorders – anorexia nervosa and bulimia nervosa F:M ratio ~ 10:1 ▪ lifetime prevalence of around 1% in the female population for anorexia and 2-4% for bulimia Higher risk: ▪ display “perfectionist” traits ▪ Have a past history of sexual abuse ▪ feel that they lack control in other dimensions of their lives ▪ Expectations (i.e. athletic) regarding weight Gymnasts, dancers Wrestlers Anorexia diagnostic criteria A. intake and weight: restriction of energy intake relative to requirements, leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. ▪ Significantly low weight ! a weight that is less than minimally normal B. fear or behaviour: intense fear of gaining weight or of becoming fat, or persistent behaviour that interferes with weight gain, even though at a significantly low weight C. perception: disturbance in the way in which one’s body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or persistent lack of recognition of the seriousness of the current low body weight Note: criteria A tends to be based on BMI criteria wrestlers, gymnasts, dancers (athletes) can have a lot of muscle mass but still have disordered eating habits Bulimia diagnostic criteria A. recurrent episodes of binge-eating; an episode of binge-eating is characterized by both of the following: ▪ eating, in a single period of time, an amount of food that is larger than what most individuals would eat during a similar period of time and under similar circumstances ▪ a sense of lack of control over eating during the episode B. recurrent inappropriate compensatory behaviour in order to prevent weight gain such as: ▪ self-induced vomiting ▪ misuse of laxatives, diuretics, enemas, or other medications ▪ Fasting ▪ excessive exercise C. the binge-eating and inappropriate compensatory behaviours both occur, on average, at least once a week for 3 mo D. self-evaluation is unduly influenced by body shape and weight E. the disturbance does not occur exclusively during episodes of AN Dangers of eating disorders Eating disorders can cause significant physical harm – a short list below for anorexia and bulimia Starvation/Calorie Restriction Binging + Purging Hypotension, bradycardia Gastric dilation or rupture Dysrhythmias, congestive heart Esophageal damage/tearing failure Pancreatitis Vitamin deficiencies Dysrhythmias (due to K+ loss from Constipation, delayed gastric vomiting or use of laxatives) emptying Damage to teeth (purging) Decreases thyroid hormone, Aspiration pneumonia amenorrhea, osteoporosis Gastric contents cause Increased risk of seizure due to pneumonia when they are electrolyte abnormalities accidentally “breathed in” Severe restriction can cause renal failure and edema Benzodiazepines Act as anxiolytics or hypnotics BDZ commonly ▪ Anxiolytic example: Diazepam (Valium®) have “zepam” Also used for certain types of seizures and “zolam” ▪ Hypnotic example: Triazolam (Halcion®) endings What is their mechanism of action? ▪ Facilitate binding of GABA to GABA-R How could this explain their anxiolytic, hypnotic, and anti-seizure effects? Benzodiazepine Adverse Effects Selected adverse effects (most common with hypnotic use): Hangover effects ▪ Wake up feeling groggy ▪ More common with long half-life agents Early morning rebound insomnia ▪ Wake up too early ▪ More common with short half-life agents ▪ Can lead to taking a second pill during the same sleep cycle, which makes tolerance more likely to develop Benzodiazepine Adverse Effects Tolerance ▪ Usual dose of drug no longer sufficient to get therapeutic effect ▪ May be due to downregulation of ? How can you still get a therapeutic effect once tolerance occurs? ▪ Unfortunately, this increases likelihood of dependence Dependence ▪ Brain requires the drug to generate normal amounts of GABA activity ▪ Leads to more severe withdrawal symptoms when drug is discontinued Benzodiazepine Adverse Effects Withdrawal symptoms ▪ Mild symptoms can occur after short-term use and/ or low-doses, including: Extra-sensory awareness ▪ Ex acute hearing Muscle twitching or tremors Rebound excitation ▪ Patients should be counselled to expect a few nights bad sleep at the end of a course of BDZ During this time, a new prescription should not be given * Use of BDZ’s more than 14-21 nights in a row makes tolerance/ dependence/several withdrawal symptoms more likely Benzodiazepine Adverse Effects Withdrawal symptoms ▪ Severe symptoms usually occur on abrupt discontinuation after long-term use and/or high doses, and include: Increased blood pressure, Can you rationalize temperature and pulse this group of Rage symptoms? Hallucinations and paranoia Seizures ▪ Withdrawal symptoms can also occur during chronic drug use – why? Benzodiazepines Adverse Effects General warnings/precautions associated with the use of hypnotics to treat insomnia include: ▪ Abnormal thinking and behavioral changes Visual and auditory hallucinations, “sleep-X” events ▪ The need to evaluate for an underlying primary psychiatric and/or medical illness for the insomnia Hypnotic use coupled with an underlying primary disorder can cause: ▪ Worsening of insomnia, worsening of depression (including suicidal thoughts), etc BDZ Antagonist Flumazenil = BDZ antagonist ▪ Competitive inhibitor of BDZ ▪ Therapeutic uses include: Removal of effects of BDZ once therapeutic effects no longer needed ▪ Ex after an in-office procedure Treatment of BDZ OD ▪ Caution with multi-drug overdose ▪ Shorter duration of action than BDZ What is the implication for someone who had a BDZ for an in-office procedure, then was given flumazenil to reverse its effects? Case: Discuss with a partner/small group A patient is admitted to the emergency room with severe CNS depression from a probable drug overdose ▪ Signs include including ataxia, hypotonia, and respiratory distress ▪ Empty bottles of diazepam, amitriptyline, and bupropion were found at his bedside An intern starts to prepare a flumazenil IV ▪ Do you stop her and ask her to re-evaluate the treatment, or do you go ahead with administering flumazenil? Pathology 3.06 - Depression Major Depression and Bipolar Disorders Dr. Albert Iarz, ND, RMT BMS 150 Week 6 Overview Overview of psychiatry Definitions of common psychiatric presentations Major Depressive Disorder Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Bipolar 1 and 2 Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Mechanism of action of antidepressant and antimanic medication Learning Objectives Describe the role of psychiatry in health care Define common psychiatric presentations including psychosis, delusion, hallucination, depressive disorder, mania, hypomania, delirium Describe the epidemiology, major clinical features and diagnostic criteria major depressive disorder (MDD) and bipolar disorders 1 and 2 Describe the neurochemistry and neuropathology contributing to the disorders of MDD including role of circadian rhythm abnormalities, excitotoxicity, inflammatory hypothesis, monoamine hypothesis and neurotrophic hypothesis Describe the neuropathology and biochemistry of bipolar disorders, particularly the role of increase glycolysis and reduced oxidative phosphorylate in metabolic imbalance associated with these pathologies Describe mechanism of action of selected common antidepressant and anti- manic agents, such as SSRI, MAO inhibitors, and others Overview of Psychiatry Branch of medicine which focuses on the prevention, assessment and treatment of mental, emotional and behavioural disorders Disorders include substance abuse/ addictions, mood, anxiety, eating disorders, personality disorders and psychotic disorders Treatments can include medications, psychotherapy, electroconvulsive therapy, and other forms of medicine Common Psychiatric Presentations Definition for Delusion Delusion A belief that is clearly false and indicates an abnormality in content of thought False belief cannot be explained by the person’s cultural or religious background or intelligence level Belief is held despite being presented with evidence against it (“fixed” – firmly maintained) Patient is convinced the delusion is real Can be due to: mental disorder, neurological or medical disorder Examples: schizophrenic, substance abuse, bipolar disorder, major depressive disorder (MDD), delirium and dementia Definition for Hallucination Hallucination “A sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs” Not under voluntary control Vivid, clear, full force and impact of normal perceptions Visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive Formed (i.e. voice making a command) or unformed (i.e. non- specific sound) With insight – px is aware that its not real only hallucination OR without insight – px is unaware and accepts the experience as reality Can occur in illness and in health (i.e. grief) Can be due to: psychiatric disorder, neurological or medical disorder Definitions for Psychosis Psychosis Hallucination (without insight), delusion OR hallucination (without insight) and delusion Loss of contact with external reality Central component: Impaired reality testing Can occur in psychiatric and neurological disorders Additionally: Disorganized thoughts and impairment in cognitive function (i.e. reduced verbal fluency) Mood changes Reduced attention and concentration Sleep disturbances Definition for Delirium Delirium Acute, fluctuating change in attention (reduced) and consciousness including disorganized thoughts Altered consciousness: hypervigilant, unresponsive, near-coma, severe agitation May include: psychosis; delusions and hallucinations, altered mood Can vary in duration: days (typically) or months Triggered by: change in medication, infection, surgery, trauma, stroke, withdrawal, very extensive list Definition for Depressive Episode Depressive Episode Experience of low or depressed mood Loss of interest in most activities Additional possible symptoms: Fatigue Changes in appetite (and weight) Feelings of worthlessness Recurrent thoughts of death Unexplained physical ailments unresponsive to treatment (i.e. digestive problems, pain) Conditions include: MDD, anxiety disorder, bipolar, schizophrenia, post-stroke, bereavement, and others Definition for Mania Mania Characteristics: increased talkativeness, rapid speech, decreased need for sleep, racing thoughts, distractibility, increase in goal-direct activity, psychomotor agitation May include: elevated mood, mood lability, impulsivity, irritability, grandiosity Duration: 1 week or more OR if severity of symptoms warrants hospitalization Conditions: bipolar disorder, certain medications and substances may cause sx of mania, neurological causes can include stroke, brain tumor or injury Definition for Hypomania Hypomania Differentiating factors from mania: Duration: at least 4 days (rather than at least 1 week) Does NOT cause major deficit in social or occupational functioning Conditions: bipolar disorder, substances, neurological causes (i.e. encephalitis, dementia, lupus) Major Depressive Disorder (MDD) Epidemiology Major clinical feature Diagnostic Criteria Neurochemistry/ Neuropathology Major Depressive Disorder (MDD) Epidemiology Predicted to be the 2nd leading cause of disability world wide by 2030 (according to WHO) Canada: 4.7-5.4% of population experience MDD, higher rates in at-risk groups Risk Factors: Exposure to traumatic life events (death, abuse, parental psychopathology…) Chronic pain and chronic disorders (cancer, stroke, MS, others) and physical health Low income, increased caregiver burden, lack of social support Family history (first degree relative 3x risk of developing MDD) MDD: Clinical Features Mood Symptoms Physical Sx Cognitive Sx Feeling sad/ low Lack of energy / tired Slow thinking Lack of interest in Difficulty sleeping; Difficulty general waking early concentrating Anhedonia Restless/ agitated Slow movement Low self-esteem Weight loss Forgetfulness Lacking confidence Low libido Difficulty planning Feelings of guilt or Low appetite/ Difficulty making worthlessness overeating decisions Suicidal thoughts MDD: Diagnostic Criteria DSM-5 Category A – must include the first two components and a total of 5 or more components: Depressed mood (subject report of observations of others) Anhedonia – loss of interest/ pleasure in almost all activities These 2 sx must be present most of day, every day for at least 2 weeks in a row Unintentional weight loss or gain (>5% in 1 mo) or significant change in appetite Sleep disturbance (insomnia/ hypersomnia) Psychomotor changes (agitations/ retardation) Fatigue, low energy, decreased efficiency with routine tasks Sense of worthlessness or excessive/ inappropriate guilt (i.e. guilt about being sick) Impaired ability to think/ concentrate/ make decisions Recurrent thoughts of death, suicide ideation or attempts MDD: Diagnostic Criteria DSM-5 Additional diagnostic requirements: These sx must cause significant distress OR impair social, occupational or other important areas of function Sx are not due to direct physiological effects of a substance (i.e. meds, drug abuse) OR medical condition (i.e. hypothyroidism) Px has never experienced a manic or hypomanic episode This condition is not better explained by schizophrenia spectrum or other psychotic disorders MDD: Neuropathology and Neurochemistry Multifactorial disease with various causes and triggers Psychosocial causes Genetics Nutritional deficiencies Pollution/ environment Gut-brain axis Leading biomedical theories Monoamine hypothesis Stress-induced depression hypothesis Neurotrophic / Neuroplasticity hypothesis Cytokine hypothesis/ Neuroinflammation hypothesis Circadian hypothesis of depression GABA-glutamate-mediated depression hypothesis Monoamine Hypothesis Altered levels of monoamine neurotransmitters, specifically serotonin and noradrenaline, and/or dopamine cause depression Based on antidepressant therapies that increase the presence/ function of one or more neurotransmitter resulting in reduced depression Critiqued in that abruptly decreasing serotonin and/or dopamine doesn’t cause depression in a healthy person Other neurochemicals are implicated in depression beyond these Probable causes: genetics, environment, stress Stress-induced depression hypothesis Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis Prolonged, moderate stress is the problems, versus minor daily stresses OR one strong stressor Examples: maternal stress, maternal smoking, early grave loss, child abuse Early trauma may have more sig impact than in adult life (impact how HPA is developed in utero) Chronic HPA activation leading to: excess cortisol secretion and pro-inflammatory agents that damage glia and neurons, interfere with neurogenesis and reduce glutamate and GABA Stress-induced depression hypothesis Clinical studies support this in some patients with severe depression: measurable increase in cortisol which is not reduced through negative feedback (also increased CRH) Resistance of the glucocorticoid receptor (GR) Antidepressants appear to restore the functioning of the GR and thus improve negative feedback and normalize cortisol levels Critique: hypercortisolism is not a feature of all MDD cases AND not clear what causes HPA dysregulation (i.e. loss of GR sensitivity) Neurotrophic and neuroplasticity hypothesis Brain-derived neurotrophic factor (BDNF) promotes neurogenesis, regulates differentiation and growth of neurons Neurogenesis may offer resilience against stress by enhancing the negative feedback loop with HPA Observations: Decreased BDNF gene expression, decreased BDNF levels and receptors in MDD patients Increased cortisol can inhibit BDNF Same triggers that elevated cortisol appear to block neurogenesis Antidepressants Have been demonstrated to stimulate neurogenesis in adult hippocampus (animal studies) – takes 4 weeks Correlates with the 3-4 week expectation of achieve improvement in mood Cytokine and Neuroinflammation hypothesis Observation: MDD px have increased levels of pro-inflammatory markers: TNFalpha, IL-1, IL-6, C-reactive protein (CRP) vs healthy px, as well as increased level of macrophage/monocyte activation Frequent correlation b/w MDD and inflammatory conditions such as asthma, diabetes, arthritis, obesity, CAD Animal studies: injecting pro-inflammatory cytokines induces depressive sx Some antidepressants have anti-inflammatory properties Earlier case reports observed improvement in mood in patients with treatment resistant MDD treated with anti- inflammatory medications, particularly in context of other inflammatory conditions (like IBD) However, several clinical trial failed to reproduce these results Circadian Physiology Healthy state: Light inhibits pineal gland from producing melatonin (by activating neurons with suprachiasmatic nucleus (SNC) of the hypothalamus) SCN regulates production of melatonin throughout the body Melatonin production increases at night during conditions of dark Circadian Hypothesis Stressful events lead to changes in diurnal molecular rhythms in cells that in vulnerable px triggers MDD Bidirectional link with sleep disturbance and depression Insomnia is a predisposing factor Sleep deprivation therapy – reduces MDD sx (may reset the circadian clock) Genes controlling circadian rhythms in anterior cingulate cortex are dysregulated in depression Phase advance in cortisol rhythm and reduced amount of melatonin production seen in some patients with MDD Altered circadian rhythms can also affect reward systems, particularly social interaction Same 5-HT receptors have been implicated in both sleep rhythms and depression; serotonin is involved in phosphorylation of CLOCK protein, which regulate suprachiasmatic circadian rhythms Sleep disturbances have also been correlated with pro-inflammatory cytokines Excitatory Neurotransmitters Hypothesis Glutamate may cause excitotoxicity resulting in neuronal atrophy and reduced synaptic connectivity Stress induced changes may be accelerated in the presence of elevated Glu Reduced GABA in CSF of MDD px – may be d/t change in serotonin which modulates GABA, which in turn modulates glutamate Reduced GABA and glutamate within glial cells and neurons of the prefrontal cortex (PFC) Astrocytes recycle glutamate and transport to presynaptic neurons Elevated metabolism of glucose within same areas of PFC, and reduction of the gray matter in this region Ketamine – modulates glutamate transmission Approved for tx of treatment resistant MDD Glutamate Excitotoxicity Excessive accumulation of glutamate within synaptic cleft results in over stimulation of postsynaptic glutamate receptors Via NMDA receptor glutamate promotes calcium influx Review: how does increased cytosolic Ca2+ result in necrosis? Bipolar Disorders Epidemiology Canada 1.5% of pop experience bipolar disorder Clinical Features Mania Hypomania Depression (most of time spent in depressive state) Cyclical changes between these states a common to be part of the disorder Manic psychosis, which may include delirium Bipolar 1 At least 1 manic episode and usually depressive episodes Bipolar 2 Major depressive episodes with at least 1 hypomanic episode Bipolar Disorders - DDX Bipolar Disorder 1: Exclusion of hyperthyroidism (TSH and T4) Exclusion of stimulant drug abuse (blood/urine) Clinical based on DSM-5: At least 1 episode of mania/hypomania lasting for at least 4 consecutive days AND be present most of the day, almost every day 3 or more symptoms (representing sig change from norm) of mania Cause significant impairment or necessitates hospitalization Mania Symptoms 3 or more symptoms (representing sig change from norm) of mania: Inflated self-esteem or grandiosity Decreased need for sleep (feels rested after 3 hours of sleep) More talkative than usual or pressure to keep talking Flight of ideas or subjective experience that thoughts are racing Distractibility (i.e. attention too easily drawn to unimportant / external stimuli) Increase in goal-directed activity (purposeful) or psychomotor agitation (purposeless) Excessive involvement in activities that have a high potential for painful consequences (i.e. foolish business investments, unrestrained buying sprees) Bipolar Disorders - DDX Bipolar Disorder 2: No/never experienced episode of mania Exclusion of/ not better explained by: schizophrenia, delusional or psychotic disorder or unspecified schizophrenia spectrum Clinically significant distress from symptoms Hypomania episode Hypomania Episode (DSM-5) Elevated, expansive or irritable mood with persistently increased activity or energy; 4+ days, most of the day, nearly every day 3 or more additional mania symptoms Episode is different from px regular non symptomatic experience Observers can note change in mood and function Not severe enough to impair functioning or necessitate hospitalization (no psychotic features) Episode is not triggered by substance (drug, medication, other treatment) Pathophysiology of Bipolar Disorders Circadian Rhythm Dysfunction Metabolic Dysfunction Mitochondria Dysfunction Glutamate Excitotoxicity Circadian Rhythm Dysfunction During mania there is a reduced need for sleep Observations in patients with bipolar disorders: Changes in melatonin levels Changes in melatonin receptor expression with CNS Changes in cortisol profiles (patterns of release) Sleep deprivation as well as light therapy have been effective as adjunct in some cases of bipolar disorder Correlation between polymorphism in CLOCK genes as well as positive response to lithium therapy (common drug used in bipolar management) Metabolic Dysfunction Various metabolic abnormalities have been found in patients with bipolar disorder such as: Increased risk of obesity, type 2 diabetes, and reduced longevity due to increased cardiovascular problems Increased amount of leptin secreted in obese patients with bipolar compared to obesity alone Leptin regulated appetite AND sleep duration A hypothesis suggests that the body is forced to compensate for the high metabolic demand of the brain during manic states: Reduced appetite Reduced sleep Increased energy expenditure Mitochondria Dysfunction Impairment in mitochondrial function resulting brain metabolism shifting towards glycolysis Observations: Polymorphisms within mitochondrial DNA linked to BD Reduced levels of phosphocreatine within frontal cortex. Phosphocreatine is a reserve for ATP and this implied chronic deficiency in ATP synthesis Evidence of impaired oxidative phosphorylation Increased amounts of alpha-ketoglutarate and pyruvate – review: how do these substrates relate to ATP production? Reduced expression of genes coding for various complexes of the electron transport chain in hippocampus Glutamate Excitotoxicity Observation: increased glutamate in frontal cortex of px with BD Mood stabilizers appear to return glutamate levels to normal Increased levels of excitatory glutamate appear to result an increased energy demand on the neuron Increased glucose consumption in areas of high glutamate synaptic activity Hypothesis: increased shift to glycolysis may be due to increased glutamate stimulation Antidepressants Pharmacology Dr. Heisel BMS150 Objectives Provide a potential mechanism for antidepressants that addresses their delayed therapeutic effects Discuss the demographics of antidepressant-related suicide risk Provide the therapeutic mechanism of action for SNRI’s, SSRI’s, MAOI’s, trazodone and bupropion Describe the adverse effects (including OD effects) of antidepressants, including a mechanism where applicable Describe the causes, symptoms and treatment for serotonin syndrome Mechanism Overview Review: select theories of depression Overall: NT ▪ Potentially related to low levels of NT’s, such as? levels too low, Low levels of NT’s lead to receptor receptor levels upregulation too high Possible mechanisms of antidepressant action ▪ Reuptake inhibitors Immediate: increase levels of NT’s (ex serotonin) NT reuptake  Mechanism Overview Possible mechanisms of antidepressant action ▪ Reuptake inhibitors continued Delayed: down-regulation of NT receptors ▪ Could explain time needed to see antidepressant effects ▪ The 5HT1a receptors are autoreceptors – they inhibit release of NT from presynaptic terminals If they’re down-regulated ! increased NT release ▪ Sustained antidepressant therapy is also associated with increased production of BDNF, which is likely linked to efficacy ▪ FYI: Reuptake enhancers Approved in Europe, have opposite mechanism: lead to decreased NT levels  Mechanism Overview Depression and anxiety disorders are complex, multifactorial illnesses and research is still developing re: how pharmacotherapies actually work Theories that attempt to explain the MOA of SSRIs or SNRIs need to account for the delayed onset of action ▪ Weeks before clinically-relevant effects in mood are seen  Antidepressant Suicide Risk Take home: increased suicide risk in children, adolescents and young adults upto 24 years of age when taking antidepressants. https://online.epocrates.com/noFrame/monographPrint? activeTab=0&activeDrugId=135&activeSectionId=11&activeFormulary=-1 Main Classes of Antidepressants SNRI’s: Serotonin & Norepinephrine Reuptake Inhibitors ▪ Examples: Know generic names, brand names are FYI only* TCA’s (tricyclic antidepressants) such as amitriptyline (Elavil®) ▪ “-triptyline” suffix = TCA (but not all TCA’s are “-triptylines”) Venlafaxine (Effexor®) SSRI’s: Selective Serotonin Reuptake Inhibitors ▪ Example: fluoxetine (Prozac®) “-oxetine” suffix = SSRI (but not all SSRI’s are “-oxetines”) Other ▪ MAOI’s: monoamine oxidase inhibitors ▪ Trazodone (Desyrel®) ▪ Bupropion (Wellbutrin®, Zyban®)* * Need to recognize these two brand names SNRI’s: TCA’s One of first types of antidepressants discovered ▪ Therapeutic mechanism? ▪ Adverse effects Many are due to non-therapeutic block of M, alpha 1 and H1 receptors ▪ M and alpha 1 receptor review: Where are each found? What main NT binds and activates each? Does their activation typically lead to parasympathetic or sympathetic effects? M, H1, and alpha 1 receptor review: Muscarinic (M) Receptors Muscarinic receptors are a type of acetylcholine receptor and are part of the G protein-coupled receptor (GPCR) family They play a significant role in the parasympathetic nervous system M, H1, and alpha 1 receptor review: Alpha-1 Adrenergic Receptors Alpha-1 adrenergic receptors are another type of GPCR that primarily respond to the catecholamines norepinephrine and epinephrine. These receptors are predominantly involved in the sympathetic nervous system, which is responsible for the "fight or flight" response. M, H1, and alpha 1 receptor review: H1 Receptor a type of histamine receptor, which is a member of the G protein-coupled receptor (GPCR) family. These receptors play a crucial role in the body's response to allergens and inflammatory processes. They are predominantly involved in mediating the effects of histamine in allergic reactions and are distributed throughout various tissues in the body.  AUTONOMIC NERVOUS SYSTEM Review Sp. Cd. Sympathetic α,β, : Heart, ACH N NE Sm. mus. Glands ACH N → E, → Ad. M. NE Brainstem Parasympathetic or Sp. Cd. M: Heart, ACH N ACH Sm. mus. Glands Receptor Review M-receptors ▪ What adverse effect would result from blocking M-receptors on the following: Salivary glands Intestines Bladder Pupil Alpha 1-receptors ▪ What adverse effect would result from blocking alpha-1 receptors on blood vessels? Receptor Review M-receptors ▪ What adverse effect would result from blocking M-receptors on the following: Gastrointestinal: Dry mouth (xerostomia) due to reduced salivary secretion. Constipation due to reduced gastrointestinal motility. Genitourinary: Urinary retention due to relaxation of bladder smooth muscle. Ocular: Blurred vision due to cycloplegia. Sensitivity to light (photophobia) due to pupil dilation. Alpha 1-receptors ▪ What adverse effect would result from blocking alpha-1 receptors on blood vessels? - Orthostatic Hypotension, Dizziness and Headache, Nasal Congestion, Fatigue and weakness, Reflex tachycardia Receptor Review H1-receptors ▪ Review: Found in the CNS and mediate what? Can also inhibit feeding ▪ What two adverse effects are therefore expected from block of H1? Receptor Review H1-receptors Help to control ▪ Appetite and Thermoregulation ▪ Wakefulness and Arousal  TCA: Common Receptor-block Adverse Effects M-block Alpha 1-block H1-block ▪ Dry mouth Orthostatic Weight gain ▪ Constipation hypotension Sedation/ ▪ Urinary retention Sedation drowsiness ▪ Mydriasis Sexual dysfunction ▪ Blurred vision ▪ Confusion TCA: Other Adverse Effects Adverse effects not fully explained by M-, alpha 1 -and H1-blocks are: ▪ Sexual dysfunction Caused by serotonin acting at 5-HT2a receptors ▪ Antidepressant effect of serotonin is via 5-HT1a receptors ▪ Weight gain Could also be due to remission of depression and/or direct stimulation of appetite TCA: Overdose TCA OD can lead to life-threatening cardiac arrhythmias ▪ FYI: Main mechanism is block of Na+ channels in myocardial cells, slowing propagation of the action potential ▪ What else can make TCA’s “hard on the heart”? Hint: Think about their mechanism of action and their receptor blockades SNRI’s: Venlafaxine Venlafaxine is also an SNRI It differs from TCA’s in the following ways: ▪ Also weakly inhibits dopamine reuptake ▪ No significant alpha 1, H1 or M-block Less likely to cause related adverse effects, including sexual dysfunction and weight gain (may cause weight loss) SSRI’s Most commonly prescribed antidepressant class Therapeutic mechanism? Adverse effects often related to M, α1, H1-block ▪ Receptor blocks less potent than with TCA’s, related adverse effects typically more mild Exception: sexual dysfunction is typically worse ▪ What is the role of serotonin? ▪ Additional NO (vasodilator) synthesis block Weight disturbances can include weight loss ▪ Transient, followed by potential long-term weight gain Does not have the same cardiotoxicity as TCA’s ▪ Does have the potential for serotonin syndrome SSRI’s: Serotonin Syndrome Serotonin syndrome can occur in response to increased serotonin levels ▪ Often caused by a combo of two drugs (such as?) Can also be caused by a “high-normal” dose in a sensitive individual ▪ Triad of symptoms (examples on next slide) Altered mental status Autonomic hyperactivity Neuromuscular abnormalities SSRI’s: Serotonin Syndrome Triad of symptoms (know bolded examples) ▪ Altered mental status Ex: Anxiety, agitation, disorientation ▪ Autonomic hyperactivity Diaphoresis, mydriasis, tachycardia, hyperthermia, hypertension, dramatic swings in pulse & bp, vomiting, and diarrhea ▪ Patient is often hot and sweating with a fast heart rate and high blood pressure that goes up and down ▪ Neuromuscular abnormalities Tremor, clonus, muscle rigidity, hyperreflexia, bilateral Babinski sign ▪ Hyperreflexia and clonus are particularly common and are more often pronounced in the lower extremities SSRI’s: Serotonin Syndrome How might you treat serotonin syndrome? ▪ Remove the causative agent Most cases typically resolve 24 hrs after ▪ Interfere with serotonin action Cyproheptadine can be given – what do you think its therapeutic mechanism might be? ▪ Symptomatic treatment Treat the agitation with benzodiazepines (BDZ) ▪ More on BDZ coming up soon! MAOI’s Historical use, some patients may still take them Therapeutic mechanism ▪ Block monoamine oxidase, the enzyme that metabolizes NE, resulting in higher NE levels Can induce a hypertensive crisis when combined with foods containing tyramine ▪ Tyramine has synergistic effect on NE levels How do high NE levels precipitate a hypertensive crisis? Other: Trazodone Trazodone ▪ Inhibits serotonin reuptake, but not considered an SSRI Also acts directly as an antagonist at serotonin 5-HT2A receptors ▪ What is the benefit of this antagonist action? ▪ Adverse effects H1-block and potent alpha 1 block effects ▪ Strong sedative effects May be useful for patients with anxiety, or for helping with sleep patterns of depressed patients Weight gain tends to be minimal Other: Bupropion Need to know brand names to distinguish therapeutic uses: ▪ Wellbutrin® = antidepressant ▪ Zyban® = smoking cessation therapy Mechanism of action: ▪ Relatively weak inhibition of NE and dopamine reuptake Important adverse effect: ▪ Dose-related seizure risk Suspected OD should lead to hospitalization Contraindication? Study Guiding Questions 1. Create a compare and contrast table for the definitions 2. Create a flow chart or alternative schematic linking the different neuropathology hypothesis of depression into a unified theory (where possible) 3. How does the neuropathology of bipolar disorders differ from the hypotheses of major depressive disorders? References ▪ Filatova E, et al. Major depression: one brain, one disease, one set of intertwined processes. Cells. 2021; 10(6): 1283 ▪ Kiran C, et al. Understanding deluisions. Ind Psychiatry J. 2009; 18(1): 3-18 ▪ Kim Y, et al. Molecular mechanisms of bipolar disorder: progress made and future challenges. Front Cell Neurosci. 2017; 11:30 ▪ Beckett C, et al. The role of immunomodulators in treatment-resistant depression: case studies. Cell Death Discovery. 2022; 8(367)