mood stabilizers NROSCI 0081
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This 0 page Bundle was uploaded by Arielle Reiner on Thursday November 12, 2015. The Bundle belongs to NROSCI 0081 at University of Pittsburgh taught by Fanselow,Erika in Summer 2015. Since its upload, it has received 34 views. For similar materials see DRUGS AND BEHAVIOR in Neuroscience at University of Pittsburgh.
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Date Created: 11/12/15
Affective Disorders 11122015 2 main types Affective disorders aka mood disorders characterized by extreme positive andor negative moods There are 2 main categories of affective disorders 0 Major depression aka unipolar depression clinical depression recurrent episodes of negative mood negative thoughts and related physical symptoms 0 Bipolar disorder aka manicdepression or manicdepressive illness cyclical mood swings from depression to mania elation Mood disorders are common and have been described as early as 400 BC The Greeks referred to depression as quotmelancholiaquot meaning quotblack bilequot and knew it to be associated with anxiety and heavy alcohol use Risk factors for affective disorders Genetic contribution the amount of genetic contribution can be determined using studies of twins Concordance rate likelihood of 2 people sharing a trait or condition For identical twins the concordance rate for affective disorders is 65 same exact genes For fraternal twins the concordance rate for affective disorders is 20 not the same genes What does this concordance rate mean o It is concluded that the genetic contribution is about 4050 0 If genetics was the only determining factor the concordance between identical twins would be 100 but since it is about 65 this means that genetics does play a role but that genetic predisposition interacts with life events and conditions that might in uence the development of affective disorders Note that while there does appear to be a genetic contribution n speci c genes or sets of genes have been found that cause affective disorders Characteristics of major depression Prevalence of major depression about 1520 Mean age of onset is about 27 years Women are at a greater risk for depression than men but it is not understood why that is Major depression is experienced differently by different people In addition there appear to be subtypes of depression characterized by speci c clusters of symptoms Comorbid 2 or more conditions present simultaneously in the same person 0 Major depression is often comorbid with other conditions such as anxiety especially GAD and social anxiety andor alcohol abuse 0 Comorbidity of these disorders predicts more severe and persistent symptoms that are harder to treat Symptoms of major depression Common symptoms include 0 Feeling down and listless o Lacking energy to do basic things 0 A lack of interest in doing things previously enjoyed 0 These can be referred to as dysphoria sense of unease or dissatisfaction dys Greek for badillunhappy phoria Greek for havingbeing eu Greek for wellgood 0 These symptoms can be experienced outside of clinical depression as during bereavement 0 But in clinical depression the mood disorder is so severe that a person withdraws from life and most or all social interactions Subtypes of major depression Reactive depressionsituational depression depression in response to a life circumstance eg loss ofjob divorce death of a loved one Endogenous depression no obvious cause does not necessarily start in response to an event Postpartum associated with childbirth Dysthymic disorder milder form of depression lasting over 2 years Seasonal affective disorder depression symptoms occurring at a particular part of the year usually winter Psychotic involves depression with a break from reality Symptoms of major depression 0 Speci c physical symptoms 0 O O O 0 Loss of appetite Crying Diminished sex drive Either motor retardation or agitation Insomnia fatigue early morning awakening Speci c psychological symptoms 0 O O O 0 Thoughts of suicide Difficulty concentrating remembering making decisions Loss of interest in almost everything Feelings of hopelessness worthlessness sadness guilt desperation Anhedonia inability to experience pleasure in anything Course of major depression episodes and recurrence throughout life 0 An untreated episode of depression typically improves in 69 months Recurrence 5080 of people experiencing one episode of depression will experience another during their lifetime 0 With further episodes probability of recurrence increases 0 O 0 If a person has 1 episode of depression the likelihood of having a second is about 50 If 2 episodes likelihood of a 3rd is about 70 If 3 episodes likelihood of more is about 90 Untreated depression uni or bipolar can be fatal 0 The vast majority of people who commit suicide have an affective disorder about 65 have depression Suicide is the 10th leading cause of death in the US among people 10 years or older 0 Risk factors for suicide 0 000000 Family history of suicide History of abuse History of depression History of substance abuse Feelings of hopelessness Major life loss Social isolation Risk factors for depression 0 Stress O O lntense periods of environmental stress and anxiety often precede episodes of depression especially for the rst few episodes Depressed patients often have increased levels of stress hormones including cortisol which plays a role in preparing a person to have energy to respond to stress This is usually a transient effect with cortisol itself working as a brake to prevent constant preparation for dealing with stress This set point in cortisol levels and related hormones and molecules may be in uenced by early life traumas that move the normal set point for cortisol This makes a person have an overly responsive reaction to stress increasing the likelihood of later depression anxiety and alcohol abuse Additionally constantly elevated cortisol levels can damage the immune system organ function and the hippocampus Other factors 0 O 0 Blood relatives with a history of depression bipolar disorder alcoholism or suicide History of other mental health disorders such as anxiety disorder eating disorders or post traumatic stress disorder Traumatic or stressful events such as physical or sexual abuse the death or loss of a loved one a difficult relationship or nancial problems 0 Abuse of alcohol or illegal drugs Certain personality traits such as low self esteem and being too dependent self critical or pessimistic Childhood trauma or depression that started when you were a teen or a child Being lesbian gay bisexual or transgender in an unsupportive situation Serious or chronic illness including cancer stroke chronic pain or heart disease Certain medications such as some high blood pressure medications or sleeping pills talk to your doctor before stopping any medication Bipolar disorder Alternating periods of mania and depression Lifetime prevalence is about 1 Rates of bipolar disorder are the same in women and in men 0 Age of onset is typically 2030 years of age 0 Episodes tend to recur throughout the lifespan Symptoms of mania Common psychological symptoms of mania 0 000 O Feelings of elation faultlessness full of fun bursting with energy Grandiose thinking Unlimited con dence Racing thoughts and ideas Can include irritability belligerence impatience Common physicalbehavioral symptoms for mania 0 Signi cantly reduced need for sleep OO 0 Extremely talkative Impulsive decisions High risk behavior including reckless driving buying sprees foolish business investments In some cases mania can involve a great deal of creativity and productivity Characteristics of bipolar disorder Bipolar I at least 1 episode of mania usually also alternating with depressive episodes 0 Bipolar hypomania not as extreme as mania alternating with depressive episodes 0 Related cyclothymic disorder milder form of bipolar disorder with patients alternating between hypomania and milder depression 0 Notes manic or hypomanic symptoms can sometimes occur at the same time as depressive symptoms knows as a mixed state Kindling theory cycles of mania and depression alter the brain and predispose it to further episodes Risk factors for bipolar disorder and common comorbid conditions 0 Risk factors similar to those for major depression but possibly with a stronger genetic contribution of about 3080 0 O O 0 Having a first degree relative such as a parent or sibling with bipolar disorder Periods of high stress Drug or alcohol abuse Major life changes such as the death of a loved one or other traumatic experiences 0 Common comorbid conditions 0 O 0 Anxiety disorders examples include social anxiety disorder generalized anxiety disorder PTSD ADHD has symptoms that overlap with bipolar disorder and for this reason bipolar disorder can be difficult to differentiate from ADHD or someone may have both Addiction or substance abuse many people with bipolar disorder also have alcohol tobacco or drug problems Drugs or alcohol may seem to ease symptoms but they can actually trigger prolong or worsen depression or mania 0 Physical health problems including heart disease thyroid problems or obesity Affective disorder spectrum An open hotly debated question in psychiatry and psychiatric research is there a continuum encompassing the bipolar disorder variants and major depression Medications for these disorders do overlap somewhat but can also cause harm if someone is misdiagnosed Also these types of frameworks guide diagnosis research content funding and policy Questions being askeddebated is unipolar major depression different from the depression experienced in bipolar disorder 0 Current model these are different in both origin and symptoms 0 Alternative model bipolar disorder is depression with comorbid mania or vice versa There are many studies seeking a biomarker that can be used to differentiate between unipolar and bipolar depressants but what if they are not different in the rst place Questions being askeddebated do some people who initially appear to have unipolar depression later develop bipolar disorder and if so can one predict whether this will happen 0 The answer to this depends in large part on the de nitions one is using for diagnosing these disorders 0 Again often the drugs given to treat bipolar disorder manic or depressive phases are different from those for unipolar depression Mood stabilizersantidepressants 11132015 What neurochemical changed cause affective disorders 0 The monoamine hypothesis proposed that depression is caused by a reduction in monoamine levels in the CNS and that mania was caused by an increase in monoamines Many types of antidepressants do alter the monoaminergic systems 0 Other evidence supporting the monoamine hypothesis 0 Depressed patients had lower levels of the metabolites of norepinephrine and serotonin in their CSF o The manic like activity produced by amphetamine and cocaine is correlated with increases in dopamine and norepinephrine at the synapse o The monoamine hypothesis was the best idea when it was developed largely in the 19705 but is likely overly simplistic and has not been shown to be causal Beyond the monoamine hypothesis 0 For the monoamine hypothesis it is still not understood 0 Which of the monoamines is most closely involved in depression 0 How the monoamines are related to cause the symptoms of depression 0 Why the neurochemical effects of antidepressants can happen quickly hours but the therapeutic effects take weeks to happen 0 Other issues to consider 0 The noradrenergic and serotonergic neurons in the brainstem can in uence one another 0 Depression is not a homogenous illness Symptoms can differ by person and even for a given person over time o Other hypotheses about the neurochemical basis for depression 0 Hormonal dysregulation caused by stress 0 Chemicals that help neurons grow and change synapses are decreased The monoamine hypothesis 0 Focus on serotonin 0 Why would a decrease in serotonin levels be a likely culprit in causing depression Serotonin affects emotionality and responses to negative consequences Serotonin is involved in regulating sleep and appetite Low levels of serotonin metabolites are found in brains of people with depression and particularly in brains of people who committed suicide 0 However low levels of serotonin do not lead to depression in all people If a drug is given that transiently reduces serotonin production by 7080 Patients with depression but who were in remission ie not currently depressed would have a recurrence of depression symptoms Healthy people with a family history of depression also showed symptoms of depression Healthy people with no family history of depression did not get symptoms of depression Thus only having low levels of serotonin in the brain is not sufficient to cause depression symptoms 0 A possible genetic contribution The gene for the serotonin reuptake transporter has 2 forms a short and a long a The short version is associated with depression but only if there has also been increased stress in someone s life I Could this be part of the reason some people get depression in response to a negative life event whereas others do not Involvement of norepinephrine a No consistent ndings about whether norepinephrine levels are altered in patients with depression D But patients treated with norepinephrine reuptake inhibitors can have a reduction in symptoms Interactions between the noradrenergic and serotonergic systems 0 One part of the brainstem sends norepinephrine to the brain and another sends serotonin to the brain 0 There are neurons that let these 2 areas communicate with one another suggesting they can in uence one another Antidepressant ef cacy and administration 0 Well designed research studies show that no one type of antidepressant medication is more effective than another 0 There are no good ways to predict which drug would be best for a given patient 0 About 65 of patients with depression are helped by antidepressant medications 0 Symptoms are not always eliminated just decreased o It can often require trying several types of antidepressant medications to nd one that works for a given patient 0 One strategy is to combine 2 or more antidepressants Differences in the neurobiological effects of each type of antidepressant means that they affect different types of symptoms and different side effects 0 Current antidepressants require chronic administration usually daily o It is often recommended that antidepressant medications be continued after symptoms go away to prevent relapse 0 Some patients continue inde nitely if relapse is frequent for them Pharmacological treatments for affective disorders Antidepressants 0 Four main groups of pharmacological antidepressant medications Monoamine oxidase inhibitors Tricyclic antidepressants Second generation antidepressants have 2 types a Atypical antidepressants n Selective monoamine reuptake inhibitors Third generation antidepressants I Still under development and study 0 Non pharmacological treatments for depression ECT VNS Sleep deprivation Transcranial magnetic stimulation Monoamine oxidase inhibitors MAOls These drugs were discovered in the 19505 by observing that a tuberculosis drug iproniazid led to elevated mood not just from its effects on tuberculosis o The way iproniazid works in my inhibiting monoamine oxidase MAO 0 Found in axon terminals among other places in the body 0 Enzyme that metabolizes monoamines in the axon terminal that are not packaged into vesicles 0 Affects dopamine norepinephrine and serotonin neurons 0 Thus if MAO is inhibited ie if it is prevented from doing its job there is more monoamine neurotransmitter to be put into vesicles and released 0 Antidepressant effects are not only due to this direct in uence on monoamine availability 0 MAOls can take several weeks to reach a therapeutic effect Neurotransmitter metabolism Neurotransmitters can be broken down by enzymes 0 One example is monoamine oxidase which breaks down monoamines in the presynaptic axon terminal MAOI side effects MAOls have side effects some of which can be dangerous 0 Insomnia o Overeatingweight gain 0 Use of any other drug that increases norepinephrine can cause a dangerous stimulant effect eg cold medications anti asthma drugs amphetamines cocaine etc o MAO is also used by the liver so decreasing it there can prevent degradation of some molecules in foods eg cheeses certain meats pickled products and various other foods and this can cause high blood pressure and strokes o MAOls also inhibit other enzymes so drugs such as alcohol and opioids can have prolonged and intensi ed effects 0 But they can be used with dietary restrictions in patients who do not respond to other antidepressants MAOls can also be used to treat anxiety and help with mood for patients with eating disorders MAOI examples nardil marplan parnate Tricyclic antidepressants TCAs TCAs bind to presynaptic neurotransporter proteins which inhibits reuptake of neurontransmitters into the presynaptic neuron This means neurotransmitters stay in the synaptic cleft longer and have more effect on the postsynaptic receptors Some TCAs block both norepinephrine and serotonin while others preferentially block one of these Like MAOls TCAs require several weeks to take effect All TCAs are effective antidepressants but they cause different side effects 0 In addition to affecting norepinephrine and serotonin TCAs also Block histamine receptors causes sedation fatigue Block acetylcholine receptors dry mouth confusion impaired memory blurred vision Cardiovascular problems TCAs have a small margin of safety they can be fatal at 10x the therapeutic dose TCA example imipramine Second generation antidepressants These were developed to try to create antidepressants with fewer side effects They were developed to be more selective than MAOls or TCAs 0 They do have fewer and less dangerous side effects 0 These also have a larger therapeutic index so are safer for suicidal patients 0 They are not more effective than MAOls or TCAs and do not reduce depression symptoms faster Still takes a few weeks 0 These include selective serotonin reuptake inhibitors SSRls and dual norepinephrineserotonin modulators o Eg Prozac Zoloft paxil Neurotransmitter reuptake o Neurotransmitter is removed from the synaptic cleft by being brought back into the presynaptic neuron via transporter molecules in the cell membrane Selective serotonin reuptake inhibitors SSRls SSRls block the presynaptic reuptake transporter for serotonin 0 Currently SSRls are often the rst choice among antidepressants Side effects 0 Anxiety paradoxically SSRls can also be used to treat anxiety 0 Movement disorders 0 Insomnia 0 Sexual dysfunction occurs in 4070 of patients and is a frequent reason for stopping SSRls o Serotonin syndrome disorientation confusion movement problems exaggerated autonomic functions such as elevated blood pressure and increased heart rate Dual norepinephrineserotonin modulators More effective than enhancing a single monoamine o Eg Cymbalta remeron increases release of both norepinephrine and serotonin also blocks a speci c subset of serotonin receptors works as well as TCAs but has fewer side effects Third generation antidepressants 0 Third generation antidepressants are still in the development and testing stages One goal for these is to have them reduce symptoms faster Example IV ketamine as discussed in the last lecture O O Ketamine is a glutamate receptor antagonist Can reduce depression symptoms in a few hours 0 Therapeutic effects can last from 1 to 3 weeks far longer than 0 the half life for ketamine Effects might be ketamine induced signs of synaptic formation Mood stabilizers Mood stabilizers are used to reduced manic and depression symptoms in bipolar disorder It is not entirely clear why mood stabilizers can reduce emotional extremes in both directions mania and depression Mood stabilizer treatment is often life long because bipolar disorder is highly recurrent Lithium O O O O Lithium has no effect on mood or behavior in healthy individuals ls effective in 5060 of patients with bipolar disorder Can dramatically reduce mania Not as good at treating depression in bipolar disorder so is often used together with an antidepressant Can also prevent future episodes of mania and depression Reduces suicide and hospital stays in patients with bipolar disorder Lithium is not metabolized it is a single ion Lithium has a very low therapeutic index and blood levels must be monitored frequently to prevent reaching toxic levels Side effects Milder impaired concentration and memory tremor weight gain Toxic kidney dysfunction confusion seizures coma death
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