Antidepressants Drugs

Question Answer **What type of depressive disorder is this? "transient (days, weeks), appropriate response to event (usually disappointing event), low grade mood changes, minimal to no social/occupational dysfunction" Reactive Dysphoria **What type of depressive disorder is this?"longer lasting, appropriate/adaptive response to significant loss, minimal/mod/severe emotional distress (6-12mo),min distress can cont (1-3 yrs),social/occupational dysfunction but usually maintain obligations" Grief. also has significant dysphoria but self-esteem remains intact. "What type of depressive disorder is this? "significant and persistant dysphoria, ranging from minor to major depressive episodes, anxiety disorders can be comorbid, psychosis can co-present in severe MDEs" Clinical Depression **What are the three types of clinical depression? Minor depression, Major Unipolar Depression and Bipolar Disorders. **Describe Minor Depressions Have Dysthymia (persistant mild depression) for 2 years plus, and experience residuals of major depressive episodes (MDEs) **Describe Major Unipolar Depressions It is reactive, biological, reactive-biological and atypical **What are the three sub-types of bipolar disorders? BD1, BD2, BD NOS (not otherwise specified). **Describe the main differences between the three types of depressive disorders. Reactive Dysphoria is transient (days or weeks), while grief is long lasting significant dysphoria but self-esteem intact & clinical depression is significant and persistant dysphoria. Reactive is response to event while Grief is response to loss ** If MDEs are recurring what is this? Major Depressive Disorder (MDD) (different to major unipolar depression) **In NZ clinical depression affects 1 in 6 adults, 1 in 7 before the age of 24. Why is it important to recognise and treat depression? Because can have significant social and occupational costs which can be potentially fatal leading to suicide risk if left untreated. There are four key causes of major depression. What is this one? "altered reaction to stressor, adversely affects brain function, results in physiological symptoms (inability to react to stress after identificable stressor)" Reactive-Biological There are four key causes of major depression. What is this one? "illness, hormonal changes, drug effects, endogenous differences in brain, with physiological symptoms in the absence of identifiable psychological stressors" Biological (**depression is due to neural-level differences in the brain!) There are four key causes of major depression. What is this one? "Reaction to acute stressor, chronic stressor, past stressor or traumatic event(s)" Reactive (**depression is due to psychic conflict!) There are four key causes of major depression. What is this one? "Particular symptomology: reactive dysphoria, profound fatigue, hypersomnia, increased appetite, weight gain, hypersensitivity to interpersonal stress, with Bipolar disorder possible after" Atypical **Why is aetiology important? Because it dictactes how we treat the depressive disorder If the aetiology of a depressive disorder is reactive, how would we treat this? Using psychotherapy If the aetiology of a depressive disorder is biological, how would we treat this? Biologically change brain If the aetiology of a depressive disorder is reactive-biological, how would we treat this? Using both psychotherapy and biology If the aetiology of a depressive disorder is atypical, how would we treat this? need to figure out what is causing it to know whether to treat biologically or with psychotherapy. **There are 3 critical steps to treat depression. What are they? 1) Recognition of depression, 2) Agreement to therapy, 3) Adherence to therapy. Have to have all three for treatment to be successul **In the 1960s the Biological (Biogenic) Amine Hypothesis was developed. Explain this hypothesis! (in test) Hypothesis that depression is due to a deficiency in monoamine neurotransmitters, especially norepinephrine and seratonin. Hypothesis was based on case study observations **What are the two shortcomings of the Biogenic Amine Hypothesis?? 1) Not everyone that is depressed has deficiencies in these monoamine NTs (NET and 5-HT). 2) There is a mismatch time cause in therapy.When you give person drugs they do not feel better until month later but the drugs effect the brain in a couple of days. ** Later in the 2000s, the Neurogenic Theory of Depression was developed. Explain this theory. Says that depression is due to impaired neuronal repair and neurogenic capacities, in either response to stressors or non-induced. This is a newer theory but most drugs still work on the Biogenic Amine Hypothesis **What are the four targets of neuropharmacological interventions? 1) Synthesis, 2) Release, 3) Post-synaptic receptors, 4) Clearance : reuptake & metabolism The neurotransmitter Norepinephrine is a C___________________. Norepinephrine transporter is the specific reuptake transporter for norepinephrine. Norepinephrine is derived from _____________ and is synthesized initially from t________. Catecholamines, dopamine, tyrosine. Norepinephrine is enzymatically degraded by a monoamine oxidase (MOA) called ________ MOA-A **What are the two ways that NE is cleared? Pre-synaptic reuptake transporters (NET) and monoamine oxidase (MOA-A). **What are the TWO things to Note about Norepinephrine? That there is an alpha 2 (Gi) autoreceptor and that there is a NET (norepinephrine transporter) **Serotonin is synthesized from t______________. **what is a key receptor of 5-HT? And how is 5-HT cleared? Tryptophan, 5HT 1 and 5 which are metabotropic, Gi receptors. Cleared via presynaptic serotonin transporters called SERT and the monoamine oxidase called MAO-A. **What are the TWO things to Note about Serotonin? That there is a 5-HT 1 (Gi) pre-synaptic receptor and that there is a Serotonin transporter (SERT) **List five reasons for why we might be seeing higher rates of depression in the 21st Century? 1) Social acceptance of depression & the use of treatment 2) Direct-to-Consumer advertising, 3) World events (financial recession) 4) Internet-cyberbullying & social isolation 5) An undermining of the Westernized work – need for 'perfect' life. **One 1st generation treatment strategy used is Monoamine Oxidase Inhibitors (MOAIs). What is the Mechanism of Action? MAOS bind nonselectively and inversibly (cant be reversed) to MAO so inhibit the degradation of biogenic amines. **What is the Mechanism of Action for MOAIs? They act as antidepressants so created approved affect and activity levels in depressed people. The usual pattern is volitional improvement first and then affect improvement second. What is the major downfall of MAOIs? The use is limited by severe drug-drug and drug-food interactions. This means you have to be careful with other drug use and have a strict die which decreases compliance to take drug in first place **If taking MAO inhibitors for depression, ingesting certain foods can cause a serious hypertensive crisis (the '________ effect'). Therefore patients must follow a strict diet. Why would these foods interact badly with MAOI drugs? the 'cheese effect'. Because all of these foods contain tyramine, which is normally broken down by MAO. So by taking MOAIs tyrosine cant get broken down which is bad because tyrosine displaces NE from vesicular stores SO get a sudden surge of NE **By taking foods with tyrosine while taking MAOIs, the tyrosine cant be broken down. And because tyrosine displaces NE from vesicular stores what happens? You get a sudden surge of NE and this sudden high level of NE can cause rapid changes in Blood Pressure and Heart Rate = HYPERTENSIVE CRISIS ** **Tricyclic Antidepressants (TCAs) are a second 1st generation drug for depression. What is the mode of action? In depressed patients, it assists in elevating mood and activity, increases appetite and sleep and reduces morbid preoccupations **What is the Mechanism of Action for TCAs? 1) blocks NET and SERT to give antidepressant effects. 2) antagonist for Histamine and mACh receptors, and others (side effects of drowsiness etc) (unselective effect, unintentional) **In terms of the metabolism of TCAs a key point is that they have ____________ _____________ active metabolites that can last up to 4 days. **TCAs are still considered the 'gold standard' in terms of antidepressant efficacy – so why then have we gone on to develop more and more drugs? (2 reasons) Because of the two downfalls of TCAs: 1) side effects and 2) toxicity (cardiotoxicity can be fatal and this toxicity can be fatally exploited intentionally (suicide) or unintentionally (take too much by accident or be sensitive to low dose) **What are the two 1st generation anti-depressant drugs? Monoamin Oxidase Inhibitors and Tricyclic Antidepressants. **SSRIs are 1st or 2nd generation drugs? and stand for? and are inhibitors for what? 2nd, Selective Serotinin Reuptake Inhibitors, inhibit serotonin transporters **SSRIs have equal mode of action as TCAs but…..? (its a big benefit!) do not have any cardiotoxicity/fatality overdose risks. **What is the MOA for SSRIs? Blocks/inhibits SERT so creates an anti-depressant effect plus side effects **Fluoxetine (Prozac) is an example of a SSRI. What is key about its metabolism? And why is this bad? It can inhibit certain CYP isoforms. So if taking another drug that requires CYP to break it down this means the other drug wont be broken down and person will have too much of the other drug in their system. Prozac has a prolonged duration of action following discontinuation, but it also has a **slow onset of action (4-6 weeks). **Why is this 4-6 week delay worth noting? *it highlights a discrepency in the biogenic amino hypothesis. *it can contribute to non-compliance – stop taking as they take ages to start working. **There are a lot of side effects of SSRIs. What are the 3 majors ones of concern and what are they caused by? *activat. of 5HT2receptors=insomnia,anxiety,agitation,sexual dysfunction, 5HT syndrome symptoms *activat. of 5HT3 receptors=nausea&vomitng(GI upsets)*nonselectve activat= headaches,GI motility+/-,postural hypotension,fatigue,drymouth, dizines,REMreduction **Activation of what 5HT receptor is the worst? 5HT 2 as it causes sexual dysfunction **To reduce SSRI side effects it would be useful to combine an SSRI with a 5HT-2 receptor antagonist. What is an example of this? Nefazodone (Serzone) is a dual -action drug (SNRI + SSRI) that also has strong 5HT-2 receptor blocade properties. **Serotonin Syndrome is when there is too much 5HT in the system
–> altered cognition, altered behaviour, alters dysfunction. This can prompt **discontinuation of the drug (self- or GP-directed) which may precipitate….? Withdrawal symptoms called Serotonin Withdraw Syndrome **Define Serotonin Withdrawal Syndrome when long term use of SSRIs can generate physical dependence. **Since symptoms lessen with re-introduction of SSRI this is an example of ____________ _______________? negative reinforcement. **Many antidepressant drugs carry black-box warnings of increased suicide risk – initial phases of use – particularly in youth. **Why might these drugs be associated with this risk? (list the first 3 1)the drugs increase activity levels before affect improves so have the will to carry out suicide. 2) drug takes ages to work so frustrations/hopelessness leads to suicide. 3) less cost to a youth as a result of suicide compared to others with obligations Should antidepressants be our first line of defence for "feeling sad"? **When should antidepressants be prescribed? No. For clinical depression as it is a FATAL disease! **We have a host of antidepressant drugs available to us in 2014, yet we continue to design and develop more drugs? WHY? (4 reasons) 1) Side effects of current drugs that limit compliance. 2)Toxicity of current drugs. 3) Food-Drug interactions of current drugs that limit compliance. 4) From a business standpoint –> better drugs means more money. **What are some of the current targets in antidepressant drug development? (1)Add adjunct to therapy:give anther drug at same time as anti-depres.drug e.g.Abilify (blocks 5-HT so less sideeffects)or Modafinil orfolate(2)Use 5-HT1 receptor agonists such as Buspirone. (3) Use neuromodulators (4) incr. CREB-mediated transcription.