Wk1-Lecture3 & 4 Depression And Schizophrenia Handout PDF

1 PSYC2091 Biological  Psychology Dr. Hui YU ([email protected]) Week 1 Lecture 3 & 4 Psychological Disorders Depression & Schizophrenia  2 Heredity...

1 PSYC2091 Biological  Psychology Dr. Hui YU ([email protected]) Week 1 Lecture 3 & 4 Psychological Disorders Depression & Schizophrenia  2 Heredity The monoamine Depression hypothesis Antidepressant drugs Heredity The dopamine hypothesis Psychological Schizophren The glutamate Disorders ia hypothesis Antipsychotic Kolb, Whishaw & drugs Teskey Chapter 16  3 Affective Disorders  Or mood disorders, include depression and mania.  Major depression - feeling sad and helpless everyday for weeks and includes the following characteristics:  Little energy.  Feelings of worthlessness.  Suicidal thoughts.  Feelings of hopelessness.  Difficulty sleeping.  Difficulty concentrating.  Little pleasure  4 Depression  Similar symptoms can result from hormonal problems, head injuries, brain tumors, substance abuse, or other illnesses.  Absence of happiness is more reliable symptom than increased sadness.  Occurs at any age, but uncommon in children  Twice (to 3 times) as common in women  10% lifetime prevalence.  5 Depression  A few cases of depression are linked to viral infections.  Borna disease is a viral infection which may predispose people to depression (esp. bipolar)  Illustrates that many different causes can lead to similar behavioural results  6 Depression  Postpartum depression is depression after giving birth.  Affects about 20% of women and most recover quickly  More common among women who have suffered depression at other times.  May be associated with a drop in oestradiol and progesterone levels.  Testosterone drop in men also associated with increased probability  7 Depression  Depression is also associated with the following brain anomalies:  Larger ventricle size (loss of brain tissue)  Decreased total brain activity, particularly in the caudate nucleus and the dorsolateral prefrontal cortex  Increased activity in the amygdala and the prefrontal cortex  Manic episode of bipolar patient: an increase of brain activity  8 Is there a cure for depression  Depression on the rise? It seems that modern life style is associated with greater risk of anxiety and depression.  https://www.youtube.com/watch?v=MB5I X-np5fE  Changes must take place at all levels: biology is the at the most basic level.  9 Heredity of Depression  Studies of twins and adopted children suggest a moderate degree of heritability.  Some of the genes associated with depression are also associated with anxiety disorders, ADD, OCD, substance- abuse disorders, bulimia, migraine headaches, irritable bowel syndrome, and several other conditions.  Risk is elevated among relatives of women with early-onset depression (before 30).  10 Linking serotonin to Depression Discovered by clinical serendipity  11 The Monoamine Hypothesis of Depression  The monoamine hypothesis: depression involves reduced activity of monoamine neurotransmitters, especially at norepinephrine and serotonin synapses.  Focus is on serotonin in this module. MAO enzymes Adapted from: 12  Drug Action at ACETYLCHOLINE SYNAPSE Acetylcholine always excites skeletal muscles to contract. Agonists excite muscles, increasing muscle tone  Antagonists inhibit muscles, decreasing muscle tone  14 Serotonin Transporter Gene  One gene identified controls the serotonin transporter protein.  controls the ability of the axon to reabsorb the neurotransmitter after its release.  Two “short forms” of the gene are associated with an increased likelihood of depression after stressful events.  May alters people’s reactions to stressful events or make them more sensitive to environmental influences  15 Gene – Environment Interaction Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H.,... & Poulton, R. (2003). Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science, 301(5631),  16  The orchid and dandelion children  Some individuals are more susceptible than others to both negative (risk-prompting) and positive (development- enhancing) environmental conditions  Some children could have more Examples of sick leave due to poor environment environment than others in the and biological similar condition. interaction  Possible reasons:  stress hormones  neuro-plasticity and etc.  17 Tryptophan Hydroxylase-2  A hTPH2 mutation was discovered 10 times more frequent seen in major depression patients than in nondepressed controls (Zhang et al, 2005).  The hTPH2 mutation produces a defective form of protein that results in approximately 80% loss of function in serotonin production.  Depressed patients with this gene are not responsive to antidepressants that block reuptake of serotonin, simply because not enough serotonin is produced in the first place.  18 Antidepressant Drugs  Many drugs used to treat psychiatric disorders discovered by accident  Categories of antidepressant drugs include:  Tricyclics.  Selective serotonin reuptake inhibitors.  MAOI’s.  Atypical antidepressants.  19 Antidepressant Drugs  Tricylclics - operate by blocking transporter proteins that reabsorb serotonin, dopamine, and noradrenaline into the presynaptic neuron after release.  Examples: imipramine (Tofranil)  Also block histamine receptors, acetylcholine receptors, and certain sodium channels.  Creates side-effects (dry mouth, difficulty urinating, heart irregularities)  20 Antidepressant Drugs  Selective serotonin reuptake inhibitors (SSRIs) - works by blocking the reuptake of the neurotransmitter serotonin.  Examples: Fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa) and paroxetine (Paxil).  Work in a similar fashion to tricyclics but are specific to the neurotransmitter serotonin.  Milder side effects but same effectiveness  21 Antidepressant Drugs  Monoamine oxidase inhibitors (MAOI’s) - blocks the enzyme monoamine oxidase that metabolises monoamine neurotransmitters into inactive forms.  Blockage of the enzyme results in more of the transmitters in the presynaptic terminal available for release.  Usually prescribed if SSRI’s and tricyclics are not effective.  22 Antidepressant Drugs  Atypical antidepressants - a miscellaneous group of drugs with antidepressant effects and mild side effects.  Example: bupropion (Wellbutrin)  Works by inhibiting the reuptake of dopamine and to some extent, noradrenaline but not serotonin. Figure 4.6 Serotonergic Pathways in the Brain  24 Antidepressant Drugs  Studies indicate half of people show a good response within weeks after use of antidepressant drugs  About same percentage respond to therapy  30% respond to a placebo  Combination of both benefits only a slightly higher percentage  Little difference regarding the various types of antidepressant drug  25 Response to Treatment  26 Antidepressant Drugs  Benefits of antidepressant is greatest for people with severe depression.  Antidepressants are generally ineffective for people who suffered abuse, neglect, or other trauma during early childhood.  Usually respond better to psychotherapy  Use of antidepressants in children controversial  Most studies found ineffective and can sometimes increase suicidal thoughts  27 Antidepressant Drugs  Exactly how antidepressant drugs work is unclear.  Antidepressant alter synaptic activity quickly but the effects on behaviour are not derived until weeks later.  Reveals depression is not directly and solely the result of low serotonin levels.  Blood samples show normal levels of serotonin turnover in depressed people.  28 Antidepressant Drugs  In some depressed people, neurons in the hippocampus and the cerebral cortex shrink.  Behavioural effects of antidepressant drugs often take longer than the effect on our neurochemistry which happen within hours  One explanation is that antidepressant drugs increases the release of BDNF which promotes neuron growth and survival.  29 Other Treatment of Depression  Electroconvulsive therapy (ECT) is an electrically induced seizure that is used for the treatment of severe depression.  Used with patients who have not responded to antidepressant medication or are suicidal.  Applied every other day for a period of two weeks.  Side effects include memory loss.  30 Depression Summary  Depression cannot be explained by a single gene or single transmitter.  Monoamine transmitters may play important roles in depression to different degrees in different people.  Gene – environment interaction has to be considered.  31  Schizophrenia  32 Dreamland – can you tell it from reality? In most people, we can (or we think we can) compartmentalize the good/bad dreams from reality. You open your eyes in the morning, you know what happened in your dream was not real. How about if you cannot tell what is real and what is not? Your brain does NOT have separate systems producing “reality” vs. “dream”…  33 Schizophrenia  Schizophrenia is a disorder characterised by deteriorating ability to function in every day life and some combination of the following:  Hallucinations  Delusions  Thought disorder  Movement disorder  Inappropriate emotional expression  34 Schizophrenia  Causes are not well understood but include a large biological component.  Symptoms of the disorder can vary greatly.  Can be either acute or chronic:  Acute - condition has a sudden onset and good prospect for recovery.  Chronic - condition has a gradual onset and a long-term course.  35 Schizophrenia  Positive symptoms are behaviours that are present that should be absent  Two cluster of positive symptoms of schizophrenia include:  Psychotic  Disorganised  36 Schizophrenia  Negative symptoms are behaviours that are absent that should be present.  Weak social interaction.  Emotional expression.  Speech.  Working memory.  Negative symptoms are usually stable over time and difficult to treat.  37 Schizophrenia  Schizophrenia affects about 1% of the population and range in severity.  Occurs in all parts of the world, but is 10 to 100 times more common in the United States and Europe than in third-world countries.  More common in men than in women by a ratio of about 7 to 5 (or equal?).  More severe and earlier age of onset for men (early 20’s versus late 20’s). Schizophrenic Vision 38  39 Heredity  Twin studies suggest a genetic component, but does not depend on a single gene.  Monozygotic twins have a much higher concordance rate (agreement) than dizygotic twins.  But monozygotic twins only have a 50% concordance rate.  Other factors may explain the difference.  Greater similarity between dizygotic twins than siblings suggests a prenatal/postnatal environmental effect. 40 Genes Associated with Schizophrenia in a Large Database Analysis SOURCE: Allen et al. (2008) Genes Related Function Neurotransmissio n Dopamine receptors DRD1, DRD2, DRD4 Serotonin production TPH1 Serotonin transporter SLC6A4 NMDA glutamate receptor function DAO NMDA glutamate receptor subunit GRIN2B Glutamate release DTNBP1 GABAA receptor GABRB2 Enzyme that deactivates neurotransmitters, COMT e.g. dopamine Development MTHFR Enzymes involved in neural development PLXNA2 Axon guidance Anural Damage APOE Neurodegeneration IL1B Immune and inflammatory responses HP Immune and inflammatory responses TP53 Gene mutation prevention 41  42 The Dopamine Hypothesis  The dopamine hypothesis: schizophrenia involves excessive dopamine activity in the brain.  Reverse engineering: amphetamine overdose causes psychotic behaviours almost indistinguishable from schizophrenia (hallucinations and paranoid delusions), by increasing dopaminergic activity.  Research indicates increased activity specifically at the D2 receptor.  43 The Dopamine Hypothesis  Limitations of the dopamine hypothesis include the following:  Direct measurement of dopamine and its metabolites indicate generally normal levels in people with schizophrenia.  Antipsychotic drugs block dopamine within minutes but effects on behaviour gradually build over 2 to 3 weeks.  44 Dopaminergic Pathways in the Brain The mesolimbocortical system is a set of neurons that project from the midbrain tegmentum to the limbic system.  45 The Glutamate Hypothesis  The glutamate hypothesis of schizophrenia suggests the problem relates partially to deficient activity at glutamate receptors.  Especially in the prefrontal cortex.  In many brain areas, dopamine inhibits glutamate release or glutamate stimulates neurons that inhibit dopamine release.  Increased dopamine thus produces the same effects as decreased glutamate  46 The Glutamate Hypothesis  Schizophrenia is associated with lower than normal release of glutamate and fewer receptors in the prefrontal cortex and hippocampus.  47 The Glutamate Hypothesis  Effects of phencyclidine (PCP, aka Angel Dust) support glutamate hypothesis.  PCP works primarily as an NMDA receptor antagonist, where it blocks the activity of the NMDA receptor.  Low doses produce intoxication and slurred speech  Larger doses produce positive and negative symptoms  Produce little psychotic responses in preadolescents  produces relapse in people with prior schizophrenia  48 Antipsychotic Drugs  The mesolimbocortical system is a set of neurons that project from the midbrain tegmentum to the limbic system.  Site where drugs that block dopamine synapses produce their benefits.  Drugs also block dopamine in the mesostriatal system, which project to the basal ganglia.  Result is tardive dyskinesia, characterised by tremors and other involuntary movements.  49 Antipsychotic Drugs  Second-generation antipsychotics (atypical antipsychotics) are a class of drugs used to treat schizophrenia but seldom produce movement problems.  Examples: clozapine, amisulpride, risperidone, olanzapine, aripiprazole.  More effective at treating the negative symptoms and are now more widely used.  Have less effect on dopamine D receptors and 2 more strongly antagonise serotonin type 5-HT2 receptors.  50 Schizophrenia Summary  Schizophrenia cannot be explained by a single gene or single transmitter.  Dopamine and glutamate may play important roles in schizophrenia to different degrees in different people.  Schizophrenia involves multiple genes and abnormalities in dopamine, glutamate, serotonin and GABA.