Mood Disorders
• Mental illness results from the combination of biological predisposition and experiences.
– Both play an important role.
• A solid understanding of both aspects is necessary for successful treatment.

Mood Disorders
• Major depression - feeling sad and helpless everyday for weeks and includes the following characteristics (DSM-IV):
– Little energy.
– Feelings of worthlessness.
– Suicidal thoughts.
– Feelings of hopelessness.
– Difficulty sleeping.
– Difficulty concentrating.
– Little pleasure

Mood Disorders
• 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 as common in women
• 10% lifetime prevalence.

Mood Disorders
• 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).

Mood Disorders
• Predisposition depends on a variety of genes.
• Effects of these genes have varied between studies

Mood Disorders
• 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

Mood Disorders
• A few cases of depression are linked to viral infections.
• Borna disease is a viral infection which may predispose people to depression
• Illustrates that many different causes can lead to similar behavioral results

Mood Disorders
• 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 estradiol and progesterone levels .
• Testosterone drop in men also associated with increased probability

Mood Disorders
• Depression is also associated with the following brain activity:
– Decreased activity in the left prefrontal cortex.
– Increased activity in the right prefrontal cortex.

Mood Disorders
• Many drugs used to treat psychiatric disorders discovered by accident
• Categories of antidepressant drugs include:
1. Tricyclics.
2. Selective serotonin reuptake inhibitors.
3.
MAOI’s.
4. Atypical antidepressants.

Mood Disorders
• Tricylclics - operate by blocking transporter proteins that reabsorb serotonin, dopamine, and norepinephrine 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)

Mood Disorders
• Selective serotonin reuptake inhibitors
(SSRIs) works by blocking the reuptake of the neurotransmitter serotonin.
– Examples: Fluoxetine (Prozac), setraline
(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

Mood Disorders
• Monoamine oxidase inhibitors (MAOI’s) blocks the enzyme monoamine oxidase that metabolizes catecholimines and serotonin 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.

Mood Disorders
• 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, norepinephrine but not serotonin.

Mood Disorders
• St. Johns’ wort is an herb that is often used as a treatment for depression by many.
• Marketed as a nutritional supplement and not regulated by the FDA.
• Believed to work in the same way as SSRI’s but effectiveness is controversial.
• Increases the effectiveness of a liver enzyme that can decrease the effectiveness of other medications.

Mood Disorders
• 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

Mood Disorders
• 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

Mood Disorders
• Exactly how antidepressant drugs work is unclear.
• Antidepressant alter synaptic activity quickly but the effects on behavior 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.

Mood Disorders
• In some depressed people, neurons in the hippocampus and the cerebral cortex shrink.
• Behavioral effects of antidepressant drugs often take longer than the effect on our neurochemisrty which happen within hours
• One explanation is that antidepressant drugs increases the release of BDNF which promotes neuron growth and survival.

Mood Disorders
• 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.
– Memory loss can be minimized if shock is localized to the right hemisphere.

Mood Disorders
• A drawback of ECT is the high risk of relapse.
• Usually accompanied with drug treatment, psychotherapy and periodic ECT after initial treatment.
• How exactly ECT relieves depression is unknown.
• altering of the expression of genes in the hippocampus and frontal cortex is suggested.

Mood Disorders
• “Receptive transcranial magnetic stimulation” is another treatment for depression in which an intense magnetic field is applied to the scalp, to stimulate the neurons.
• Like ECT in its level of effectiveness.
• Exact mechanisms of its effects are also unknown.

Mood Disorders
• Disruption of sleep patterns is common in depression.
– Typically fall asleep but awaken early and are unable to get back to sleep.
– Enter REM sleep within 45 minutes and have an increased average number of eye movements during REM sleep.
• Sleep pattern disruption also increases the likelihood of depression and is a lifelong trait of people that are depressed.

Mood Disorders
• A night of total sleep deprivation is the quickest method of relieving depression.
• Increases proliferation of new neurons in the hippocampus
• Half become depressed again after the next night’s sleep.
• Extended benefits derived from altering sleep schedule on subsequent days and combining sleep alteration with drug therapies
• Exact mechanism are not unknown.

Mood Disorders
• Hormone leptin has shown some promise as an alternative treatment.
• Regular exercise is also effective.
• Increases blood flow to the brain.
• Reduces the effects of stress.
• Can be combined with other treatments to magnify benefits.

Mood Disorders
1. Unipolar disorder is characterized by an alternating states of normality and depression.
2.
Bipolar disorder (manic-depressive disorder) is characterized by the alternating states of depression and mania.
– Mania restless activity, excitement, laughter, self-confidence, rambling speech, and loss of inhibition.

Mood Disorders
• Bipolar disorder I - characterized by full blown episodes of mania.
• Bipolar disorder II - characterized by much milder manic phases, called hypomania, of which anxiety and agitation are the primary symptoms.
• Each approximately 1% of people.
• Average age of onset is in the early 20’s.
• Brain’s use of glucose increases during periods of mania and decreases during periods of depression.

Mood Disorders
• Research suggests a heritability basis for bipolar disorder (Craddock & Jones, 1999).
• Twin studies suggest monozygotic twins share a 50% concordance rate.
• Dizygotic twins, brothers, sisters or children share a concordance rate of 5-10%.
• Comparison of chromosomes have identified several genes that are somewhat more common in people with the disorder.
• Genes simply increase the risk but do not cause the disorder.

Mood Disorders
• Treatments for bipolar include:
1. Lithium - a salt that stabilizes mood and prevents relapse in mania or depression
2. Drugs - anticonvulsant drugs such as valproate (depakote) and carbamazepine
• Drugs work by:
• decreasing glutamate activity
• blocking the synthesis of the brain chemical arachidonic acid, which is produced during brain inflammation.

Mood Disorders
• Seasonal affective disorder (SAD) is a form of depression that regularly occurs during a particular season.
• Patients with SAD have phase-delayed sleep and temperature rhythms; most depressed people have phase-advanced patterns.
• Treatment often includes the use of very bright lights.
• Most likely explanation is that the light affects serotonin synapses and alters circadian rhythms.

Schizophrenia
• Schizophrenia is a disorder characterized by deteriorating ability to function in every day life and some combination of the following:
– Hallucinations
– Delusions
– Thought disorder
– Movement disorder
– Inappropriate emotional expression
 (DSM-IV)

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.

Schizophrenia
• Positive symptoms are behaviors that are present that should be absent
• Two cluster of positive symptoms of schizophrenia include:
1. Psychotic
2. Disorganized

Schizophrenia
1. Psychotic - consists of delusions and hallucinations.
– Delusions: unfounded beliefs
– Hallucinations: abnormal sensory experiences associated with increased activity in the thalamus, hippocampus and cortex
2. Disorganized - inappropriate emotional displays, bizarre behaviors and thought disorders (difficulty using and understanding abstract concepts).

Schizophrenia
• Negative symptoms are behaviors 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.

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.
• More severe and earlier age of onset for men
(early 20’s versus late 20).
– May be related to release of dopamine

Schizophrenia
• 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.

Schizophrenia
• Adopted children studies suggest a genetic role, but prenatal environment of the biological mother can not be discounted.
• Attempt to schizophrenia to an identified gene have provided inconsistent results.
• Research has identified a gene for childonset schizophrenia but cases are rare.
• Schizophrenia most likely depends on a combination of genes or different genes in different families.

Schizophrenia
• Researchers have identified more than a dozen genes that appear to be more common in people with schizophrenia.
• DISC1 (disrupted in schizophrenia 1) gene controls the rate of generation of new neurons in the hippocampus.
• Another gene important for brain plasticity and development.
• New gene mutations are also an explanation.
(microdeletions and microduplications more common)

Schizophrenia
• The neurodevelopmental hypothesis suggests abnormalities in the prenatal or neonatal development of the nervous system.
• Leads to subtle abnormalities of brain anatomy and major abnormalities in behavior.
• Abnormalities could result from genetics, trouble during prenatal development, birth, or early postnatal development.
• Environmental influences later in life aggravate the symptoms.

Schizophrenia
• Supporting evidence for the neurodevelopmental hypothesis includes:
– Several kinds of prenatal or neonatal difficulties are linked to later schizophrenia.
– People with schizophrenia have minor brain abnormalities that originate early in life.
– Abnormalities of early development could impair behavior in adulthood.

Schizophrenia
• Risk factors increasing the likelihood include:
– Poor nutrition of the mother during pregnancy.
– Premature birth.
– Low birth weight.
– Complications during delivery.
– Head injuries in early
– Extreme stress of mother during pregnancy

Schizophrenia
• Mother/child blood type differences increase the likelihood of schizophrenia.
• If the mother has a Rh-negative blood type and the baby is Rh-positive, the child has about twice the probability of developing schizophrenia.
– Response weak in first child but stronger in later pregnancies

Schizophrenia
• The season-of-birth effect refers to the tendency for people born in winter to have a slightly (5% to 8%) greater probability of developing schizophrenia.
– More pronounced in latitudes far from the equator.
– Might be explained by complications of delivery, nutritional factors, or increased likelihood of viral infection in mother

Schizophrenia
• Viral infections in mother can:
• Increase cytokines in mother that impair brain development of fetus
• Cause fever which damages the fetal brain
• Other infections during childhood can also increase risk
– Taxoplasma gondii

Schizophrenia
• Associated with mild brain abnormalities:
– Strongest deficits found in the left temporal and frontal lobe of the cortex.
– Thalamus smaller than average
– Larger than normal ventricles (especially common in those with complications during birth)
– dorsolateral prefrontal cortex (areas that mature slowly)
• Schizophrenics have deficits in working memory and attention.

Schizophrenia
• At a microscopic levels, smaller cell bodies than usual, especially in the hippocampus and prefrontal cortex.
• Differences in lateralization include the right planum temporale of the temporal lobe being the same size or larger than the left.
– Usually the right side is larger.
• Also lower than normal overall activity in the left hemisphere, suggesting subtle changes in early development.

Schizophrenia
• Overall, abnormalities are small and vary from person to person.
• Reasons behinds brain abnormalities are not certain.
– May be due to substance abuse.
• Results are inconclusive if brain damage associated with schizophrenia is progressive.
• No sign of neuron death

Schizophrenia
• Schizophrenia typically develops after the age of 20 but many show sign at an earlier age.
– Deficits in attention, memory and impulse control.
• Prefrontal cortex damage may not show signs of damage until later.
– Structure matures slowly and does not do much at an earlier age.
– Neurodevelopmental hypothesis is thus plausible but not firmly established.

Schizophrenia
• Antipsychotic/neuroleptic drugs are drugs that tend to relieve schizophrenia and similar conditions.
• Chlorpromazine (thorazine) is a drug used to treat schizophrenia that relieves the positve symptoms of schizophrenia.
– Relief usually experienced 2-3 weeks after taking the drug, which must be taken indefinitely.

Schizophrenia
• Two chemical families of drugs used to treat schizophrenia include:
1. Phenothiazines - includes chlorpromazine
2. Butyrophenones - includes halperidol
(Haldol)
• Both drugs block dopamine synapses.

Schizophrenia
• The dopamine hypothesis of schizophrenia suggests that schizophrenia results from excess activity at dopamine synapses in certain areas of the brain.
• Substance-induced psychotic disorder is characterized by hallucinations and delusions resulting from repeated large doses of amphetamines, methamphetamines, or cocaine.
– Each prolongs activity of dopamine at the synapse, providing further evidence for dopamine hypothesis.

Schizophrenia
• Research indicates increased activity specifically at the D
2 receptor.
• 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 behavior gradually build over 2 to 3 weeks.

Schizophrenia
• 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.

Schizophrenia
• Schizophrenia is associated with lower than normal release of glutamate and fewer receptors in the prefrontal cortex and hippocampus.
• Further support comes from the effects of phencyclidine (PCP/angel dust).

Schizophrenia
• Effects of phencyclidine (PCP) support glutamate hypothesis.
• Low doses produce intoxication and slurred speech
• Larger doses produce positve and negative symptoms
• Produce little psychotic responses in preadolescents
• produces relapse in people with prior schizophrenia
• Glycine increases effectiveness of glutamate

Schizophrenia
• 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, characterized by tremors and other involuntary movements.

Schizophrenia
• 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
2 receptors and more strongly antagonize serotonin type
5-HT
2 receptors.

Schizophrenia
• 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.