Mood Disorders and Schizophrenia

Biological vs. social models of mental disordersDepression

Unipolar Symptoms Biochemistry: Catecholamines, serotonin,histamine Treatment: Tricyclics and MAO inhibitors (Prozac)Bipolar Symptoms Biochemistry: Catecholamines and cholinergics Treatment: Lithium, anticonvulsants

SchizophreniaSymptoms: Positive & negativeBiochemistry: Excess dopamine Treatment: Phenothiazines

Mood Disorders

• Major depression - feeling sad and helpless every day for weeks at a time and includes:– Little energy.– Feelings of worthlessness.– Suicidal thoughts.– Feelings of hopelessness.– Difficulty sleeping.– Difficulty concentrating.– Little pleasure from sex or food.

Mood Disorders

• Similar symptoms can result from hormonal problems, head injuries, brain tumors, or other illnesses.

• Often comorbid with other disorders such as schizophrenia, substance abuse, anxiety or Parkinson’s.

• Absence of happiness is more reliable symptom than increased sadness.

• Occurs at any age.• Twice as common in women and about 10%

lifetime prevalence.

Mood Disorders

• Studies of twins and adopted children suggest moderate heritability.

• Some 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 elevated among relatives of women with early-onset depression (before 30).

Mood Disorders

• Predisposition depends on a variety of genes.

• One identified gene leads to an 80% decrease in the brain’s ability to produce serotonin.– Most depressed people do not have this gene.– Those who have the gene have a higher

predisposition.

Mood Disorders

• Another gene controls the serotonin transporter protein.– Protein controls the ability of the axon to

reabsorb the neurotransmitter after its release.• Two “short forms” of the gene are

associated with increased likelihood of depression after stressful events.– Perhaps alters the way people react to stressful

events.

Mood Disorders

• Specific hormones are also involved with depression.

• A likely trigger for an episode of depression is stress and the release of cortisol.

• Prolonged elevated levels exhaust the body’s energy, impair sleep and immune function.– Set the stage for an episode of depression.

Fig. 15-6, p. 460

Mood Disorders

• Postpartum depression is depression after giving birth.

• Affects about 20% of mothers. Most recover quickly.

• .1% enter a serious, long-lasting depression.• More common among women who:

– have suffered depression at other times.– experience sever discomfort during the times around

menstruation.• May be associated with a drop in estradiol and

progesterone levels.

Mood Disorders

• Childhood depression is equally common in both boys and girls.

• After puberty, depression is twice as common in females.

• The finding is consistent across cultures, suggesting a biological factor.

Mood Disorders

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

• Many people become seriously depressed after left-hemisphere damage.

• Occasionally, people with right hemisphere damage become manic.

Mood Disorders

• Some cases of depression may be linked to viral infection.

• Borna disease is an infection with behavioral effects of periods of frantic activity alternating with periods of inactivity.

• Found in a variety of species of animals.• Found more commonly in depressed people or

people with bipolar.• Predisposes people to various psychiatric

disorders.

DepressionA more accurate name for mood disorders like depression and bipolar disorder might be hypothalamic-pituitary-adrenal disorders. They affect

* The hypothalamus -- the "main switch" that affects sleep, hunger, thirst, and sex drive,* The pituitary gland -- the master gland that controls hormonal secretions, and* The adrenal glands -- two glands that affect stress and steroid hormones, growth, cell repair, sugar consumption, and immune system functioning.

Mood Disorders

• Categories of antidepressant drugs include:1. Tricyclics.2. Selective serotonin reuptake inhibitors.3. MAOI’s.4. Atypical antidepressants.

Fig. 15-9, p. 463

Mood Disorders

• Tricylclics - a category of antidepressant drugs that prevent the presynaptic neuron from reabsorbing serotonin, dopamine, or norepinephrine after release.– Examples: imipramine (Tofranil)

• Block histamine receptors, acetylcholine receptors, and certain sodium channels.

• Side-effects include dry mouth, difficulty urinating, heart irregularities, and possible fatal overdose potential.

Mood Disorders

• Selective serotonin reuptake inhibitors (SSRIs) - a class of antidepressant drugs that block 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 specific to the neurotransmitter serotonin.

• Mild side effects include nausea, headache and occasional nervousness.

Mood Disorders

• Monoamine oxidase inhibitors (MAOI’s) - a class of antidepressant drugs that blocks the enzyme monoamine oxidase.

• Monoamine oxidase metabolizes catecholimines and serotonin into inactive forms.

• Blockage of the enzyme results in more transmitter in the presynaptic terminal available for release.

• Usually prescribed after SSRI’s and tricyclics.

Mood Disorders

• Atypical antidepressants - a miscellaneous group of drugs with antidepressant effects and mild side effects.– Example: bupropion (Wellbutrin)

• Works by inhibiting reuptake of dopamine and to some extent norepinephrine but not serotonin.

• Nefazodone is an antidepressant drug which specifically blocks serotonin type 2A receptors and also weakly blocks reuptake of serotonin and norepinephrine.

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 most likely depend on two slow changes in the brain:1. Drug increases the release of BDNF which

promotes neuron growth and survival.2. Desensitize autoreceptors and thereby

increase release of the neurotransmitter.

Mood Disorders

• Electroconvulsive therapy (ECT) is an electrically induced seizure used for treatment of severe depression.

• Used with patients who have not responded to antidepressant medication or are suicidal.

• Applied every other day for 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.• Animal studies suggest an altering of expression

of genes in the hippocampus and frontal cortex.

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.

Fig. 15-11, p. 466

Mood Disorders

• A night of total sleep deprivation is the quickest known method of relieving depression.

• Half who experience relief become depressed again after the next night’s sleep.

• Extended benefits can be derived from altering sleep schedule on subsequent days.

• Combining sleep alteration with drug therapies can provide long-lasting benefits.

• Exact mechanism of how sleep disruption relieves depression is unknown.

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 - full blown episodes of mania.• Bipolar disorder II - milder manic phases, called

hypomania; anxiety and agitation are the primary symptoms.

• Affects approximately 1% of people.• Average age of onset is early 20’s.• Brain’s use of glucose increases during periods of

mania and decreases during periods of depression.

Bipolar Symptoms

A Long-Term Illness That Can Be Effectively TreatedEven though episodes of mania and depression naturally come and go, bipolar disorder is a long-term illness that currently has no cure. Staying on treatment, even during well times, can help keep the disease under control and reduce the chance of recurrent, worsening episodes.

Mood Disorders

• Research suggests a heritability for bipolar disorder (Craddock & Jones, 1999).

• Monozygotic twins share a 50% concordance rate.• Dizygotic twins, brothers, sisters or children share

a concordance rate of 5-10%.• Several genes are somewhat more common in

people with the disorder.• Genes 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 depression2. Drugs - anticonvulsants such as valproate

(depakote) and carbamazepine Usually prescribed for bipolar II.

• All three drugs block synthesis of arachidonic acid, which is produced during brain inflammation.

Mood Disorders

• Seasonal affective disorder (SAD) is depression that occurs during a particular season.

• SAD Patients have phase-delayed sleep and temperature rhythms; most depressed people have phase-advanced patterns.

• Treatment often includes use of very bright lights.• Most likely explanation is that the light stabilizes

circadian rhythms.

Fig. 15-13, p. 468

Schizophrenia

• Schizophrenia is a disorder characterized by deteriorating ability to function in everyday life and some combination of:– 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 acute or chronic:

– Acute - sudden onset and good prospect for recovery.

– Chronic - gradual onset and a long-term course.

Schizophrenia

• Two clusters of positive symptoms of schizophrenia:

1. Psychotic 2. Disorganized

Schizophrenia

1. Psychotic - delusions and hallucinations.– Delusions: unfounded beliefs– Hallucinations: abnormal sensory experiences

associated with increased activity in hypothalamus, hippocampus and cortex

2. Disorganized - inappropriate emotional displays, bizarre behaviors and thought disorders (difficulty using and understanding abstract concepts).

•Two clusters of positive symptoms:

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

• affects about 1% of the population and ranges in severity.

• Occurs in all parts of the world, but 10 to 100 times more common in the US 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 onset for men (early 20s versus late 20s).

• Likelihood increases as age of father at birth increases.

Schizophrenia

• Twin studies suggest a genetic component.• Monozygotic twins have higher concordance rate

(agreement) than dizygotic twins.• monozygotic twins have a 50% concordance rate.

– Other factors may explain the difference.• Greater similarity between dizygotic twins than

siblings suggests a prenatal/postnatal environmental effect.

Fig. 15-14, p. 472

Schizophrenia

• Adopted children studies suggest a genetic role, but prenatal environment of the biological mother can not be discounted.

• Attempts to link adult-onset schizophrenia to a gene have provided inconsistent results.

• Research has identified a gene for child-onset schizophrenia but cases are rare.

• Schizophrenia most likely depends on a combination of genes or different genes in different families.

Schizophrenia

• One study identified a gene linked to high levels of negative symptoms (Fanous et al., 2005).

• Perhaps genetic research should focus on specific aspects of schizophrenia rather than schizophrenia in general.

• Schizophrenia most likely results from environmental factors in addition to biological factors.

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, difficulty during birth, or combination of both.

Schizophrenia

• Supporting evidence for the neurodevelopmental hypothesis:– 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

• Prenatal risk factors increasing the likelihood of schizophrenia include:– Poor nutrition of the mother during pregnancy.– Premature birth.– Low birth weight.– Complications during delivery.

• Head injuries in early childhood are also linked to increased incidence of schizophrenia.

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.

Schizophrenia

• Certain viral infections may be an alternative or supplement genetic influences.

• The season-of-birth effect: tendency for people born in winter to have a 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 infections

Schizophrenia

• Schizophrenia is associated with mild brain abnormalities:– Strongest deficits found in the left temporal and frontal

lobe of the cortex.– Larger than normal ventricles.

Especially common in those with complications during birth.

• Areas that mature slowly such as the dorsolateral prefrontal cortex.– Schizophrenics have deficits in working memory.

Fig. 15-15, p. 474

Schizophrenia

• At a microscopic levels, smaller cell bodies than usual, especially in 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.

Schizophrenia

• typically develops after age 20; many show signs earlier.– Deficits in attention, memory and impulse control.

• Prefrontal cortex 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.

Fig. 15-17, p. 476

Schizophrenia

• Antipsychotic/neuroleptic drugs tend to relieve schizophrenia and similar conditions.

• Chlorpromazine (thorazine) relieves positive symptoms of schizophrenia.– Relief usually experienced 2-3 weeks after starting the

drug, which must be taken indefinitely.

Schizophrenia

• chemical families of drugs used to treat schizophrenia include:1. Phenothiazines - includes chlorpromazine2. Butyrophenones - includes halperidol

(Haldol)• Both block dopamine synapses.

Fig. 15-18, p. 477

Schizophrenia

• The dopamine hypothesis of schizophrenia suggests that schizophrenia results from excess activity at dopamine synapses.

• 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 D2 receptor.

• Limitations of the dopamine hypothesis:– Direct measurement of dopamine and its

metabolites indicate generally normal levels in schizophrenics.

– 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 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.

Fig. 15-19, p. 479

Schizophrenia

• Schizophrenia is associated with lower than normal release of glutamate and fewer receptors in prefrontal cortex and hippocampus.

• Further support comes from the effects of phencyclidine (PCP/angel dust).– Inhibits the NMDA glutamate receptors.– Produces positve and negative symptoms at

high doses.

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 projects to the basal ganglia.– Result is tardive dyskinesia, characterized by

tremors and other involuntary movements.

Fig. 15-20, p. 479

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 D2 receptors and

more strongly antagonize serotonin type 5-HT2 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.