Schizophrenia and the Affective Disorders Chapter 16.

SchizophreSchizophrenia and nia and

the the Affective Affective

DisordersDisordersChapter 16Chapter 16

Schizophrenia Schizophrenia SymptomsSymptoms

Negative and Cognitive Negative and Cognitive symptoms are closely symptoms are closely related, may involve related, may involve dysfunction in similar brain dysfunction in similar brain areasareas

Negative and Cognitive Negative and Cognitive symptoms are not specific symptoms are not specific to schizophreniato schizophrenia

See Table 16.1See Table 16.1

PROJECTIONSPROJECTIONS

Mesolimbic DopamineMesolimbic Dopamine VTA-amygdalaVTA-amygdala Drugs that agonize DA Drugs that agonize DA

release (cocaine, etc.) release (cocaine, etc.) can also cause positive can also cause positive symptoms of symptoms of schizophreniaschizophrenia

Major CNS dopaminergic Major CNS dopaminergic systems include:systems include: Nigrostriatal System Nigrostriatal System

(role in movement)(role in movement)

Mesolimbic System (role Mesolimbic System (role in reinforcement/reward)in reinforcement/reward)

Mesocortical System Mesocortical System (role in short-term (role in short-term memory, planning, and memory, planning, and problem solving)problem solving)

DOPAMINE & DOPAMINE & POSITIVE POSITIVE

SYMPTOMSSYMPTOMS

POSITIVE SYMPTOMSPOSITIVE SYMPTOMS

Brain ImagingBrain Imaging

►Measure DA Rs in brains of recently Measure DA Rs in brains of recently diagnosed schizophrenics not diagnosed schizophrenics not previously exposed to neuroleptics previously exposed to neuroleptics Radioactive ligand of the D2 R was injected Radioactive ligand of the D2 R was injected

iv & its concentration measured in the iv & its concentration measured in the corpus striatumcorpus striatum

Two ResultsTwo Results► Brains of schizophrenics have an Brains of schizophrenics have an

abnormally high # of D2 Rsabnormally high # of D2 Rs► Higher level of occupancy of those Rs by Higher level of occupancy of those Rs by

DADA

►Suggest both pre & postsynaptic Suggest both pre & postsynaptic abnormalitiesabnormalitiesToo much release & too many Too much release & too many

receptors (modest) receptors (modest)

Side-Effects of Long-Term Side-Effects of Long-Term Anti-Schizophrenic DrugsAnti-Schizophrenic Drugs

Similarly to long-term use of Parkinson’s drug Similarly to long-term use of Parkinson’s drug treatments, there can be side-effects with long-term treatments, there can be side-effects with long-term use of anti-psychotic drugs.use of anti-psychotic drugs.

Tardive DyskinesiaTardive Dyskinesia TardusTardus – slow – slow DyskinesiaDyskinesia- faulty movement- faulty movement Late-developingLate-developing

TD: unable to stop movingTD: unable to stop moving SupersensitivitySupersensitivity: possible that DA receptors become : possible that DA receptors become

hypersensitive if they are blocked for long periods of hypersensitive if they are blocked for long periods of timetime

DD22 receptors in caudate and putamen receptors in caudate and putamen

Problems with the DProblems with the D22 TheoryTheory

Schizophrenia associated with brain Schizophrenia associated with brain damagedamage Little damage to dopamine circuitryLittle damage to dopamine circuitry Damage not explained by dopamine theoryDamage not explained by dopamine theory

It takes several weeks of neuroleptic It takes several weeks of neuroleptic therapy to alleviate schizophrenic therapy to alleviate schizophrenic symptomssymptoms

Conventional neuroleptics (DConventional neuroleptics (D2 2 blockers) blockers) mainly effective for positive symptomsmainly effective for positive symptoms

Negative and cognitive symptoms might Negative and cognitive symptoms might be caused by brain damagebe caused by brain damage

May be best to think of schizophrenia as May be best to think of schizophrenia as multiple disorders with multiple causesmultiple disorders with multiple causes

Schizophrenia as a Schizophrenia as a Neurological DisorderNeurological Disorder

Predisposing factors (genetic, Predisposing factors (genetic, environmental, or both) give rise to:environmental, or both) give rise to:

1.1. Abnormalities in both DA transmission and Abnormalities in both DA transmission and PFC PFC

2.2. Abnormalities in DA transmission that cause Abnormalities in DA transmission that cause abnormalities in PFCabnormalities in PFC

3.3. Abnormalities in PFC cause abnormalities in Abnormalities in PFC cause abnormalities in DA transmission DA transmission

Schizophrenia: Brain Schizophrenia: Brain AbnormalitiesAbnormalities

Evidence of Evidence of brain damagebrain damage Negative and Negative and

cognitive cognitive symptomssymptoms

Loss of brain Loss of brain tissuetissue Lateral Lateral

ventricles ventricles more than more than twice as twice as large in large in schizophrenischizophrenic patients c patients than control than control subjectssubjects

Possible Causes of Brain Possible Causes of Brain AbnormalitiesAbnormalities

Epidemiological StudiesEpidemiological Studies Season of birthSeason of birth Viral epidemicsViral epidemics Population densityPopulation density Prenatal malnutritionPrenatal malnutrition Maternal stressMaternal stress

Possible Causes of Brain Possible Causes of Brain AbnormalitiesAbnormalities

Season of birth (seasonality)Season of birth (seasonality) Late winter and early spring (northern Late winter and early spring (northern

hemisphere)hemisphere) Reverse in southern hemisphereReverse in southern hemisphere Possible link: virusesPossible link: viruses Effect seen in cities, not in countrysideEffect seen in cities, not in countryside

See Figure 16.5See Figure 16.5

Possible Causes of Brain Possible Causes of Brain AbnormalitiesAbnormalities

Vitamin D deficiencyVitamin D deficiency Dealberto (2007)Dealberto (2007) Northern Europe: 3-fold increase in schizophrenia in Northern Europe: 3-fold increase in schizophrenia in

immigrants (equatorial regions)immigrants (equatorial regions)

Thiamine deficiencyThiamine deficiency Two-fold increase in incidence of schizophrenia in Two-fold increase in incidence of schizophrenia in

offspring of women pregnant during severe food offspring of women pregnant during severe food shortage in WWII (Germany and Netherlands)shortage in WWII (Germany and Netherlands)

Maternal/paternal substance abuse – smokingMaternal/paternal substance abuse – smoking

Complications during childbirthComplications during childbirth Mother: Diabetes of mother, bleeding, preclampsia Mother: Diabetes of mother, bleeding, preclampsia

(high blood pressure, protein in urine)(high blood pressure, protein in urine) Other: oxygen or blood flow deprivationOther: oxygen or blood flow deprivation

Evidence for Abnormal Evidence for Abnormal Brain DevelopmentBrain Development

Home movies from families with schizophrenic Home movies from families with schizophrenic childchild Compared to normal siblings, schizophrenic child Compared to normal siblings, schizophrenic child

displayed more negative affect and more abnormal displayed more negative affect and more abnormal movementsmovements

265 Danish children (11-13 years) were videotaped 265 Danish children (11-13 years) were videotaped eating luncheating lunch Children who later developed schizophrenia displayed Children who later developed schizophrenia displayed

less sociability and deficient psychomotor functioningless sociability and deficient psychomotor functioning

Hypothesis – although schizophrenia is not seen in Hypothesis – although schizophrenia is not seen in childhood, the early brain development of children childhood, the early brain development of children who become schizophrenic is not normalwho become schizophrenic is not normal

Age of OnsetAge of Onset

Symptoms rarely begin before late adolescence or Symptoms rarely begin before late adolescence or early adulthoodearly adulthood

Progression:Progression: Negative symptoms Negative symptoms cognitive symptoms cognitive symptoms positive positive

symptoms symptoms

See Figure 16.8See Figure 16.8

Abnormal Brain Abnormal Brain DevelopmentDevelopment

Brain damage is sudden Brain damage is sudden (during young adulthood)(during young adulthood)

Thompson et al. (2001)Thompson et al. (2001) Adolescence with early Adolescence with early

onset schizophreniaonset schizophrenia MRIMRI

Normals:Normals: Loss of 0.5-1.0%Loss of 0.5-1.0%

Schizophrenic patients:Schizophrenic patients: 2-3%2-3%

See Figure 16.9See Figure 16.9 Loss:Loss:

Parietal to temporal lobeParietal to temporal lobe

Somatosensory and motorSomatosensory and motor

Prefrontal cortexPrefrontal cortex

Abnormal Brain Abnormal Brain DevelopmentDevelopment

Hypofrontality and Negative and Cognitive Symptoms Hypofrontality and Negative and Cognitive Symptoms Decreased activity of the prefrontal cortex (dlPFC); believed to Decreased activity of the prefrontal cortex (dlPFC); believed to

be responsible for the be responsible for the negative negative symptoms of schizophrenia.symptoms of schizophrenia. Above fig: Task required increased concentration and attentionAbove fig: Task required increased concentration and attention Possibly caused by Possibly caused by decreaseddecreased DA activity in prefrontal regions DA activity in prefrontal regions

See Figure 16.10See Figure 16.10

NMDA , NMDA , Dopamine and Dopamine and HypofrontalityHypofrontality

PCP and ketamine can PCP and ketamine can cause positive, negative cause positive, negative and cognitive-like and cognitive-like symptomssymptoms NMDA receptor NMDA receptor

antagonistsantagonists; decrease DA ; decrease DA and metabolic activity in and metabolic activity in frontal cortex frontal cortex

Role of D2 Receptors in Role of D2 Receptors in Development of Development of SchizophreniaSchizophrenia

Abnormalities in the striatal DA system may Abnormalities in the striatal DA system may be the cause of schizophreniabe the cause of schizophrenia

Virus inserted into striatum that increased Virus inserted into striatum that increased D2 recpetorsD2 recpetors Caused the development of behavioral deficits Caused the development of behavioral deficits

characteristic of schizophreniacharacteristic of schizophrenia Abnormal activity of dlPFCAbnormal activity of dlPFC

Treatment with Partial DA Treatment with Partial DA Receptor AgonistsReceptor Agonists

Atypical drugs are able to Atypical drugs are able to reduce ALL symptomsreduce ALL symptoms Increase DA activity in Increase DA activity in

PFCPFC Reduce DA activity in the Reduce DA activity in the

NANA

AripoprazoleAripoprazole: Atypical: Atypical Partial Partial DA agonistDA agonist

High affinity for receptor High affinity for receptor but less than ligandbut less than ligand

Can act like an antagonistCan act like an antagonist Nucleus accumbensNucleus accumbens

Can act like an agonistCan act like an agonist Prefrontal cortexPrefrontal cortex

http://www.youtube.com/watch?http://www.youtube.com/watch?v=USxHsSWCaJAv=USxHsSWCaJA

Chapter 16

• Bipolar Disorder – serious mood disorder characterized by cyclical periods of mania and depression.

• Men and women in equal numbers• Mania: last days or weeks• Depression: typically 3x as long as manic episodes

• Major Depressive Disorder – serious mood disorder that consists of unremitting depression or periods of depression that do not alternate with periods of mania.

• Continuous• Episodes

DEPRESSION

Little energy Move and talk slowly May pace aimlessly and

restlessly Cry Anhedonia Loss of appetite for food and

sex Disturbed sleep Depressed bodily functions

Constipated Decreased saliva production

MANIA

Sense of euphoria not justified by circumstances

Nonstop speech and motor activity

Delusions Full of their own

importance & become angry or defensive if contradicted

Long periods without sleep Working on “unrealistic”

projects

Chen and Dilsaver (1996)15.9% of people with MDD attempt to commit suicide29.2% of people with BD attempt to commit suicide

Evidence indicates a tendency for affective disorders to be heritable, although many genes may be involved.

Monozygotic twins – 69%

Dizygotic twins – 13%

Copyright © Allyn & Bacon 201024

Animal tests of depression Animal tests of depression Forced swim testForced swim testSucrose preference test (test of anhedonia)Sucrose preference test (test of anhedonia)

Animal Models of depressionAnimal Models of depression Learned helplessnessLearned helplessness Social defeatSocial defeat

Porsolt swim test• measures the effect of antidepressant

drugs on the behaviour of rats/mice

Animals are subjected to two trials during which they are forced to swim in an glass cylinder filled with water The first trial lasts 15 minutes.

24-hours later, a second trial is performed that lasts 5 minutes.

The time that the test animal spends without moving in the second trial is measured.

Immobility time is decreased by antidepressants.

Social defeat• Repeated exposure to an aggressive male mouse• Decrease in subsequent social interaction• Increased time immobile in the forced swim test

Berton et al., 2006

MDD• MOAIs• SSRIs & SNRIs• ECT• Transmagnetic stimulation (TMS)• Deep brain stimulation (DBS) • Vagus nerve stimulation• Low-dose Ketamine• Bright-light therapy (phototherapy)• Sleep deprivation

Bipolar Disorder• Lithium• Anticonvulsant drugs

1950s• TB drugs found to elevate mood• First antidepressants

• MAO inhibitors

Monoamine oxidase (MAO) inhibitors• IPRONIAZID (e.g.)• MAO breaks down monoamines in the terminal buttons• Increases release of DA, NE and 5-HT (not specific)

MAO inhibitors: Cheese Effect• Dangerous dietary interaction• Excess tyramine hypertension

Tricyclic antidepressants (TCAs)• E.g. Imipramine• Inhibits the reuptake of

norepinephrine and serotonin but also affects other neurotransmitters.

• Safer than MAOI’s

‘Selective’ Reuptake Inhibitors

• SSRIs: serotonin• Prozac, paxil

• SNRIs: norepinephrine & • 5-HT•

Fewer side-effects than TCAs

• No more effective than TCAs, but side effects are few and they are effective at treating other disorders

‘Selective’ is relative as they still have effects on both 5-HT and NE though range in affinity:

• Affinity for 5-HT:NE• Milnacipran 1:1• Venlafaxine 1:30

MDD• MOAIs• SSRIs & SNRIs• ECT• Transmagnetic stimulation (TMS)• Deep brain stimulation (DBS) • Vagus nerve stimulation• Low-dose Ketamine• Bright-light therapy (phototherapy)• Sleep deprivation

Bipolar Disorder• Lithium• Anticonvulsant drugs

Treatment-resistant Depression

Electroconvulsive TherapyEarly 1900s: von Meduna (drug induced)1930s: Cerletti (electrical)

• Electroconvulsive Therapy (ECT) – brief electrical shock, applied to the head, that results in an electrical seizure; used to treat depression.

• Antidepressant effects are seen quickly (unlike antidepressant drugs)

• May exert effects through activation of inhibitory neurotransmitter systems• Increased GABA & Neuropeptide Y

• Potential cognitive impairments

• Transmagnetic stimulation (TMS)• Strong localized magnetic field into the brain by

passing an electrical current through a coil of wired placed on the scalp

• Response rate <30%

• Deep brain stimulation (DBS):• Subgenual ACC

• 1 month – 35% improvement, 10% remission• 6 months – 60% improvement, 35% remission

• NA• Reduce symptoms in ~50%

• Vagus nerve stimulation• Low-dose Ketamine

33

NORMALNORMAL DEPRESSIONDEPRESSION TREATEDTREATED

Underactivity of serotonin and norepinephrine synapses

Monoamine antagonists can produce the symptoms of depression• Reserpine (lower blood pressure) – blocks the activity

that transporters that fill synaptic vesicles in monoaminergic terminals with NTs

• Blocks release of NA and 5-HT

Monamine agonists treat depression• TCAs, SSRIs, SNRIs, MAOIs

Copyright (c) Allyn & Bacon 201035

OBSERVATIONS:

• Depleting tryptophan from diet does not alter mood in healthy volunteers

• Does in others on antidepressant treatment• And in healthy people with family history of

depression

• 2-3 weeks for antidepressants to become effective

• Some people never respond to drug therapies

Amygdala: involved in the expression of emotion

• Negative emotion• 50-75% blood flow and metabolism in amygdala

increases during depressive episodes• Abercrombie et al. (1998)

• Activity in amygdala of depressed patients correlated with severity of depression

• Metabolic activity of amygdala increases in normal Ss when they look at faces with expressions of sadness

• Metabolic activity in amygdala increases when depressed Ss remember episodes in their lives that made them sad

Medial Prefrontal Cortex:• Subgenual ACC lower

level of activation (right) in depression

• Increased during mania

Figure 16.19Figure 16.19

5-HT transporter (5-HTT)The promoter region that codes for the 5-HTT comes in two

forms:

Short

Long

Three possible combinations:

S-S

S-L

L-L

5-HT transporter (5-HTT)The promoter region that codes for the 5-HTT comes in two

forms:

Short

Long

Three possible combinations:

S-S

S-L

L-L

Caspi et al (2003)Caspi et al (2003) ScienceScience 847 people for 20 years847 people for 20 years

Stressful events (> # of stressful Stressful events (> # of stressful event; > depression)event; > depression)

Increase was greater for those with the Increase was greater for those with the short alleleshort allele

See Figure 16.20See Figure 16.20

Suicide ideationSuicide ideation Major depressionMajor depression

The Role of the 5-HT The Role of the 5-HT TransporterTransporter

Rausch et al. (2002)• People with 2 long alleles tend to respond better to drug treatment

Lee et al. (2004)• Depressed people with 2 long alleles treated with antidepressants

have better long-term outcome

Rhodes et al (2007)• People with higher levels of 5-HT transporter in amygdala showed

less activation of the amygdala when the people looked at emotional faces

Several meta-analyses of studies investigating the role of 5-HTT promotor in depression No significant effects!

• Stressful experiences that produce depression (in animals) suppress hippocampal neurogenesis

• Administration of antidepressant treatments increases neurogenesis (in animals)

• Delay in action of antidepressant treatments = length of time it takes for newborn neurons to mature

• If neurogenesis is suppressed by low-level dose of radiation, antidepressant drugs lose their effectiveness (in animals)

• No way to measure adult human neurogenesis

Symptom of depression: disordered sleep• Reduced Sleep Latency• Reduced REM Latency• Reduced Slow-Wave Sleep• Increased Sleep Disruption

1 of the most effective antidepressant treatment – sleep deprivation (total or REM selective)

• REM selective - therapeutic effect occurs slowly, long-term improvement after deprivation is discontinued

• Total sleep deprivation – effects are immediate, but depression returns the next day

• Intermittent total sleep deprivation can have beneficial results

SEASONAL AFFECTIVE DISORDERSEASONAL AFFECTIVE DISORDER

Attacks of depression and lethargy typically occur every winter

Cause: Attacks are triggered by a reduction in

sunlight• Higher incidence in Northern US than in Florida• Light therapy is often effective in reducing symptoms