8/20/2015
The Current State of
Schizophrenia
Horacio A Capote, MD, FAPA
Director Neuropsychiatry Division: Dent Neurologic Institute

Agenda
 History
 Etiology/Pathophysiology
 Signs and Symptoms
 Treatment
 Comorbidities
History

1887 – First Identified as a mental illness by Dr. Emile Kraepelin: “Dementia
Praecox”

1911 – Eugene Bleuler coined the term “Schizophrenia”

1952 – Dr. Henri Laborit, a French Surgeon, discovers chlorpromazine

1954 – FDA approves Chlorpromazine

1980s – Brain imaging techniques show structural and functional
abnormalities in schizophrenia patients

1980s – Second Generation Antipsychotics first introduced with Clozapine
Source:
Cunningham C, Peters K. Aetiology of Schizophrenia and Implications for Nursing Practice: A Literature Review. Issues
In Mental Health Nursing [serial online]. October 2014;35(10):732-738. Available from: CINAHL with Full Text, Ipswich,
MA. Accessed July 30, 2015.
History of Schizophrenia. http://schizophrenia.com/history.htm. Accessed July 6, 2015.
1
8/20/2015
Etiology and Pathophysiology
 Dopamine Hypothesis
 Glutamate Hypothesis
 Inflammatory Hypothesis
 Environmental link
 Genetic Link
Dopamine Hypothesis
 Increased Dopamine in the mesolimbic pathway
 Hyperstimulation of D2 receptors
 Positive Symptoms
 Decreased Dopamine in the mesocortical pathway
 Hypostimulation of D1 receptors
 Negative symptoms and Cognitive Impairment
Source: Abi-Dargham, Anissa. The Dopamine Hypothesis of Schizophrenia. Schizophrenia Research Forum. 2012.
http://www.schizophreniaforum.org/for/curr/AbiDargham/default.asp
Glutamate Hypothesis
 Stemmed from observations of Phencyclidine (“PCP”)
 Glutamate regulates the mesocortical and mesolimbic dopamine
pathways
 Glutamate reduction leads to dopamine hyperactivity in the
mesolimbic pathway and hypoactivity in the mesocortical,
nigrostriatal, and tuberoinfudibular pathways
 A 2009 study found a reduction in glutamate receptors in the
dorsolateral prefrontal cortex in schizophrenic subjects
Source: Steele D, Moore R, Swan N, Grant J, Keltner N. Biological Perspectives: The Role of Glutamate in Schizophrenia
and Its Treatment. Perspectives In Psychiatric Care [serial online]. July 2012;48(3):125-128. Available from: CINAHL with Full
Text, Ipswich, MA. Accessed July 30, 2015.
2
8/20/2015
The Role of Genetics
 Strong genetic component supported by twin studies
 Polygenic
 Genome-wide association studies: 108 gene loci implicated in
schizophrenia

Many identified loci were associated with D2 receptors and
glutamatergic neurotransmissiom and synaptic plasticity

Many Loci had strong associations in tissues with immune
function
Source: Biological insights from 108 schizophrenia-associated genetic loci. Nature [serial online]. July 24, 2014;511(7510):421427. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed August 10, 2015.
Role of the Environment
 Prenatal Infection: A study found that maternal infuenza during the
first trimester results in a sevenfold increase in the risk of
schizophrenia for the offspring
 Maternal Malnutrition
 Obstetric complications
 Urbanicity
 Geographic (Northern Hemisphere)
 Cannabis Exposure
Source:
Richard M, Brahm N. Schizophrenia and the immune system: Pathophysiology, prevention, and treatment. American Journal
Of Health-System Pharmacy [serial online]. May 2012;69(9):757-766. Available from: CINAHL with Full Text, Ipswich, MA.
Accessed July 30, 2015.
Keshavan M, Nasrallah H, Tandon R. Review: Schizophrenia, “Just the Facts” 6. Moving ahead with the schizophrenia
concept: From the elephant to the mouse. Schizophrenia Research [serial online]. April 1, 2011;127:3-13. Available from:
ScienceDirect, Ipswich, MA. Accessed July 30, 2015.
Inflammatory Hypothesis
 Psychosis has been shown to cause neuro-inflammation
 Many studies have shown increased pro-inflammatory
cytokines
 Several studies have found that adding an anti-inflammatory
agent to an antipsychotic can improve therapeutic response,
particularly during first episode psychosis
Source: Nasrallah H. Beyond dopamine: brain repair tactics in schizophrenia. Current Psychiatry [serial online]. 2015;(6):12.
Available from: Academic OneFile, Ipswich, MA. Accessed July 30, 2015.
3
8/20/2015
Signs and Symptoms
 Prodromal Period
 Positive and Negative Symptoms
 Cognitive Impairment
Prodromal Period
 80% of schizophrenia patients initially experience changes
in thought perception, thought process, and thought content
 Sub-delusional changes: i.e. becoming suspicious
 Difficulty following conversation, easy distractability, poor
attention
 Avolition and anhedonia
 The largest decline in social and occupational function
occurs during the prodromal period
Sources:
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
National Institute of Mental Health. Schizophrenia. http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml.
Accesses July 29, 2015.
Positive and Negative Clusters
Positive Cluster
Negative Cluster

Hallucinations

Flat Affect

Delusions

Avolition

Disorganized thought and speech

Alogia
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
4
8/20/2015
Hallucinations
 Auditory
 Visual
 Somatic
 Olfactory
 Gustatory
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
Delusions
 Persecutory
 Grandiose
 Somatic
 Erotomanic
 Thought Broadcasting
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
Disorganized
Thought Process and Speech

Blocking

Clanging

Circumstantiality

Neologisms

Tangentially

Echolalia

Preservation

Flight of Ideas

Loosening of associations

Derailment

Ideas of Reference
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
5
8/20/2015
Cognitive Deficits
 Poor Executive Functioning
 Trouble focusing and paying attention (sensory processing
data)
 Deficits in working memory
 Slower Processing Speed
Lieberman J, Stroup T, Perkins D. Essentials of Schizophrenia. Arlington, VA: American Psychiatric Publishing Inc.; 2012.
Treatment
 FGAs and SGAs
 First Episode Psychosis
 Maintenance Therapy
 Treatment Resistance/Treatment Failure
 Non-pharmacologic treatment
Treatment
First Generation
Antipsychotics

Chlorpromazine

Haloperidol

Fluphenazine

Thioridazine
Second Generation
Antipsychotics

Aripiprazole

Olanzapine

Asenapine

Paliperidone

Clozapine

Quetiapine

Iloperidone

Risperidone

Lurasidone

Ziprsasidone

Brexpiprazole
6
8/20/2015
First Episode Psychosis

Odds of achieving remission decrease by 15% for each year psychosis goes
untreated

Second Generation Antipsychotics are recommend as first line treatment over
First Generation Antipsychotics

Dosages should be in the lower half of the treatment range and lower than
dosages used in multi-episode schizophrenia

Treatment guidelines and experts recommend 1-2 years of treat in FEP before
discontinuation

Studies are limited on the use of Long Acting Injectable Antipsychotics for
FEP, but have shown improved symptom control, adherence to medication,
reduced relapse rates and re-hospitalization, less reduction in white brain
matter volume, and no difference in EPS or prolactin-associated side effects
Gardner, K, Nasrallah, H. Managing first-episode psychosis: Rationale and evidence for nonstandard first-line treatments
for schizophrenia Part 1. Current Psychiatry . 2015 May 14(5):33, 38-45, e3.
Gardner, K, Nasrallah, H. Managing first-episode psychosis: Rationale and evidence for nonstandard first-line treatments
for schizophrenia Part 2. Current Psychiatry . 2015 July 14(7):33, 38-45, e3.
Maintenance Therapy
 Second-generation antipsychotics are first line treatment
 Use the lowest dose that was effective at reducing positive
symptoms in the acute phase of treatment
 Patients who experience continuous symptom relief should
continue antipsychotic treatment in order to maintain
symptom relief and reduce risk of relapse
Kreyenbuhl J, Buchanan R, Dickerson F, Dixon L. The Schizophrenia Patient Outcomes Research Team (PORT): Updated
Treatment Recommendations 2009. Schizophrenia Bulletin [serial online]. January 2010;36(1):94. Available from: Publisher
Provided Full Text Searching File, Ipswich, MA. Accessed July 31, 2015
Long Acting Injectables
 Haloperidol
 Fluphenazine
 Risperdal Consta
 Zyprexa Relprevv
 Abilify Maintena
 Invega Sustenna (1 month), Invega Trinza (3 month)
7
8/20/2015
Non-Pharmacologic Treatment

Electroconvulsive Therapy

TMS:
The combination of ECT with antipsychotic can increase the effectiveness of the medication


Meta-analysis found strong evidence that TMS is is an efficacious adjunctive treatment for negative symptoms, particularly in
early stage schizophrenia (Shi)

Cognitive Behavioral Therapy

Social Skills Training:



Shown to be an effective option the positive symptoms of psychosis
A 2013 study showed that 91% of patients receiving medication plus SST had achieved remission compared to only 66% in the
medication only group. 58% of the SST group showed functional improvement compared to just 1% in the medication only group
Family Psychoeducation and Therapy:

reduce the levels of burden and distress in family members and are widely accepted and recommended as key elements of a
comprehensive treatment approach
Source:
Valencia M, Fresan A, Juárez F, Escamilla R, Saracco R. The beneficial effects of combining pharmacological and psychosocial treatment
on remission and functional outcome in outpatients with schizophrenia. Journal Of Psychiatric Research [serial online]. December 1,
2013;47:1886-1892. Available from: ScienceDirect, Ipswich, MA. Accessed July 30, 2015.
Shi C, Yu X, Cheung E, Shum D, Chan R. Revisiting the therapeutic effect of rTMS on negative symptoms in schizophrenia: A metaanalysis. Psychiatry Research [serial online]. March 30, 2014;215(3):505-513. Available from: PsycINFO, Ipswich, MA. Accessed August 10,
2015
Treatment Resistance and
Failure
 An adequate medication trial is defined as the maximum tolerated
dose for 16 weeks
 Considerations for treatment failure: smoking, drug interactions
(Carbazepine causes hypercatabolism), illegal substance use, take
with or without food, time of day
 Clozapine:
 superior choice for treatment refractory schizophrenia
 Guidelines for use: failure of 2 adequate antipsychotic trials
 Consider ECT
Citrome, L. The Handbook of Treatment-resistant Schizophrenia. London, UK. Spinger Healthcare Ltd.; 2013.
Comorbidities
 Cardiovascular Risk Factors
 Substance Abuse
 Mood Disorders
 Schizophrenic patients are 40% less likely to receive
treatment for medical comorbidities
Source:
Ignaszewski M, Yip A, Fitzpatrick S. Schizophrenia and coronary artery disease. (Cover story). British Columbia Medical
Journal [serial online]. May 2015;57(4):154-157.
8
8/20/2015
Cardiovascular Risk

More likely to have multiple risk factors and a higher chance of developing 3
or more risk factors

Increased risk of diabetes

75% of people with schizophrenia smoke compared to 25% of population

Physical inactivity is 3x greater

CATIE Study: 43% of schizophrenia subjects had metabolic syndrome

Antipsychotic medications also increase risk
Source:
Ignaszewski M, Yip A, Fitzpatrick S. Schizophrenia and coronary artery disease. (Cover story). British Columbia Medical
Journal [serial online]. May 2015;57(4):154-157.
Nasrallah H. The urgent need for monitoring and intervention to reduce metabolic risk factors in patients with schizophrenia.
CNS Spectrums [serial online]. June 2008;13(6 Suppl 10):5-6.
Substance Abuse
 More likely to have substance abuse
 A study including 1460 individuals with schizophrenia found that
60% use at least one substance of abuse and 37% had evidence of
a substance abuse disorder
 Substance abuse is associated with increased psychotic symptoms,
non-adherence to medication, and increased hospitalization
 “Self-medicate”
Source:
Kerfoot K, Rosenheck R, Stroup T, et al. Substance use and schizophrenia: Adverse correlates in the CATIE study sample.
Schizophrenia Research [serial online]. November 1, 2011;132:177-182.
Mood Disorders
 Increased prevalence of mood disorders
 As much as 57% suffer from comorbid depression
 A meta-analysis found 38% of schizophrenia patients
present with at least one anxiety disorder
Source:
Achim A, Sutliff S, Roy M. Treating comorbid anxiety disorders in patients with schizophrenia: a new pathway. Psychiatric
Times [serial online]. 2015;(1)
Tsai J, Rosenheck R. Psychiatric comorbidity among adults with schizophrenia: A latent class analysis. Psychiatry Research
[serial online]. November 30, 2013;210:16-20.
9
8/20/2015
Questions?
10