Notes: Neuroscience Models of Schizophrenia

Schizophrenia is a condition characterized by : 1. hallucination, 2. thought disorder, 3. absence of behavior, and 4. lack of motivation.

►Basic symptoms are: associative, affective and personality disturbances, autism and ambivalence.

►Secondary symptoms are: hallucinations, delusions, catatonia and speech disturbances (neologisms, “word salad”)

►Kurt Schneider: Symptoms of 1. and 2. degree (diagnosis of S., if at least one symptom of 1. degree present).

►First degree: acoustic (commenting) hallucinations, disturbances of thinking (incoherent, obsessive, stereotypical, elusive), will (ambivalent, helpless) and perception (derealization, depersonalization)

►Second degree: coenesthetic, optical, olfactory and gustatory hallucinations

►Plus (positive) and minus (negative) symptoms.

►Positive symptoms: delusions, hallucinations, thinking disturbances, bizarre behavior.

►Negative symptoms: affect and speech impoverishment, apathy, disturbed vigilance and concentration

►Affective disturbances dominate in almost 100%, followed by formal thinking disturbances (90%), drive disturbance (85%), diminished attention (84%) and delusions (70%).

Several clinical types:

►Paranoid (hallucinatory) type (ICD 10: F 20.0. DSM-IV 295,30)

►Hebephrenic S. (F 20.1)

►Catatonic S. (F 20.2)

►Undifferentiated S. (F 20.3)

►S. simplex (F 20.6)

►Other S.’s (F 20.8) (e.g. jealousy delusions)

Types of Schizophrenia Symptoms

Paranoid Type:

►Delusional ideas, mostly accompanied by acoustic hallucinations and other S. symptoms.

►Examples of delusional ideas are: persecution, megalomania, particular (religious or other) mission, particular connections.

►Hallucinations consist of commenting or commanding voices (possibly driving to suicide)

► Olfactory or coenesthetic hallucinations may occur

Hebephrenic Type:

►Affective disturbances are predominant

►Inappropriate mood, with affectation, smiling or laughing, grimaces, mannerisms

►Thinking disturbed, speech longwinded, often ridiculous behavior.

►Delusions and hallucinations are short and less severe

Catatonic Type:

►Mainly psychomotor disturbances between stupor and excitement

►Behavior is often characterized by robot-like automatism, rigid and bizarre bodily positions are kept for long time

►Rare in Western countries.

►Often intensive scenic hallucinations

►Severe state with high lethality, emergency state

Other Types:

►Undifferentiated type: Characteristic schizophrenic symptoms without fitting into one of the specific types.

►S. simplex: rare form with only few symptoms, strange behavior, cognitive faculties progressively disturbed, apparently less psychotic than the previously described types. As a rule no delusions or hallucinations. Diagnosis often difficult.

►Postschizophrenic depression (ICD 10: 20.4) consists of mainly negative symptoms, depression, lack of initiative, low level functioning.



Epidemiology of Schizophrenia

►Prevalence: 0.5 – 1% (about the same all over the world)

►Yearly incidence: 0.01%

►Life prevalence: 0.6

►males = females

►Illness begin on average at 21 years (males) and 26 years (females). Hebephrenic form begins with puberty, paranoid-hallucinatory form in about the 4th decade. “Late schizophrenia” begins after 40.



  • Higher familial occurence (Häfner 1993)
  • Family and twin studies: concordance rate in monozygotic twins reaches 44-50%, in heterozygotic twins 10-12%, in siblings 7%.
  • However, no single gene is related to the aetiology of S.;
  • Polygenetic heredity seems to cause the illness.

►Adoption studies (Tienari 1991)

  • “Multifactorial” aetiology
  • Certain neurophysiological or biochemical changes may take place in the brain, leading to higher vulnerability and predisposition.
  • Unfavorable social conditions heighten the chances to develop S. in vulnerable individuals.
  • Coping strategies or protective factors favor better prognosis or subclinical illness.

►Association studies

  • Searching for a gene, genotype, an allele, or a certain DNA sequence variant occuring more frequently than expected in S. populations as risk factor.
  • “Candidate genes” as genetic risk carriers: genes for various dopamine-receptor constellations, e.g. on chromosome 6.

►Morphological and neuropathological findings

  • S. patients have larger brain ventricles than normal population. Atrophic process concentrates mainly on the temporal lobe and the limbic system (thalamus, pallidum, s. nigra, temporal lobe, corpus callosum etc.), diminishing the amount and the arrangement of neurons.
  • Such atrophic processes seem to begin at an early age
  • Brain imaging makes it possible not only to find morphological correlations to S., but also to “observe” dynamic processes occuring in the brain of “normal” and psychotic individuals. Reduced blood perfusion and metabolism could be located in the frontal area
  • Findings are heterogeneous and show great variability.

►Biological hypotheses

  • Dopamine hypothesis: (Experience through dopaminergic drugs: neuroleptics as dopamine-D²-antagonists. Dopamine agonists cause psychotic symptoms) Dopaminergic hypoactivity in the frontal area (leading to “negative symptoms”) and dopaminergic hyperactivity in the mesolimbic system (® “positive symptoms”)
  • Cholinergic hypothesis: also based on the mechanism of cholinergic side-effects of neuroleptics
  • Glutamate hypothesis: Hypofunction of the glutamatergic receptor system (narrowly associated with dopaminergic system)
  • Serotonergic system: Receptor Serotonin-5HT-2a (atypical neuroleptic drugs inhibit these receptors)
  • Complex receptor systems involved (dopaminergic, glutamatergic, serotonergic, gabaergic): balance and interactions between the different systems disturbed
  • Thalamus function disturbance: striato-thalamic pathways filter sensory stimuli reaching the brain cortex. Through disturbance of this mechanism the cortex is poorly protected and thus overstimulated
  • Immunological hypothesis: changes affecting the immune system may follow viral infections. Inconstant findings involving higher antibody titers to cytomegalic, herpes, influenza or measles viruses.

►Psychosocial hypotheses

  • “Schizophrenogenic mother” (Fromm-Reichmann 1950): dominant, possessive, overprotective, rigid and emotionally cold mother “driving” child into “madness” (S.)
  • Double bind hypothesis (Bateson et al. 1956): pathological (double bind) communication between mother and infant, which lead to intellectual and emotional confusion. Lack or passivity of father increases helplessness and frustration of the child, who reacts with withdrawal into psychosis. First group dynamic hypotheses.
  • “Expressed emotions” hypothesis (EE): High emotional level and overprotective-hostile behavior could be found in the families of s. patients, which may lead to frequent s. episodes. Relapse risk predictable by high EE-score (Vaugh & Leff 1976). No specific theory for S., but for all psychiatric conditions
  • “Life Event” hypothesis (Brown & Birley 1970): In about 50% of cases, important life events were found three weeks prior to the beginning of a s. episode. LE are considered as precipitating factors, but not involved in the genesis of the disease
  • Multifactorial theory: Genetic and familial factors concurring (Tienari 1991). At present, multifactorial theory is favorized in all psychiatric and psychosomatic conditions
  • Group dynamic hypothesis (Ammon 1971): Destructive dynamics of the primary group (hostile, manipulative, parentifying, abusive, emotionally traumatizing and confusing atmosphere provoking guilt feelings) interiorized by the child and later enhanced by and acted out in other significant groups (school, work etc.)

Detailed information is found in this lecture:

Schizophrenia is not one disease (in some cases the term disease is not appropriate). There are subtypes of schizophrenia syndromes and  it also occurs in a spectrum.

What Neuroscience has uncovered and theorized so far:

1. Imaging: reduction of brain tissue and dysconnectivity (Gruber, Meisenzahl, Koutsouleris),


2. Global Circuitry /models : cortex-striatal complex-thalamus-cortex; cortex-brain stem (Carlsson; Grace)

3. Local / regional networks: ”dysconnection” hypothesis; cerebral PFC (Murray & Wang, Deco & Hugues)

Impaired coupling of local and global functional feedbacks that underlies abnormal synchronization and negative symptoms of schizophrenia. (Woh 2013)

These are results from Magnetic encephalography (MEG) studies. “In this study, we found that coupled local and global feedback (CLGF) circuits in the cortical functional network are related to the abnormal synchronization and also correlated to the negative symptom of schizophrenia.”

4. Neurotransmission: dopamine (+), serotonin (+), glutamate (-), GABA (-); (Antipsychotics: Gründer)

The differences in the excitation-inhibition balance in patients with normal and schizophrenic symptoms can be explained by observing these:

Smaller & fewer dendritic spines, reduced GABA synthesis, increased suppression of GABA release, fewer GABA a1 receptors, reduced GABA re-uptake and more GABA 2 receptors.

a) Working memory task induces lower change in activation in schizophrenia compared to healthy subjects.

b) NMDA-receptor antagonist ketamine evokes similar patterns

c) A computational model of working memory, comprised of task-activated (top) and task-deactivated (bottom) modules highlighting a possible mechanism for deactivation, followed by results. We tested whether ‘disinhibition’ via reduced NMDA receptor conductance onto GABA cells (E–I) (small red arrow) would resemble activation/deactivation BOLD findings under ketamine and observations in schizophrenia.


  1. Synaptic specifities: D2R / D1R predominance e.g. PFC (signal / noise ratio in information processing; Voit)

6. Subcellular molecular networks (Gebicke-Haerter)

7. Genes:for enzymes, receptors … susceptibility genes, including neuregulin-1, ErbB4, nNOS, PICK1, and DISC1, (Rujescu, Schmitt)


Ammon, G. (1971): Auf dem Wege zu einer Psychotherapie der Schizophrenie (Towards a psychotherapy of schizophrenia). Dyn. Psychiat. 4: 9-28 (English summary)
Bateson, G. et al. (1956): Toward a theory of schizophrenia. Behav. Science 1: 251-264
Fromm-Reichmann, F. (1950): Principles of intensive psychotherapy. Chicago: Univ. Chicago Press
Gaebel, W. (2005): New developments and treatment issues in schizophrenia. In: Christodoulou, G. N. (Ed.): Advances in Psychiatry, Vol. 2. World Psychiatric Association, 45-52
Kaplan & Sadock’s Synopsis of Psychiatry (2003) (KSSP). Philadelphia: Lippincott Williams & Wilkins, 471-504
Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 2 Vol. (2000) (KSCT). Philadelphia: Lippincott Williams & Wilkins, 1096-1231
Vaugh, C., Leff, J (1976): The measurement of expressed emotions in the families of psychiatric patients. Brit. J. Soc. Psychol. 15: 157-165