Textbook of Psychiatry/Psychotic Disorders

Schizophrenia and Related Psychotic Disorders

Introduction
Psychosis, a syndrome with many causes, traditionally refers to an impaired ability to distinguish between false and real perceptions and beliefs. Schizophrenia is the prototypical psychotic disorder. The most common psychotic symptoms are positive symptoms such as abnormal perceptions (including illusions and hallucinations), false beliefs, including a wide variety of delusional thoughts (e.g., paranoid delusions, delusions of reference, grandiose, somatic, etc.), and disorganized thinking. In addition, patients with schizophrenia might have prominent negative symptoms such as affective flattening, alogia (decreased thought/speech production), and avolition, together with amotivation, anhedonia and social isolation. Disorganized or bizarre behavior is a separate symptom dimension of the disorder. Affective symptoms can also be present and cognitive and social deficits are common.

This chapter focuses on primary psychotic disorders, as illustrated by schizophrenia, meaning that the clinical picture of psychosis is not deemed to be secondary to other processes. It is important to note that in addition to the primary psychoses a number of psychiatric and somatic conditions affecting the brain homeostasis can produce psychotic symptoms.

Patients with personality disorders (PDs) can present with overt psychotic symptoms in response to stress (e.g., paranoid PD, schizotypal PD, borderline PD). Schizoid PD is considered a risk factor and might precede Schizophrenia and Delusional Disorder. With regards to mood disorders, severe psychotic depression can present with mood congruent (e.g., nihilistic delusions, delusional guilt) and/or auditory hallucinations making critical and negative comments. At the opposite end of the spectrum, severe mania can present with grandiose and religious delusions, delusions of special powers, and auditory hallucinations (God’s or angelic voices). Late life psychosis can be present in the later stages of dementia disorders. Conditions that affect the brain structure, either acutely [e.g., rapidly growing brain tumors, traumatic brain injury, strokes, infectious/inflammatory processes such as tertiary syphilis, multiple sclerosis or systemic lupus erythematosus (SLE)], or chronically [e.g., nutrient and vitamin deficiencies such as B12, niacin deficiency (pellagra), etc.] can present with a variety of psychotic symptoms. Last but not least, a number of drugs (prescribed and illicit) can be associated with psychotic symptoms either during treatment/intoxication or withdrawal.

This chapter will first review the definitions of the different types of psychotic symptoms, as the basis for the discussion about the approach (including initial assessment as well as short and long-term treatment plans) to a patient with a generic psychotic syndrome. For the remainder of the chapter schizophrenia is used as the foundation for the discussion of clinical diagnosis, differential diagnosis, epidemiology, pathophysiology, genetics and treatment. Pertinent details of schizophrenia-related disorders will be discussed (compared and contrasted whenever the case) within the confines of the broader schizophrenia mainframe.

Clinical Manifestations and Definition of Terms

 * Positive Symptoms are thought of as an excess of normal function. Overvalued misperceptions that become illusions and hallucinations and overvalued ideas that become delusions (fixed ideas) are classical examples of positive symptoms.


 * Negative Symptoms refer to a lack of what is considered to be normal function. Normally, a degree of volitional ability is expected; therefore decreased or absent volition (avolition) is a negative symptom. Similarly, a lack of motivation (amotivation), a lack of ability to enjoy things (anhedonia), or decreased ability to engage in social activities (social isolation) are other classical negative symptoms.


 * Catatonia refers to two extreme (and fundamentally opposite) states. Agitated catatonia refers to a state of excessive, extreme behavioral agitation (not in response to internal stimuli), while catatonic immobility refers to extreme negativism (the patient actively resists any attempts to have his extremities or whole body moved) or catalepsy (waxy flexibility). Other catatonic symptoms include posturing (assuming strange body postures), grimacing, mannerisms, stereotyped movements, echolalia (where the patient repeats in parrot-like fashion the words of another person), and echopraxia (where the patient imitates in mirror-like fashion the movements of another person).


 * Disorganized thinking (formal thought disorder) refers to an alteration in the thought process. Normally the flow of thinking is coherent, linear and goal directed. In psychotic patients the associations may be loose to the point of being non-existent. The psychotic patient’s thought form may present with tangentiality (ideas are only marginally connected) or circumstantiality (the patient responds to questions moving in gradually more focused, concentric circles until eventually reaching the answer). In extreme cases, even the structure of the sentence might be lost which results in word salad.


 * Disorganized behavior refers to the patient difficulty to complete most goal oriented activities. A range of behaviors have been described: actively responding to inner stimuli (e.g., talking to oneself or shouting for no apparent reason), aimless, repetitive movements and activities, poor ability to maintain one’s basic hygiene and perform routine actives of daily living (which often results in a disheveled appearance, and poor grooming and hygiene), or uncensored public sexual activity (being naked, or masturbating in public).


 * Active phase refers to a period of time when a combination of the above symptoms are prominently manifested.


 * Prodromal and residual phases refer to periods of time of attenuated symptoms that either precede (prodromal) or follow (residual) the active phase period.


 * Cognitive Symptoms: Memory (more specifically working memory), attention, concentration, processing speed, problem solving (executive functioning), and social cognition are a few of the many cognitive domains shown to be impaired in schizophrenia.


 * Insight is a multidimensional concept referring to awareness of illness, specific symptoms and their consequences, as well as need for treatment. Insight refers to the patient’s ability to understand that some of his or her non-reality based experiences (usually hallucinatory experiences and delusional representations) are secondary to having schizophrenia rather than reality. Awareness and attribution of both current and past symptoms represent specific aspects of insight.   Additional dimensions of insight include a more global understanding of the diagnosis and need for treatment.

Approach to the Patient with Acute Psychosis
The following major issues should be kept in the forefront:


 * 1) What is the most accurate diagnosis?
 * 2) Is there a treatable or reversible component to the psychosis?
 * 3) Is the patient safe?
 * 4) Can the physician help to alleviate the positive symptoms?
 * 5) Can the physician help to alleviate the negative, cognitive symptoms and insight deficits to improve social/functional outcomes?

History
The history should clarify the onset (acute versus gradual), tempo (slow/protracted versus rapid), chronology, course (persistent versus episodic), and type of symptoms.

Onset and tempo

An acute or subacute onset of psychosis may represent delirium, psychosis due to a general medical condition, or a substance induced psychosis and should trigger the search for intoxication, infection, or metabolic derangement.

Duration

According to the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision (DSM-IV-TR) a diagnosis of schizophrenia requires the presence of a combination of prominent positive, negative, disorganized thinking (formal thought disorder), catatonia, or behavior type of symptoms for at least a month (active phase), with a total duration of the episode (including active phase, and some type of prodromal or residual symptoms) for at least 6 months and resulting in social and occupational dysfunction.

A schizophrenia-like presentation that lasts more than a month but less than 6 months would be more appropriately diagnosed as schizophreniform disorder. Brief psychotic disorder should be diagnosed when the total duration of symptoms is shorter than a month. Schizoaffective disorder trumps schizophrenia if in addition to stand alone episodes of psychotic symptoms there is also a long history of affective symptoms, and the affective symptoms occurred for a longer time than the psychotic symptoms.

Chronology

Refers to the temporal rapport between the different symptoms. Clarifying what started and what followed are essential in ruling out phenomenologically overlapping disorders. If it is determined that the psychotic symptoms followed a medical condition or drug (prescribed or illicit) psychotic disorder due to a general medical condition, substance induced psychotic disorder, or delirium need to be considered first. Mood disorder with psychotic symptoms is diagnosed if the history shows that psychotic symptoms always occurred in the context of already present, and most often severe affective (depressive and manic) symptoms.

Course

A clearly episodic course is most times indicative of a primary affective disorder. Unfortunately, schizophrenia tends to be chronic, with some level of residual symptoms following the active phase for most patients. However, for schizophrenia, after one year since the onset of the acute phase symptoms, DSM allows for a number of course based specifiers including: single episode with partial/total remission, episodic with/without inter-episode residual symptoms, and continuous.

Physical and Neurological Examination
A thorough general and neurological examination is recommended.

General physical examination

Is recommended to first rule out a systemic disease that may be responsible for the psychotic syndrome. A number of non-specific physical abnormalities including an arched palate, narrow or wide–set eyes or subtle ear malformations are more frequently reported in patients with schizophrenia than in the general population. For patients treated with antipsychotics a physical exam will document the general state of health and is important to exclude side effects of medication. Side effects include orthostatic hypotension, hypersalivaton (secondary to clozapine), anticholinergic syndrome (dry mouth, and tachycardia secondary to anticholinergics), hyperprolactinemia (lactation secondary to D2 antagonism), and metabolic syndrome (most common with clozapine and olanzapine).

Neurological examination

Is recommended to rule out neurological conditions that may present with psychotic manifestations; of note, abnormal focal neurological signs are not typically found in primary psychotic disorders. Such findings should prompt the clinician to do a more extensive neurological work-up. In addition, a neurological exam is necessary to exclude the presence of soft neurological signs and abnormal involuntary movements. Soft (neurological) signs, while not pathognomonic, are frequently seen in schizophrenia, where "soft" denotes the absence of a clearly localized ("hard") central nervous pathology that can explain the observed deficits. They include:
 * Sensory function integration abnormalities include poor audio—visual integration, astereognosis (the inability to identify an object by touch without visual input), and agraphaesthesia (the inability to recognize writing on the skin purely by the sensation of touch).
 * Motor function integration abnormalities might include balance and gait abnormalities, poor coordination, intention tremor, finger—thumb opposition difficulties.

In addition, a number of abnormal involuntary movements have been classically described in chronic schizophrenia (before the neuroleptic age) but have been much more prevalent since the introduction of antipsychotic dopamine antagonist drugs. These include:
 * Akathisia, which refers to low amplitude, high frequency movement typically involving the lower extremities. The patient reports a feeling of intolerable restlessness, specifically manifested as a need to continuously move one’s feet. The patient cannot stop pacing (paces in place when asked to sit or stand without walking),
 * Dystonia, which refers to a high amplitude, low frequency, spastic type of movement, typically involving an isolated muscle group, e.g., oculopharogyric crisis (eyes turned upwards), torticollis (neck turned sideways), laryngeal spasm (rare but serious as it might result in asphyxia), opisthotonus (arched back, rare, painful)
 * Dyskinesia, which refers to low amplitude, repetitive, moderate frequency, pseudo-parkinsonian movements that may involve any muscle group but most typically involve the fingers, hands, toes, feet, lips and lower face muscles (including perioral and mandibular muscles)
 * Tremor, which refers to a low amplitude, high frequency, repetitive movement. Tremor of the hands and fingers can be spontaneous or can be elicited by asking the patient to put his arms in a horizontal position and stretch his fingers. In addition, a parkinsonian pill rolling tremor may also be observed. In patients taking lithium a fine tremor(very low amplitude, very high frequency) may be seen.

Mental Status Examination (MSE)

 * Appearance: disheveled or bizarre appearance may be a clue to underlying psychosis. Impaired reality testing commonly results in poor grooming and hygiene.
 * Attitude: paranoid patients may be unwilling to co-operate during an interview, while very psychotic patients my be unable to engage with the interviewer.
 * Motor behavior: posturing, repetitive gestures, extreme psychomotor agitation (without any apparent precipitants or retardation) can indicate a catatonic presentation. Alternatively, the patient may present with psychomotor agitation in response to overwhelming internal stimuli (e.g., loud, demeaning voices or threatening visions) or because of severe paranoid ideation.
 * Mood: patient’s reported mood can vary from good to depressed or afraid.
 * Affect: paranoid patients present with guarded affect, eyes scanning the room, and a closed up body language.
 * Speech/thought process: can be vague, circumstantial or overtly disorganized. At times nonsensical neologisms, word salad, clang (rhyming, nonsensical associations) are present.
 * Thought content: may be positive for delusional ideation (most common ideas of references and paranoid delusions). In addition, the patient may harbor suicidal and violent thoughts due to his persistent psychotic symptoms or, at times, related to concomitant depressive symptoms.
 * Perceptual disturbances: auditory hallucinations can be commanding and order the patient to kill himself or other people. When visual hallucinations are present they tend to be unpleasant as a rule and are often overtly terrifying.
 * Insight and Judgement: judgement is mostly impaired and the patient has very limited, if any, insight.
 * Cognition: with the possible exception of decreased attention, other cognitive deficits may not be obvious during a cursory MSE.

Cognitive Examination
In schizophrenia neuropsychological testing routinely reveals deficits in working memory, executive functioning, social functioning, processing speed, verbal fluency, and/or reaction time abnormalities. Unfortunately, the ability to test for these deficits routinely in clinical practice is limited by the lack of good, time efficient screening cognitive instruments for schizophrenia and related disorders.

Laboratory Tests
There are no tests that can rule in a diagnosis of schizophrenia or related disorders. The role of laboratory investigations are to rule out substance induced disorders and general medical conditions that can present with a psychotic syndrome; to establish a baseline and monitor physiological functions that can be affected by, or can affect the metabolism of psychotropic medications; and monitor drug levels when necessary.

Investigations to exclude a substance induced disorder or general medical condition:
 * urine or blood toxicology screen: should be performed routinely in all patients presenting with new onset or exacerbated psychotic symptoms, as a number of illicit drugs can cause/worsen psychosis (e.g., hallucinogens, cocaine, stimulants, marijuana).
 * Complete blood cell count (CBC): blood dyscrasias can point to an underlying vitamin deficit that may manifest with psychosis (e.g., pernicious or megaloblastic anaemia as a sign of vitamin B12/folate deficits)
 * Rapid plasma reagin (RPR): done to rule out (tertiary) syphilis
 * Thyroid panel: indicated when there is a clinical suspicion for hypo or hyperthyroidism
 * Brain Imaging:
 * Structural brain imaging (CT or MRI) is indicated to rule out other brain pathologies (e.g., multiple strokes, demyelination, masses). Neuroimaging studies do not show a pattern of findings specific for schizophrenia or related disorders and may be normal early in the course of the disease. As schizophrenia progresses, enlarged ventricles and diffuse cortical atrophy becomes apparent. MRI scans may also show atrophy of the parahippocampal gyrus, dorsolateral prefrontal cortex, mesolimbic system, the anterior cingulate cortex, and planum temporalis asymmetry reversal or generalized reductions in grey and white matter.
 * Functional brain imaging studies (PET and functional MRI) demonstrate abnormalities in the same regions. However, none of these changes are pathognomonic for schizophrenia or related disorders.

A liver function panel and chemistry panel (to document renal function) are recommended to establish a baseline for physiological functions that can affect the metabolism of psychotropic medications. Other tests that may be indicated to monitor side effects of psychotropic medication include a blood glucose level, a lipid panel, and an ECG (as some antipsychotics have the potential of prolonging the QTc interval). A prolactin level should only be measured when prolactinemia is suspected on clinical grounds.

The following drug levels need monitoring: lithium (0.7 to 1.2 mEq/L), carbamazepine (5 to 12 mcg/mL), and valproic acid (50 to 100 mcg/mL). A clozapine level above 350 ng/mL is recommended to establish compliance and has been shown to correlate with improved efficacy for refractory schizophrenia. There is no clear evidence of a therapeutic range for other antipsychotics.

General Considerations and Differential Diagnosis
When a patient presents with a psychotic syndrome the first order of business is to establish if the presenting symptoms are due to another psychiatric or somatic condition. In other words, a psychotic syndrome is classified as "primary psychosis" only after other possible underlying pathologies have been ruled out.

In terms of somatic contributors, the main suspects should include processes that may affect the brain either acutely or chronically, in which case a diagnosis of psychotic disorder due to a general medical condition is appropriate. A substance induced psychotic disorder should be diagnosed if there is a likely cause and effect relationship between a substance (including medication, OTC products or illicit drugs) and the psychotic presentation. Psychiatric underlying pathologies include severe depressive and bipolar disorder, which may present with mood congruent psychotic features. As discussed, under stress, some personality disorders may present with transient psychotic symptoms.

The differential diagnosis between different primary psychotic disorders should take into account the type and duration of symptoms. Virtually identical symptoms are seen in schizophrenia, brief psychotic disorder, and schizophreniform disorder. The symptom duration differentiates brief psychotic disorder (1 day to <1 month) from schizophreniform disorder (1 month <6 months) and schizophrenia (>6 months). Delusional disorder is differentiated from schizophrenia based on prominent, non-bizarre delusions without any other associated symptoms. When distinct psychotic episodes are present but affective symptoms account for the majority of the clinical presentation a diagnosis of schizoaffective disorder should be considered.

Conceptual History and Diagnostic Classification

 * 1853: Morel’s curious cases of Démence Précoce: Bénédict Morel introduces the concept of Démence Précoce, literally "early dementia", described  a distinct syndrome affecting teenagers and young adults. The syndrome is characterized by bizarre behavior and mental function, withdrawal and self neglect starting in adolescence.


 * 1868: Kahlbaum’s Katatonie: Karl Ludwig Kahlbaum and Ewald Hecker publish Die Gruppierung der psychischen Krankheiten  (The Classification of Psychiatric Diseases). By considering the longitudinal course of psychiatric symptoms in addition to the clinical presentation Kahlbaum and Hecker were the first to describe and name a number of psychiatric syndromes including cyclothymia, dysthymia, paranoia, catatonia, and hebephrenia. Kahlbaum’s Katatonie was characterized by stereotyped movements, outbursts of excitement and stupor.


 * 1870: Ewald Hecker’s hebephrenia and cyclothymia: Hecker differentiates between hebephrenia, a disorder that begins in adolescence with erratic behavior followed by a rapid decline of all mental functions, and cyclothymia, a cyclical mood disorder.


 * 1891: Arnold Pick reports on a case of a psychotic disorder which he calls Dementia Praecox
 * 1893: Emil Kraepelin’s Dementia Praecox: Kraepelin new classification of mental disorders distinguishes between dementia praecox and mood disorder (termed manic depression and including both unipolar and bipolar depression).
 * Dementia Praecox: A "sub-acute development of a peculiar simple condition of mental weakness occurring at a youthful age."
 * Distinct from catatonia and dementia paranoides.
 * Kraepelin’s concept relied heavily on course (chronic versus episodic) and prognosis


 * 1899: hebefrenia, catatonia and dementia paranoides as subtypes of dementia praecox.
 * 1919: Kraepelin writes that "it is becoming increasingly clear that we cannot distinguish satisfactorily between these two illnesses and this brings home the suspicion that our formulation of the problem may be incorrect."
 * 1908: Eugen Bleuler’s Schizophrenia gk. skhizein "to split"+ phren (gen. phrenos) "diaphragm, heart, mind", where "split mind" referred to being split off from reality and unable to distinguish what is real from what is not real. Of note, Bleuler never implied that people with schizophrenia have split personalities; he proposed the term of schizophrenia to describe the separation of function between personality, thinking, memory, and perception.
 * Bleuler 4 A's: flattened Affect, Autism, impaired Association of ideas and Ambivalence.
 * Bleuler proposal for a new name also stemmed from his dissatisfaction with the implications of dementia praecox label. Bleuler noted that schizophrenia was NOT a dementia, as some of his patients improved.


 * 1887 – 1967: Kurt Schneider described the first rank symptoms (FRS), thought to be specific for schizophrenia psychosis. He included thought insertion/broadcast/withdrawal, made feelings/impulses/actions/somatic sensations (a type of delusion), third person auditory hallucinations (running commentary or arguments), delusional perception, and thought echo (echo de la pensee or gendankenlautwerden) – a type of hallucination. Only 58% of patients with a diagnosis of schizophrenia experience at least one FRS, while 20% never experience FRS. Furthermore, 10% of patients with a diagnosis of schizophrenia experience FRS.


 * Modern positive and negative symptoms based classification systems:
 * Positive symptoms include distortions or excesses of normal functioning such as, hallucinations, delusions, disorganized thinking and speech, and inappropriate affect. Frequently hallucinations are auditory in nature; rarely they may be visual, tactile or olfactory. Delusions are fixed false beliefs held despite negative evidence, and are not consistent with cultural norms. Types include persecutory, referential, somatic, grandiose, etc. Positive symptoms are generally more responsive to treatment than negative symptoms.
 * Negative symptoms involve a decrease or absence of normal behavior. They include affective flattening, impoverishment of speech and language, avolition, amotivation, lack of interest, anhedonia, and social isolation.


 * Modern classifications:
 * Andreasen's Positive and Negative Symptoms Type
 * Crow Type I and II:
 * Type I – positive symptoms, good response to treatment, relatively better outcome
 * Type II – negative symptoms, poorer response to treatment, relatively poor outcome, MRI changes.

Current classification – ICD 10/ DSM-IV-TR
Common ICD/DSM types:
 * Paranoid schizophrenia:
 * Prominent delusions, auditory hallucinations
 * Usually minimal thought disorder or negative symptoms

DSM IV only: ICD 10 only:
 * Catatonic schizophrenia is characterized by prominent psychomotor symptoms e.g., violent excitement, posturing, waxy flexibility, automatic obedience, perseveration, stupor.
 * Residual schizophrenia or "defect state", when positive symptoms give way to negative symptoms.
 * Simple schizophrenia refers to insidious development of negative symptoms without positive symptoms
 * Disorganized schizophrenia: mainly thought disorder, and negative symptoms, without prominent positive or affective symptoms.
 * Hebephrenic schizophrenia: affective abnormality, thought disorder, mannerisms. May have chronic course.

Epidemiology and Risk Factors
The life time prevalence of schizophrenia is between 0.5-1.5% in the general population and is one of the ten leading causes of disability worldwide. Of note, this 1 in 100 rate has been shown to be remarkably constant across different historical periods and across different cultures. The annual incidence is reported to be in the range of 0.5 to 5 per 10,000. The onset of schizophrenia is usually between the ages of 20-45. Most times, the course of the disorder is chronic and characterized by a gradual, progressive deterioration. However partial or complete recovery is reported to occur for 30-60% of patients following a first episode of schizophrenia.* About 20-40% of patients with schizophrenia attempt suicide at least once during their lifetime, and about 10-15% die of suicide. The prevalence in males and females is equal.

The following risk factors have been reported for schizophrenia:
 * Men tend to be diagnosed earlier than women (males age 15-25 years, females age 25 – 35 years)
 * Seasonality: winter birth excess
 * Schizoid and schizotypal personality disorders
 * A family history of schizophrenia or major affective disorders
 * A family with a high level of expressed emotions (EE)
 * Schizophrenia tends to be more frequent in urban areas and in developed countries
 * Lower socioeconomic status
 * Schizophrenia is more frequent in recent immigrants (deprivation, stress of immigration may increase risk)

Genetic Considerations
The rate of schizophrenia is increased in families with affected members. Mode of Transmission is unknown and likely to be multi-factorial, possibly polygenic. 70% of the heritability of schizophrenia is genetic. Adoption studies have shown an increased incidence of schizophrenia spectrum disorders among adopted offspring of schizophrenic parents. When one parent has schizophrenia there is a twelve fold increase in the risk of developing the disorder; with one affected sibling there is a 9 fold increase in risk; for monozygotic, identical twins the rate of concordance is around 50%. Working memory appears to be heritable and showed significant associations with DISC1, reelin, and AKT1 in schizophrenia.

Pathology
While there are no structural or functional brain changes specific to schizophrenia or other psychotic disorders a number of abnormalities are reported. Enlarged ventricles, deep cortical sulci, diffuse gray and white matter loss, increased neuronal density, decreased synapse density, and an overall decrease in brain size have been reported in schizophrenia studies using structural brain imaging (CT, structural and diffusion sensor MRI studies) or postmortem observations. Smaller frontal and temporal lobes, lower volume hippocampus, thalamus, corpus callosum, and anterior cingulate, as well as larger caudate and putamen have been reported in schizophrenia.

Decreased activation in dorsolateral prefrontal cortex (during working memory task), and increased activation of the superior temporal gyrus (during auditory hallucinations) have been also reported in functional brain imaging (fMRI and PET) studies.

Neurodevelopmental Theories
Impaired fetal or neonatal brain development may sow the seeds for the onset of psychotic symptoms in later life. Patients with schizophrenia have a lower than average IQ, and often subtle/soft neurological signs. A number of parental risk factors have been reported including multiparity, maternal bleeding during pregnancy, small baby size for gestational age, increased paternal age, and severe stress to mother during first trimester. In addition, the following environmental risk factors have been associated with increased risk of developing psychotic illness later in life: late winter birth, prenatal exposure to famine, in-utero exposure to analgesics, and cannabis use.

Electrophysiology

 * P50 sensory gating deficits: following an auditory stimulus schizophrenia patients fail to gate a subsequent stimulus that follows closely (within the normal 50 msec suppression).
 * Reduced P300 evoked response potential (ERP) [oddball deficit paradigm]: schizophrenia patients fail to respond to an odd ball stimulus administered during a series of otherwise identical stimuli.
 * Prepulse Inhibition (PPI) Paradigm.

Neurotransmitters
Dopamine (DA)
 * Hypothesis: excessive DA activity in mesolimbic and cortical brain regions. Schizophrenia is the result of a dopaminergic hyper-salient state
 * Supporting evidence:
 * Postmortem studies: increase DA receptors in schizophrenia
 * HVA (dopamine metabolite) in plasma, CSF and severity of psychosis/response to neuroleptics
 * DA Agonists
 * Amphetamines release DA at synapses and cause positive symptoms (in people who do not have schizophrenia)
 * L-dopa increases central DA concentrations and causes positive symptoms
 * DA Antagonists: All effective antipsychotics are D2 receptor antagonists; efficacy correlates with D2 occupancy
 * Limitations:
 * Amphetamines and L-dopa do not produce negative symptoms
 * Antipsychotics are ineffective in 30% of patients
 * Antipsychotics block D2 receptors instantly but antipsychotic effect not evident for days

Serotonin
 * Hypothesis: serotonin excess
 * LSD and psilocybin are potent 5HT receptor agonists and cause positive symptoms of schizophrenia (in people who do not have schizophrenia)
 * Atypical antipsychotics are potent 5HT2 receptor antagonists
 * Limitations: LSD produces visual hallucinations which are uncommon in schizophrenia

Excitatory amino acids (EAAs): glutamate and aspartate
 * Hypothesis: EAAs deficit
 * Phenylcyclidine (PCP), which antagonizes EAA receptors, can produce positive and negative symptoms in people without schizophrenia
 * Glutamate agonists (e.g., glycine), may be modestly therapeutic in schizophrenia

Psychological Factors

 * Freud: delusions as a way of making sense of a disturbed internal world ("I need to respond with aggression to protect myself as everyone is attacking me").
 * Klein: failure to resolve the paranoid/schizoid position
 * Cameron: loss of conceptual boundaries
 * Goldstein: concrete thinking
 * Difficulties in filtering sensory input (see also electrophysiological findings)

Familial/Social Factors

 * Probably more important in precipitating schizophrenia than causing it
 * Lidz’s marital schism/marital skew
 * Bateson’s double bind theory
 * High expressed emotion

Social Factors

 * Social adversity in childhood and fetal life associated with risk of developing schizophrenia and other psychoses later in life
 * Risk factors for psychoses later in life (in developed countries):
 * households receiving social welfare benefits
 * unemployment
 * single-parent households
 * low socioeconomic status
 * rented apartments

Clinical Diagnosis
According to DSM-IV Schizophrenia is diagnosed when the patient presents with a combination of positive (delusions and hallucinations) and negative symptoms, which have been present for at least 6 months and have resulted in significant dysfunction. It is also accepted that disorganized speech/behavior and/or catatonic symptoms, when combined with other positive or negative symptoms, can count toward a diagnosis of schizophrenia. Schizophrenia is a diagnosis of exclusion; in other words, it is required that there are no other medical, psychiatric, or substance-induced conditions that would explain the patient’s diagnosis better than schizophrenia.

Differential Diagnosis
Early in the disease course, other etiologies of psychosis should be excluded. These include treatable conditions such as tertiary syphilis, vitamin deficiencies, brain tumor, drug and medication intoxication, chronic infection, and mood disorders. While neuroimaging studies (CT and MRI) do not show a single specific pattern with schizophrenia or related disorders and may be normal early in the course of the disease a screening CT is recommended for patients with a first episode of primary psychosis, especially for late or acute onsets. An affective psychosis (mania or depression with psychotic features) should be ruled out if affective symptoms preceded psychotic symptoms or are dominating the clinical picture at the time of presentation. A diagnosis of schizoaffective disorder is appropriate if historically the course has been dominated by affective symptoms and there are at least some episodes of "pure" psychosis i.e., independent of the affective background. Symptom duration will separate brief psychotic disorder (<1 month), schizophereniform disorder (<6 months), and schizophrenia (>6 months).

Treatment
Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment.

Biological
Traditionally, dopamine 2 (D2) antagonists (blockers), most often labelled as first generation (typical) neuroleptics, have been the pillar of schizophrenia treatment. Some of the above issues have been resolved with the advent of the second generation antipsychotics (SGA) or atypical neuroleptics, a drug class that tends to share the mechanism of D2 and 5HT2 (serotonin) antagonism. We say "tends to share" rather than "share the characteristic" as the second generation drugs show a number of differences in terms of both receptor profile and affinities. To illustrate, the prototypical atypical neuroleptic is clozapine, a drug that has strong D4 and 5HT2A antagonism but only partial D2 antagonism. General prescribing principles:
 * D2 blockers, by decreasing the presumably excessive mesolimbic dopamine, have established efficacy for positive psychotic symptoms; however, due to concomitant blockade of the frontostriatal dopamine pathway, where dopamine is presumably decreased all along in schizophrenia, they do not improve (and in some cases can worsen) negative, cognitive symptoms, and/or functional/social outcomes.
 * Due to an alteration of the physiological dopamine/acetylcholine ratio in the basal ganglia these drugs also have a number of extra-pyramidal adverse effects (EPSEs) both short term (acute dystonia, dyskinesia, akathisia) and long term (parkinsonism and tardive diskinesia).
 * Finally, following a dopamine blockade in the tuberoinfundibular system, there is a prolactin increase with common sexual side effects, including decreased sexual interest, sexual difficulties, lactation and (in men) gynaecomastia.
 * The side effects of typical neuroleptics can be stigmatizing and are a major reason for non-adherence to treatment.
 * SGAs have fewer EPSEs and tend to be better for negative symptoms than typicals (not increasing negative symptoms).
 * Some of the atypicals (e.g., olanzapine, clozapine) increase the risk for metabolic adverse effects including significant weight gain, diabetes and dyslipidemia.
 * Clozapine is recommended for treatment resistant schizophrenia.
 * Generally SGAs, with the exception of olanzapine and clozapine, are first line treatments. This preference is based more on better tolerability (less EPSEs and cognitive adverse effects) than greater efficacy. On a case by case basis first generation antipsychotics (FGAs) may represent a reasonable alternative. Perphenazine and molindone efficacy and overall tolerability has been shown to be similar to SGAs.
 * Initial management may include use of sedative medication such as lorazepam.
 * IM medication may be required in a very disturbed, involuntary patient.
 * Depot (long-acting) neuroleptics are indicated when treatment adherence is problematic.
 * Polypharmacy is common yet not supported by evidence.
 * The goal of treatment is stability on monotherapy at the lowest effective dose.

Psychological (Individual and Family Interventions)

 * Good evidence:
 * Education of patient and carers
 * Reduction of high expressed emotion: shown to affect relapse rates
 * Supportive, solution oriented psychotherapy


 * Unclear benefit:
 * Cognitive behavioral therapy
 * Cognitive and functional rehabilitation
 * Self–help unclear

Social

 * Good evidence:
 * Regular intensive case management


 * Unclear benefit:
 * As needed case management
 * Consumer based organizations

Prognosis
15-25% of patients diagnosed with schizophrenia have one episode and no residual impairment. 25-40% have recurrent episodes and no residual impairment. 5-10% have recurrent episodes and develop significant non-progressive impairment. 30-40% have recurrent episodes and develop significant progressive impairment. Therefore, the majority of patients do not recover fully BUT DO NOT have a chronic unremitting course. There is little evidence that antipsychotics have altered the course of illness for most patients. However, evidence suggests that prolonged psychosis which is untreated has a bad prognosis. Suicide rate is up to 15%.

Good prognostic factors:
 * Female gender
 * Older age of onset
 * Married
 * Higher socioeconomic status
 * Living in a developing (as opposed to developed) country
 * Good premorbid personality
 * No previous psych history
 * Good education and employment record
 * Acute onset, affective symptoms, good adherence to medication.

Predicting risk of suicide:
 * Acute exacerbation of psychosis
 * Depressive symptoms
 * History of attempted suicide
 * Male gender
 * Command auditory hallucinations

Clinical Manifestations and Diagnosic Considerations
The clinical presentation is identical to schizophrenia, however impairment in function is not a requirement. The required duration of symptoms is of at least a month but less than 6 months. If symptoms persist for longer than 6 months it is appropriate to change the diagnosis to schizophrenia. The diagnosis requires for other pathologies that may be responsible for the clinical manifestations (e.g., medical and drug use) to be ruled out before a diagnosis of schizophreniform disorder is made. It is not clear if schizophreniform disorder is a different disorder or just a more acute, better prognosis type of schizophrenia.

Subtypes/Specifiers
With good prognostic features: Without good prognostic features: when less than 2 of the above features are present
 * Good premorbid level of function
 * Abrupt onset
 * Confusion
 * Absence of flat affect

Epidemiology
The prevalence is low overall. There may be differences between developed countries (estimated around 0.2%) and developing countries (estimated around 1%).

Treatment Considerations

 * Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment.
 * Acute psychosis should be treated with antipsychotics. Second generation antipsychotics, with the exception of olanzapine, are preferred first line.
 * Treatment should be continued for one year and reassessed after.
 * Supportive and solution oriented psychotherapy is beneficial.

Prognosis
About one third of the patients recover. The rest of the patients initially diagnosed with schizophreniform disorder progress to schizophrenia or schizoaffective disorder.

Clinical Manifestations and Diagnosic Considerations
Phenomenologically there is no difference between brief psychotic disorder (BPD), schizophreniform disorder, and schizophrenia. The difference between these three diagnoses is based on symptom duration. As indicated by its name, the duration of symptoms in BPD are brief: more than 1 day but less than 1 month. When the symptoms last longer than a month but less than 6 months the diagnosis changes to schizophreniform disorder. The psychotic symptoms should not be part of a pre-existing medical, drug induced, or primary psychiatric condition (including other psychotic or mood disorders).

Subtypes/Specifiers
DSM-IV-TR specifiers include:
 * With marked stressor(s) (brief reactive psychosis)
 * Without marked stressor(s)
 * With postpartum onset: when onset of symptoms is within 4 weeks postpartum

Epidemiology
Rare overall but more frequent in developing countries compared to developed countries.

Treatment Considerations
Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment. Neuroleptics for short term treatment should be considered on a case by case basis.

Prognosis
By definition full remission of symptoms and return to prior level of functioning is expected within a month.

Clinical Manifestations and Diagnostic Considerations
The patient presents with symptoms of schizophrenia, mania, depression or a combination of mood and psychotic symptoms. The history is significant for at least one distinct episode of psychosis not overlapping with mood symptoms and a relative temporal predominance of mood symptoms.

Differential diagnoses should include drug induced and medical conditions with secondary psychotic symptoms. While patients with schizophrenia can experience mood symptoms their duration is relatively short relative to the total duration of illness. When the psychotic symptoms represent a culmination of a severe mood episode a diagnosis of mood disorders (i.e., bipolar and major depression) with psychotic features should also be included in the differential.

Epidemiology
Unclear but possibly less common than schizophrenia.

Treatment Considerations
Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment.

Antipsychotics are recommended for acute psychotic symptoms. Second generation antipsychotics (SGA), excluding olanzepine, should be considered as first line. Mood stabilizers including lithium, valproic acid, and carbamazepine, or SGA are recommended for acute manic symptoms. A neuroleptic-mood stabilizer combination may work better than either agent alone, and augmenting a neuroleptic with lithium or valproic acid should be considered as an augmentation strategy in cases of poor response to neuroleptic monotherapy. Antidepressants should be used conservatively for depressive symptoms. Close monitoring is required as an antidepressant can precipitate a manic switch in a patient with schizoaffective disorder.

Prognosis
Better than schizophrenia but not as good as mood disorders.

Clinical Manifestations and Diagnostic Considerations
The patient presents with non-bizarre delusional beliefs but most often the mental status examination is otherwise fairly normal. The delusional ideas are restricted to a specific subject and do not contaminate other mental processes. Other psychotic symptoms may include olfactory/gustatory hallucinations, which may be prominent and are closely related to the main delusional themes. If prominent auditory/visual hallucinations are present a diagnosis of schizophrenia rather than delusional disorder may be more appropriate. Associated symptoms are rare but may include mood or anxiety symptoms. When present, such symptoms are often secondary to the delusional beliefs (e.g., "of course I feel anxious with the NSA following me around the clock"). Other conditions (medical, drug induced, other primary psychiatric disorders, including other psychotic or mood disorders) cannot better explain the clinical picture.

Subtypes/Specifiers

 * Erotomanic type: the patient erroneously believes that another person is in love with him/her
 * Grandiose type: the patient erroneously believes that he/she possesses enormous wealth, power, authority, knowledge, or has a special relationship to a deity or famous person
 * Jealous type: the patient erroneously believes that his/her partner is unfaithful
 * Persecutory type: the patient erroneously that he/she is targeted for punishment or retaliation
 * Somatic type: the patient erroneously believes that he/she has a medical condition or body deformity that is overlooked or misdiagnosed
 * Mixed type: delusions characteristic of more than one of the above types but without any one dominating theme
 * Unspecified type

Epidemiology
Rare. According to DSM-IV-TR estimated around 0.03% in the general population; 1-2% of all inpatient psychiatric admissions. The most common subtype is the persecutory type.

Treatment Considerations
Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment.

Prognosis
Variable: the jealous type may wane and wax or remit; the persecutory type is often chronic.

Clinical Manifestations and Diagnostic Considerations
Mental status examination is significant for non-bizarre delusions but otherwise is within normal limits. There are minimal associated mood or anxiety symptoms; if present such symptoms appear secondary to the tenaciously held delusional beliefs. History is significant for a close relationship with another person who presents with similar delusional beliefs and meets criteria for a psychotic disorder. The patient who first presents with delusional symptoms is designated as the "primary," the "secondary" follows. Also, usually, the primary is dominant in his/her relationship with the secondary, who acts as a more passive recipient. For example, a parent with schizophrenia and chronic paranoid delusions about FBI surveillance may be the primary while his/her child, who only recently started to believe that indeed there are FBI cameras hidden on their property, is the secondary. Other diagnoses, including medical or drug induced disorders as well as other psychotic or mood disorders, should be excluded if folie à deux is to be diagnosed.

Epidemiology
Rare overall but statistics may be misleading due to under-reporting. Preliminary data suggest an increased prevalence in women.

Treatment Considerations
Hospitalization is recommended if the acute psychotic symptoms result in danger to self or others or significant impairment. Usually removing the secondary from the primary's environment is sufficient to promote complete remission of symptoms. In addition, the primary's condition should be treated as indicated. Interestingly, a remission of the primary's symptoms is followed by the remission of the secondary's delusional beliefs.

Prognosis
When the secondary is separated from the primary the prognosis is good.