Schizophrenia and Dementia

What does the term "schizophrenia" actually mean, and what are its key epidemiological features?

Despite deriving from Greek "skhizein" (to split) and "phrēn" (mind), schizophrenia does NOT mean split/multiple personality — it means a "splitting of mental functions," reflecting the illness's presentation (in 2002, Japan renamed it "integration disorder" to reduce stigma).

Epidemiology: symptoms typically begin in late adolescence/young adulthood;
occurs at similar rates worldwide, affecting about 1% of people in their lifetime;
commonly comorbid with major depression and anxiety disorders, with lifetime substance use disorder near 50%;
social problems like long-term unemployment, poverty, and homelessness are common;
average life expectancy is 10-25 years shorter than average (from physical health problems and higher suicide rate); and it occurs 1.4 times more often in males, typically appearing earlier in men.

What environmental factors and biological theories (dopamine hypothesis) explain schizophrenia's etiology?

Environmental factors:
living environment, drug use, prenatal stressors, social isolation, immigration, racial discrimination, family dysfunction, unemployment, poor housing, childhood trauma, death of a parent, bullying/abuse, and urban living during childhood or adulthood (parenting style has no major effect, though supportive parents improve outcomes).

The dopamine hypothesis proposes:
excessive dopamine in the associative nigrostriatal pathway causes positive symptoms;
inadequate dopamine in the frontal cortex causes cognitive deficits (e.g., working memory);
dopamine deficit in the mesolimbic pathway (ventral striatum) correlates with negative symptom severity;
a hyperdopaminergic striatal state is seen in at-risk mental state subjects (30% of whom transition to schizophrenia); and
this dopamine dysregulation is thought to be secondary to a more proximal abnormal GABA-glutamate interaction.

What are the four phases of schizophrenia's clinical course?

Premorbid phase:
functionality before illness onset, where patients act odd/eccentric and avoid relationships (paranoid, schizoid, or schizotypal premorbid personalities — though not everyone with these personalities develops schizophrenia).

Prodromal phase:
transient/self-limiting psychotic symptoms plus non-specific symptoms (social withdrawal, irritability, dysphoria, anxiety, hypochondriasis, clumsiness).

Active phase: full diagnostic criteria are met (per DSM-5 in the US/research, or ICD-10 in Europe).

Residual phase: only negative symptoms remain.

What are the DSM-5 diagnostic criteria for schizophrenia?

A) Characteristic symptoms:
2+ of the following present for a significant portion of a 1-month period (or less if treated) —
delusions, hallucinations, disorganized speech, grossly disorganized/catatonic behavior, or
negative symptoms (affective flattening”reduced emotional expression”, alogia”poverty of speech”, avolition”lack motivation”);
only 1 symptom is needed if delusions are bizarre or hallucinations involve a running commentary voice or two+ conversing voices.

B) Onset causes marked decline in functioning (work, relationships, self-care) below the prior level.

C) Continuous signs persist for at least 6 months, including at least 1 month of active-phase (Criterion A) symptoms, with possible prodromal/residual periods showing only negative symptoms or attenuated positive symptoms.

D) Schizoaffective disorder and mood disorder with psychotic features are excluded (no concurrent major mood episodes, or their duration was brief relative to the active/residual periods).

E) The disturbance is not due to a substance or general medical condition.

What are the positive and negative symptoms of schizophrenia, and how do they respond to treatment?

Positive symptoms are experiences not normally present that appear in schizophrenia —
delusions, disordered thought/speech, and hallucinations (auditory, visual, tactile, olfactory, gustatory) often related to delusional content;
these generally respond well to medication.

Negative symptoms are deficits in normal emotional/thought processes — flat affect, poverty of speech, anhedonia, lack of desire for relationships, and lack of motivation;
these are less responsive to medication, contribute more to poor quality of life and caregiver burden, and are associated with poor premorbid adjustment.

What is the prognosis of schizophrenia, and what investigations and general approach are used?

Schizophrenia is a major cause of disability — active psychosis ranks as the third most disabling condition after quadriplegia and dementia;

patients have lower life expectancy and very high comorbidities with poor general health.

There is no specific diagnostic test for schizophrenia; investigations are important to exclude organic causes, monitor general health, and guide medication choice/monitor side effects.

What are the differential diagnoses for schizophrenia?

Other psychiatric illness: bipolar disorder, borderline personality disorder (psychotic symptoms), delusional disorder (non-bizarre delusions), social anxiety/avoidant/schizotypal personality disorder (social withdrawal, with schizotypal being similar but less severe), and OCD (which co-occurs more than by chance, and obsessions can be hard to distinguish from delusions).

Other medical/neurological illness: metabolic disturbance, systemic infection, syphilis, HIV, epilepsy, brain lesions, stroke, MS, thyroid disease, and dementias (Alzheimer's);
delirium must be ruled out (distinguished by visual hallucinations, acute onset, and fluctuating consciousness, indicating underlying medical illness).

Substance abuse: drug intoxication or drug-induced psychosis (e.g., amphetamines).

How is schizophrenia treated with hospitalization and antipsychotic medications, including their classification and mechanism?

Hospitalization may be voluntary or involuntary for severe episodes, though long-term hospitalization is now uncommon since deinstitutionalization began in the 1950s.

Antipsychotics are first-line,
reducing positive symptoms within 7-14 days, with continued use decreasing relapse risk; drug choice is based on benefits, risks, and cost.

Classification:
typical antipsychotics (haloperidol, chlorpromazine — dopamine antagonists),
atypical antipsychotics (risperidone, olanzapine, clozapine — dopamine AND serotonin antagonists),
and third-generation (aripiprazole — a partial dopamine agonist-antagonist).

Mechanism: typical antipsychotics non-selectively block D2 receptors (causing more side effects), while atypicals also act on serotonin receptors (especially 5-HT2A/5-HT2C).

What are the common adverse effects of antipsychotic medications?

Extrapyramidal side effects (from D2 blockade at the nigrostriatal pathway, more common with first-generation drugs):
akathisia (distressing inner restlessness),
dystonia, parkinsonism,
tremor (treated with anticholinergics and propranolol); and
tardive dyskinesia (slow, repetitive, involuntary, purposeless movements, especially of the face/lips, appearing after chronic use, more frequent with typical antipsychotics like haloperidol, often treatment-resistant and irreversible).

Hyperprolactinemia (from D2 blockade at the tuberoinfundibular pathway, rare with clozapine/quetiapine/aripiprazole): galactorrhea, gynecomastia, sexual dysfunction, osteoporosis.

Also:
orthostatic hypotension;
weight gain (prominent with clozapine, olanzapine, quetiapine via H1/5-HT2C antagonism);
and anticholinergic effects (blurred vision, constipation, dry mouth — common with olanzapine/clozapine, less with risperidone;
clozapine can paradoxically cause hypersalivation).

What are the rare/severe antipsychotic side effects, and how are treatment-resistant or non-compliant schizophrenia cases managed?

Rare but severe (< 1% incidence): neuroleptic malignant syndrome (a psychiatric emergency).

For treatment-resistant/refractory schizophrenia, clozapine is effective but carries the serious risk of agranulocytosis (lowered white blood cell count).
For patients unwilling/unable to take medication regularly, long-acting depot antipsychotic preparations reduce relapse risk more than oral medications, and combined with psychosocial interventions can improve long-term adherence.

What psychotherapy and ECT roles exist in schizophrenia treatment?

Psychosocial interventions include family therapy, supported employment, cognitive remediation, skills training, token economic interventions, and interventions for substance use/weight management;

Low role for CBT
evidence for CBT reducing symptoms or preventing relapse is minimal, and art/drama therapy are not well-researched.

ECT is indicated for suicidal attempts, catatonic stupor, and treatment-resistant cases.

What is dementia, and how does memory and other cognitive decline progress?

Dementia (Latin for "devoid of mind") is a persistent state of serious cognitive decline (memory, judgment, thinking, planning) plus functional, social, and emotional deterioration from a previously higher level of functioning —
distinct from mental retardation, which is static deficient cognitive development.

Memory decline: initially affects new learning (e.g., forgetting a recent phone call or breakfast); as it progresses, previously learned information is lost (names of famous people, local geography);
in advanced stages, patients may fail to recognize close relatives or even themselves.

Other cognitive decline: initially complex tasks (cooking multiple dishes, financial paperwork) become difficult; as it progresses, even simple tasks (paying bills, shopping) need assistance; in advanced stages, no cognitive activity is possible even with help.

What are behavioral and psychological symptoms of dementia (BPSD)?

They occur across dementia types —
vascular dementia commonly shows emotional instability, and
Lewy body dementia typically shows visual hallucinations.

Unlike cognitive symptoms, BPSD can be effectively treated.
The list includes: aggression, screaming, restlessness, agitation, hostility, wandering, hoarding, apathy, anxiety, mood changes, hallucinations, delusions, and sleep disturbance.

How is dementia classified, and what is the prevalence of the major dementing diseases?

By reversibility: dementia is by definition irreversible, but
a small proportion is reversible — hypothyroidism, B12/folate deficiency, normal pressure hydrocephalus, chronic subdural hematoma.

By patho-etiology (most accurate):
neurodegenerative (Alzheimer's disease, Lewy body dementia, frontotemporal dementia, Huntington's disease, normal pressure hydrocephalus) versus
non-neurodegenerative (vascular/multi-infarct, traumatic/chronic subdural hematoma, inflammatory/CNS vasculitis/MS, infectious/HIV/Lyme/neurosyphilis, neoplastic, toxic/alcoholism, metabolic/renal-hepatic failure, endocrinal/hypothyroidism, nutritional/B12-folate-thiamine deficiency causing Wernicke-Korsakoff psychosis).

Severe depression can mimic dementia ("depressive pseudodementia") and is also a risk factor for later dementia.

How is Alzheimer's disease diagnosed, and what are its progressive stages?

Alzheimer's disease (AD) is the most common dementia (about two-thirds of cases), causing gradual cognitive decline, often starting with recent memory loss.

Diagnosis requires one or more acquired significant impairments (with lost independence) in cognitive domains:
memory (amnesia), language (aphasia),
purposeful movement execution (apraxia), recognition (agnosia),
visuospatial function (topographical disorientation), or self-management (executive dysfunction);
other manifestations include dyscalculia, dysprosody, agraphia, perseveration, and emotional lability — other causes of dementia/memory loss must be excluded.

AD progresses through distinct stages: it may be preceded by mild cognitive impairment (MCI), then progresses through mild, moderate, and severe phases.

What are the risk factors and potential protective factors for Alzheimer's disease?

Risk factors: age over 65 (the most important, though not everyone over 65 develops dementia), female sex, Down syndrome, smoking, metabolic syndrome, midlife obesity, low educational level, depression, and the ApoE4 allele for late-onset AD (one allele doubles risk, two alleles increase risk 5-fold).

Protective factors: physical activity, high IQ/education, intellectual stimulation (reading), and antioxidant-rich food.

What is the pathology of Alzheimer's disease, and how do early-onset and late-onset AD differ?

Gross pathology shows marked brain atrophy.

The three consistent histopathological hallmarks are:
extracellular amyloid-rich senile plaques,
intracellular neurofibrillary tangles,
and neuronal degeneration —
these changes begin years before clinical symptoms appear, and a definitive diagnosis can only be made post-mortem.

Acetylcholine loss in the hippocampus correlates with AD severity, and increased (excitotoxic) glutamate also contributes to pathology.

Late-onset AD occurs after age 65, with ApoE4 as the main genetic risk factor;
early-onset AD occurs before 65, is more severe and rapidly progressive, and is linked to amyloid precursor protein (APP) and presenilin 1/2 (PSEN1/2) gene mutations.

What investigations, differential diagnoses, and treatments are used for Alzheimer's disease?

Investigations:
cognitive assessment (MMSE, MoCA), lab studies (routine chemistry, serum B12, thyroid function), and neuroimaging (CT or MRI brain in certain cases).

Differential diagnosis: normal age-related forgetfulness, other dementia causes, delirium, and other psychiatric illness with memory loss (e.g., depression in the elderly).

Treatment:
non-pharmacological (cognitive enhancement, individual/group therapy, environmental modification, safety attention);
pharmacological — cholinesterase inhibitors (donepezil, rivastigmine, galantamine, which increase synaptic acetylcholine and are the only proven treatment for mild-to-moderate dementia, slowing but not reversing progression),
memantine (an NMDA partial antagonist effective in moderate-to-severe cases),
and cautious low-dose antidepressants/antipsychotics when needed; caregiver support is also important since about a third of caregivers develop depression (no proven treatment yet slows MCI progression).

What is delirium, and what are its key clinical characteristics?

Delirium (also called acute confusional state, ICU psychosis, sundowning, encephalopathy, acute brain failure, or syndrome of cerebral insufficiency)
is a transient, usually reversible cerebral dysfunction causing a broad range of neuropsychiatric abnormalities, hallmarked by waxing and waning signs/symptoms/sensorium with fluctuating alertness — it is life-threatening but preventable.

Clinical characteristics:
acute onset (hours to days);
fluctuating consciousness that worsens in the evening (sundowning);
reduced ability to focus/maintain/shift attention;
agitation (hyperactive type) or hypersomnolence (hypoactive type), or a mixed type;
extreme emotional lability;
a cognitive/perceptual change not better explained by pre-existing dementia;
and evidence the disturbance stems from an underlying medical condition.

It occurs in 10% of hospitalized medical patients, with a further 10-30% developing it after admission; postoperative delirium occurs in 15-53% of patients and 70-87% of ICU patients.

What causes delirium, and what are its major risk factors?

Etiology is usually multifactorial: systemic illness (infections, electrolyte abnormalities, endocrine dysfunction, hepatic/renal encephalopathy, pulmonary disease with hypoxemia, cardiovascular events, CNS pathology like tumors/strokes/seizures, and deficiency states like thiamine/B12/folate); and medications (anticholinergics, analgesics, steroids, antiparkinsonian drugs, sedatives/alcohol, anticonvulsants, antihistamines, antiarrhythmics, antihypertensives, antidepressants, antimicrobials, sympathomimetics, and others like furosemide/digoxin/theophylline).

Risk factors: age over 60, prior cognitive impairment/dementia, multiple comorbidities, prior delirium/stroke/neurological disease/falls, fever, substance abuse, polypharmacy (>4 medications), anticholinergic drug use, severe acute illness, ICU admission, and high number of hospital procedures.

How is delirium tested, subtyped, differentiated from dementia, and treated?

Testing:
MMSE alone isn't sensitive for delirium, but repeated MMSEs can reveal the waxing/waning course;
the most sensitive test items are serial 7s, orientation, and recall memory (also spelling WORLD backward or counting down from 20).

Subtypes: hyperactive (hypervigilant, restless, rapid/loud speech, anger, combativeness, wandering) and
hypoactive (lethargy, decreased alertness, staring, sparse/slow speech, apathy).

Differentiation from dementia:
delirium has acute onset, fluctuating course, days-to-weeks duration, altered consciousness, impaired attention, variable psychomotor changes, and is usually reversible;

dementia has insidious onset, progressive course, months-to-years duration, clear consciousness, normal attention (unless severe), often normal psychomotor activity, and is rarely reversible (the two can coexist).

Treatment: treat the underlying cause; environmental interventions (orientation cues, frequent reorientation, familiar visitors, minimizing staff changes);
minimizing psychoactive/anticholinergic/sedating medications;
small doses of antipsychotics (haloperidol, risperidone, or low-dose quetiapine) for agitation.