Introduction
Psychotic disorders are clinical conditions characterized by major changes in thought and critical judgment, affecting individual relationships while also impairing functioning and quality. Unlike primary psychiatric conditions, where etiology is thought to be an interaction between genetic vulnerability and exposure to stressors, in organic psychoses a medical condition or treatment underlies the behavioral changes and typically determines treatment, outcome, and prognosis. In the Diagnostic and Statistical Manual of Mental Disorders , 5th Edition (DSM-5; Tables 9.1 and 9.2 ), organic psychosis can be classified in the topics substance/medication-induced psychotic disorder and psychotic disorder due to another medical condition. (See Fig. 9.1 .)
| (1) Substance/medication-induced psychotic disorder—diagnostic criteria |
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| (2) Psychotic disorder due to another medical condition—diagnostic criteria |
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In most cases, the evolution of organic psychosis varies from ordinary psychotic disorders, which more often have high rates of family abandonment, other psychiatric comorbidities, social and marital impairment, and work problems. The spectrum of clinical conditions potentially relating to the occurrence of psychotic disturbances is extremely broad and includes infectious, autoimmune, inflammatory, neurodegenerative, metabolic, and cardiovascular mechanisms ( Tables 9.3 and 9.4 ). Medication-induced psychosis is commonly related to certain specific drug categories and treatment regimens. Iatrogenic psychoses can have severe outcomes, including new-onset or worsened chronic disability, and can render clinical management extraordinarily difficult. In certain cases, psychosis precedes more severe and overt toxicity, which can lead to encephalopathy and central nervous system (CNS) depression.
| Dementia and other neurodegenerative causes of psychosis | |
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| Medical illness-related psychosis: causes | |
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In this chapter, the most important causes of organic psychotic disorders, their diagnosis, symptoms, and treatment are described and discussed.
Neurobiology and Putative Mechanisms of Organic Psychosis
The increasing knowledge of neurobiology in mental disorders has enabled further understanding of the relationship between changes in brain structure to functional and psychotic manifestations.
Genetic and neuroimaging studies
Genetic studies on first-episode psychosis have investigated the role of auto-antibodies associated with encephalitis in the autoimmune encephalitis with anti- N -methyl- d -aspartate (NMDA) and encephalopathy associated with autoimmune thyroid diseases (EAATDs). Putative mechanisms relating NMDA receptors to psychosis comprise down-regulation of glutamate receptors. The most frequent genetic syndrome implicated in schizophrenia is 22q11.2 deletion syndrome (DS), whose incidence is estimated in the range of 4300 to 7000 live births. Four classical chromosomal anomalies leading to psychosis include Prader-Willi syndrome, Turner syndrome, Klinefelter syndrome, and juvenile-onset Huntington disease, defined as onset before age 20, seen in 5% of cases. Table 9.2 : DSM-5 diagnostic criteria (American Psychiatry Association) in psychosis due to a medical condition.
Several brain regions have been implicated in the pathophysiology of psychotic-related symptoms, for instance the temporal, ventromedial, and orbitofrontal cortex, the anterior cingulate, and the nucleus accumbens . In addition, behavior disturbances may result from neuronal disruption in specific networks; as a matter of example, the cholinergic transmission might be affected by a disruption in the anterior cingulate, insula, lateral frontal, and lateral temporal circuits, leading to agitation and aggression. In patients with age-related cognitive disorders, including Alzheimer disease (AD) and mild cognitive impairment, the occurrence of psychosis and agitation is regarded as among the most common features during disease progression. Most of these patients also present aberrant motor activity, delusions, and hallucinations.
More recent neuroimaging techniques are able to explore the neuroradiologic underpinnings of organic psychosis. Using single-photon emission computed tomography (SPECT), organic psychotic symptoms have been associated with lower perfusion in distinct areas, including the prefrontal cortex (bilaterally), the left anterior cingulate, ventral striatum and pulvinar areas, the parietal lobe, and the right occipital lobe.
Some of these findings are similar to neuroanatomical abnormalities prodromally noted in functional psychosis patients. In particular, prefrontal cortex dysfunction may predispose to various psychoses (see Chapter 2 ). Paranoid symptoms have also been related to cortical thinning in the left medial orbitofrontal and superior temporal areas, and delusion and hallucination were also associated with vascular lacunae in the left basal ganglia. In one SPECT study, the severity of symptoms was associated with lower regional cerebral flow in parietal-temporal lobes in the AD group. These findings suggest that major pathologic events compromising brain-distributed networks, particularly those involved in the emotional regulation, inhibition and reward control, and sensorial interpretation (i.e., visual and auditory stimulus), underlie some of the psychopathologic features commonly reported in AD.
Neuronal networks from the right hemisphere are thought to regulate social and sexual behavior. Agitated behavior in AD seems to have a right hemisphere predominance. In addition, the temporal and inferior frontal lobes and the basal ganglia might also participate in emotional regulation, as demonstrated by studies with AD. Indeed, previous histopathologic evidence has indicated that poorer social judgment and inappropriateness of behavior in AD may be associated with neurofibrillary tangles in the orbitofrontal cortex.
Seizure-related psychosis usually involves frontal and mesial temporal dysfunction. According to Bear and colleagues, temporal lobe epilepsy (TLE) may result from altered regulation and increased connectivity of sensory limbic circuitry, mostly as a result of progressive changes secondary to epilepsy activity in these areas, clinically acknowledged as the kindling effect . Other findings related to epilepsy also include inter-hemisphere asymmetry, including smaller right temporal volume and reduced positron emission tomography (PET) metabolism in frontal, basal ganglia, and temporal areas.
Interestingly, psychosis-related changes were often reported in the anterior portion of the brain. In age-related disorders, these changes could also be found in mild cognitive impairment subjects and included higher atrophy in frontal and parietal areas, cingulate, anterior cingulate, and fornix. Conversely, age-related brain changes are often associated with cognitive decline and decrease in cognitive reserve, representing one major risk factor for drug- or medication-induced psychosis, particularly among the elderly.
Epidemiology
The prevalence of medical illness–related psychosis in the different age groups correlates directly with the underlying cause, that is, the related etiologic agent, as well as with varied sociodemographic characteristics. For example, these include exposure to bacterial and viral infectious pathogens, positive family history of autoimmune diseases, and socioeconomic characteristics (adequate nutrition conditions, basic health service access, vaccinations, regular pediatric visits). Occupational factors include exposure to neurotoxic pathogens such as mercury and lead among beauticians, painters, pesticide handlers, farmers, and mine workers. Duration of exposure and the absorbed dose are relevant prognostic factors. In adults, the use of licit and illicit drugs, such as cocaine, marijuana, and synthetic drugs, can trigger changes in thinking, such as paranoid ideation, as well as agitation and restlessness (see Chapter 8 ). The occurrence of psychosis in users of amphetamine may reach 100% and 80% in the case of cannabis and cocaine, respectively. Such changes can be identified in acute or chronic intoxication and in abstinence.
Approximately 80% of patients with systemic lupus erythematosus (SLE) develop psychotic symptoms within the first year of diagnosis and of these, 5.4% seem to present medication-induced psychosis. As already outlined, the aging process also greatly increases the occurrence of organic psychotic phenomena. Factors that are classically linked to aging, such as increased occurrence of heart disease (including atrial fibrillation and other arrhythmias), peripheral and cerebral vascular disease, regional volumetric changes of degenerative origin in the limbic system as well as temporal and frontal area structures, may each be determinants. Paraneoplastic manifestations and neurologic tumors should also be considered, especially if endocrine or CNS.
Classification of Medical Illness-Related Psychosis
A large number of potential conditions leading to psychotic disturbances should be considered (see Tables 9.3 and 9.4 ). They often vary according to age range, genetic and familiar characteristics, previous history of behavior disturbance, environmental exposure to chemical agents, pesticides, access to medication, and medical comorbidities. Thus, medical causes of psychosis can derive from multiple potential clinical causes, for example, dementia, metabolic disorders (e.g., hypothyroidism, Wilson disease, Niemann-Pick type C, porphyria), medications, or use or abuse of substances. Establishing underlying organic diagnoses is essential to determining proper treatment and prognosis.
Degenerative and other neurologic causes
One of the leading causes of medical illness-related psychosis is aging-related disorders. An estimated 40% to 60% of AD patients, for instance, experience hallucinations and delusions. The presence of psychotic symptoms in dementia increases the deterioration of life quality and accelerates institutionalization. In Lewy body dementia (LBD), visual hallucinations are one hallmark of the disease. Psychosis can be seen also in frontotemporal dementia (FTD), Pick disease, and Huntington disease. Behavior disturbances seem to be closely related to regional brain atrophy and specific network disconnection, rather than resulting from global brain degeneration. Inappropriate behaviors, like agitation, may be the result of inadequate activation of the salient network, in areas such as the insula, amygdala, striatum, and anterior cingulate.
Parkinson’s disease (PD) affects 1 in 100 individuals over 60, with new cases increasing in advanced age groups, reaching a 14% incidence rate above 70 years. Psychotic symptoms usually occur secondary to pharmacologic treatment with levodopa and dopamine agonist agents. The basic distinction between PD and LBD would be the early occurrence of cognitive symptoms in the latter, while in PD, motor symptoms usually precede cognitive deterioration. The occurrence of dementia in PD may be linked to such predictive factors as delusions and visual or auditory hallucinations. About 61% of patients with PD exhibit neuropsychiatric disorders, with hallucinations present in 27% of cases. Symptoms such as advanced age, history of depression, and sleep disorder are also considered predictors of psychosis.
Vascular dementia, secondary to stroke, can present with psychotic features, especially when the lesion is in the right temporo-parieto-occipital area. Other areas of the brain are also associated with hallucinations when injured by stroke. The occurrence of psychosis in vascular disease can reach 46%. The occurrence of psychosis may be related to decreased perfusion in the parietal lobe left anterior cingulate and prefrontal cortex.
Psychosis of epilepsy usually encompasses a wide group of disorders with etiopathogenetic mechanisms believed to be directly connected to seizure disorder. The prevalence of such conditions may be considerably higher than primary forms of schizophrenia, ranging from 7% to 10%. Most clinical manifestations, around 25% of cases, occur in post-ictal states, where the occurrence of confusion or psychotic features follows 1 week or less after a seizure.
Nutritional causes
Pellagra, a chronic niacin (vitamin B3) deficiency, usually relates to malnutrition or chronic exposure to alcohol. Niacin is contained in such common foods as grains, cereals, meat, peanuts, eggs, and fish, so pellagra incidence is declining in the general population. Classic clinical manifestations comprise the triad of dermatitis, dementia, and diarrhea. The dementia component of pellagra includes not only cognitive deficits but also a range of neuropsychiatric disorders such as confusion, affective disorders, and psychotic symptoms.
Vitamin B12 deficiency is a common condition, related to megaloblastic anemia and neurologic and psychiatric disorders. Among the psychiatric disorders described, a psychotic disorder secondary to vitamin B12 deficiency is possible, though uncommon. Neuropsychiatric disorders may occur concomitantly with anemia or even in their absence, making this diagnosis quite difficult to establish. It is important to investigate the cause of the patient’s deficiency, whether it is due to medication use (e.g., metformin), low dietary intake of B12, pernicious anemia, or other conditions.
Neurotoxic causes
Neuropsychiatric disorders associated with occupational exposure to substances such as cosmetics, paints, and pesticides are noted above. Exposure to zinc has been linked to the development of depression, anxiety, and psychosis in animal models. Exposure to lead, which is mainly related to leaded paint, can lead to a state similar to porphyria, with such neuropsychiatric changes as delusions and hallucinations, along with neurologic changes such as weakness. Pesticides, besides being important risk factors for the development of cancers and teratogenicity, may also contribute to neuropsychiatric disorders, primarily to the development of dementias such as AD and PD.
Infectious causes
Bacterial, virus, or fungi infections of CNS are often associated with organic psychosis. Herpes simplex encephalitis, caused especially by herpes simplex virus type 1, is a rare presentation of the herpes simplex infection. The clinical presentation is often fever associated with neurologic symptoms, but neuropsychiatric symptoms, such as psychotic symptoms, may occur. Diagnosis is made by biochemical abnormalities and Polymerase chain reaction (PCR) positive for herpes simplex virus in the cerebral-spinal fluid. Tertiary syphilis may rarely present with psychosis. Major symptoms usually include ataxia, headache, dizziness, and pupillary changes (i.e., Argyll-Robertson reflex). Diagnosis can be made by a Venereal Disease Research Laboratory (VDRL)-reactive test in the cerebral spinal fluid.
Psychosis secondary to arboviruses is another rare condition. Cases involving infection transmitted by the Aedes mosquitoes, such as dengue virus, Chikungunya, or Zika, and usually manifested with self-limited exanthematic disease, were reported as followed by psychotic manifestations and neurologic complications in South America and Asia.
Although infrequent, psychotic findings due to severe tuberculosis may occur, particularly when the microbe reaches the Substantia nigra (dopamine synthesis center). Neurologic changes usually follow tuberculous meningitis and are more likely to occur among immune-compromised individuals. The clinical presentation also includes fever, headache, and neck stiffness. Neuropsychiatric disorders, including psychosis, may occur at the onset or further along the disease course. Such microbes as Borrelia , Mycoplasma, and Chlamydia , among others, may cause neuropsychiatric symptoms due to CNS infection.
Other infectious agents
Other tropical diseases encompass psychotic manifestations and CNS complications as major clinical presentations. In neurocysticercosis, behavior changes, including psychotic symptoms, have been reported. These symptoms may occur due to structural damage to the brain parenchyma caused by the disease itself, or as a side effect of its treatment. In malaria, especially when there is encephalic involvement, neuropsychiatric manifestations may occur, among them psychosis. Diseases caused by protozoa of the Trypanosomatidae family, such as Chagas disease (Trypanosoma cruzi) and sleeping sickness (Trypanosoma brucei gambiense) , may also have psychiatric involvement. In the former, although encephalic involvement has been demonstrated, clinical neurologic manifestations are rare and generally transient. In sleeping sickness, hypersomnia may be accompanied by paranoia, hallucinations, and delusions. In Creutzfeldt-Jakob-Disease, a prionic disease, psychotic symptoms can accompany neurologic symptoms such as dementia, tremor, and language disturbances.
Endocrine-metabolic causes
Thyroid disease is commonly associated with behavior disturbances, regardless of its etiology. Clinical manifestation of hypo -thyroidism is commonly associated with irritability, anxiety, and mood symptoms, particularly depression. Hashimoto’s thyroiditis is a common cause of hypo -throidism, and can also lead to Hashimoto’s encephalopathy. The occurrence of psychotic crisis due to hyper- thyroidism or thyroid storm, is unusual, although psychotic symptoms associated with the rapid correction of high levels of fT4 to hypothyroidism in the form of “myxedema madness” are well described. Psychotic symptoms due to thyroid dysfunction may be accompanied by atypical features, including catatonia, multiple-modality hallucinations, and elevated anti-thyroglobulin and anti-Thyroid peroxidase (TPO) antibodies.
Genetic causes
Wilson’s disease is an autosomal recessive disease of copper metabolism, usually manifested between 6 and 60 years, most commonly affecting individuals in the first two decades of life. The dysfunction is caused by a change in the copper P-ATPase transporting enzyme and causes a disturbance in copper excretion and deposition, later affecting the kidneys and corneas. There are several mutations of Wilson disease, and several clinical presentations may occur in the same family. Presentation may include sardonic laughter, facial dystonia, and encephalopathy secondary to metabolic problems. Copper-colored corneal Kayser–Fleischer rings occur in about two-thirds of cases. Psychiatric features, including personality changes, affective disorders, and, infrequently, psychosis, may manifest soon after onset of Wilson disease. They can appear as the first symptom or during the course of the disease.
Autoimmune conditions
Autoimmune encephalitis comprises a group of autoimmune diseases caused by circulating autoantibodies, whose etiology is regarded as paraneoplastic or non-paraneoplastic. Psychotic symptoms often manifest early, due to anti- N -methyl-D-aspartate receptor (NMDAR) antibodies (NMDAR-Abs); in addition, later psychotic-related presentations may appear as the disease progresses. Other examples of autoimmune encephalitis are related to anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antibodies, anti-Caspr2 antibodies, and anti-Lgi1 antibodies. In most cases, psychiatric symptoms are the first manifestation of the disease. Some warning signs for autoimmune encephalitis in patients with progressive subacute psychiatric disease and little or no response to psychoactive drugs are reduced consciousness, disorientation, memory deficits, catatonia, autonomic dysfunction, hyponatremia, and other associated autoimmune diseases. In the presence of any of these alarm signals, evaluation should be expanded with structural imaging (magnetic resonance imaging [MRI]), serum antibodies, electroencephalogram, and lumbar puncture with cerebrospinal fluid (CSF) analysis.
Several neuropsychiatric manifestations may occur in SLE (lupus). Psychosis is more frequent in male SLE subjects and has been reported in prospective studies to vary from 0% to 17%. Current evidence supports the association of psychotic symptoms with lupus-specific autoantibodies, although clinic usefulness is impeded by low sensitivity. Delusions or hallucinations are most common early on, but can also occur later. Typically, SLE patients will exhibit signs, symptoms, and laboratory abnormalities of systemic disease, including renal, hematologic, and pulmonary function. In addition, mood disorders, cognitive dysfunction, and encephalopathy syndrome may occur.
Alcohol, medication-related causes
Psychotic-related features can be found in acute conditions involving chronic alcohol consumption, usually following the depletion of intracellular thiamine (vitamin B1). Wernicke encephalopathy (WE) is a severe complication associated with death in 20% of patients, along with a high proportion of long-term brain damage (75%). During WE, acute brain disease caused by severe abstinence, ophthalmoplegia, gait disturbance, and mental confusion may occur. When the complications of WE are not adequately addressed, the chronic condition tends to progress to the impairment of executive functions and altered memory and language that characterize Korsakoff syndrome. Additional potential causes or contributors to alcohol-related psychosis include comorbid substance abuse, alcohol-dependent withdrawal early stage, advanced age, and alcoholic idiosyncratic intoxication.
Consistent evidence has related the use of cannabis (particularly with high-concentration Tetrahydrocannabinol [THC]) to new psychotic episodes and eventual development of schizophrenia or schizophreniform disorder. The causality of this association is not clear. Sympathomimetics, such as amphetamine, cause euphoria and racing thoughts, and can also produce hallucinations and delusions similar to paranoid schizophrenia. This can persist between episodes of intoxication.
High doses of steroids can produce a condition with symptoms of mood disorders, psychosis, and delirium that rapidly shift. In SLE, the so-called steroid psychosis may represent an increased risk for acute confusional state and a threefold increased risk for death. In particular, steroids can also trigger an episode of mania in patients with bipolar I disorder. Use of or intoxication by other licit and illicit drugs should also be considered in the differential diagnosis of secondary psychosis.
Iatrogenic psychotic episodes may also be consequent to the continuous use or abrupt discontinuation of anticonvulsive therapy, including the first-generation ethosuximide, phenytoin, carbamazepine, valproic acid phenobarbital, and primidone as well as newer agents, such as vigabatrin, topiramate, levetiracetam, lacosamide, pregabalin, and parampanel. Acute withdrawal from benzodiazepines is very often tied to acute neuropsychiatric manifestations, including psychotic symptoms.
Diagnosis
differential diagnosis
The initial therapeutic approach must take into consideration the multiple factors that differentiate the clinical picture of medical illness related psychoses in distinct age groups, particularly between young adults and the elderly.
Management of primary or secondary psychosis can be complicated by multiple issues ( Fig. 9.1 ). One must carefully observe the cause-effect and temporal windows linking delusions, hallucinations, and other psychotic features with the onset timing of a medical comorbidity. Among the elderly, there is a risk of comorbidity with dementia syndromes such as FTD and Alzheimer dementia. Misdiagnosis of FTD for AD may often occur, even though there is much less literature discussion. In addition, a closer association of cerebrovascular risk factors and white matter hyperintensities has been reported in late-onset psychosis.
The occurrence of psychoses comorbid with other clinical disease has been long described in the medical literature. Psychiatric comorbidities can affect, for instance, up to 95% of multiple sclerosis (MS) patients along the illness course and are considered a core pathology of the disease. The similarity of psychiatric symptoms in MS to those observed in nonorganic psychiatric disorders makes it even more challenging for psychiatrists to differentiate between the two conditions. However, this scenario could be avoided if physicians rely on some red flags in the history and physical exam: late-onset psychiatric symptoms despite negative personal or family history of psychiatric diseases; and little or no benefit from psychiatric medications. These findings should further prompt diagnostic reappraisal in patients with potential MS symptoms. In other words, the response of MS patients to psychiatric medications is poor compared to those with pure psychiatric disorders.
In patients over 50 years old, clinical examination includes a rigorous neurologic examination, where focal signs and changes in primitive reflexes (glabellar, palmar, and snout) are observed ( Table 9.5 ). Exposure over years to pesticides (e.g., carbamates, Dichlorodiphenyltrichloroethane [DDT], glyphosate, organochlorines) or metals (e.g., organic lead, manganese, arsenic) may be related to the occurrence of hallucinations, aggression, and psychosis. Travel history and exposure to arbovirus epidemic areas may increase suspicion of encephalitis. In a SLE (lupus) patient who has already been diagnosed, it is important to differentiate whether the acute psychosis is due to lupus psychosis or to corticosteroid use, which can also trigger acute episodes of psychosis. Careful history will help determine the time courses of disease and corticosteroid use, and also to evaluate the need for a change in the therapeutic regimen ( Figs. 9.2 and 9.3 ).
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