David L. Bachman, M.D.
Nicholas J. Milano, M.D.
Clinicians have defined the term psychosis in different ways over the last two centuries. This term has been used variously as a synonym for “gross impairment in reality testing” or “loss of ego boundaries” sufficient to interfere with the capacity to meet the demands of daily life; to denote the presence of delusions and/or hallucinations; to indicate a category of psychiatric illnesses (“the psychoses”); to describe the severity of delusional and “thought disorder” symptomatology; and, more recently, to refer to a spectrum of cognitive, emotional, behavioral, and motoric symptoms and signs, each of which varies in character and severity in any given patient (Arciniegas 2015).
Briefly reviewing the history of the term psychosis, Arciniegas (2015) notes that by the mid-1990s, clinicians most commonly used the term to define a population of patients with severe social and personal impairment, characterized by social withdrawal and an inability to perform typical daily activities at home or in the workplace. He also notes that the American Psychiatric Association (APA; American Psychiatric Association 2013) and the World Health Organization (WHO; World Health Organization 1992) currently apply narrow definitions of psychosis to the diagnoses they recognize. Their definitions of psychosis require the presence of delusions, insight-impaired hallucinations, or both. Impaired reality testing remains central conceptually to psychosis in both of these definitions, where delusions are fixed false beliefs that are maintained despite evidence contrary to them and where hallucinations (perceptions occurring in the absence of corresponding external or somatic stimuli) are experienced without insight into their pathological nature.
Although the APA and WHO acknowledge that “formal thought disorder” (i.e., thought blocking, thought derailment, severely disorganized thinking, or some combination of these disturbances) occurs commonly among persons with psychotic disorders, they also recognize that mildly disorganized speech is common and diagnostically nonspecific. Accordingly, their definitions of psychosis permit thought disorder to supplant the requirement for delusions and insight-impaired hallucinations only when formal thought disorder is accompanied by grossly disorganized behavior, catatonia (for schizophrenia and schizophreniform and brief psychotic and schizoaffective disorders), and/or negative symptoms (for schizophrenia and schizophreniform and schizoaffective disorders but not brief psychotic disorder), and when the severity of thought disorder substantially impairs effective communication.
For the purposes of this chapter, then, psychosis will be used as recommended by the APA and WHO and will refer narrowly to the presence of delusions or hallucinations without insight. This use will apply to psychosis arising as an idiopathic psychiatric disorder (primary psychoses) as well as psychosis developing in the context of a neurological condition (secondary psychoses).
Clinical tradition in psychiatry and neurology generally divides the psychoses into two broad categories: primary and secondary. Primary psychoses define the schizophrenia spectrum disorders (e.g., delusional disorder, schizotypal disorder, schizophrenia, schizoaffective disorder) and arise in mood disorders (e.g., major depressive disorder, bipolar disorder) and other idiopathic psychiatric disorders. Secondary psychoses, in contrast, are associated with developmental, degenerative, and acquired neurological conditions such as adrenoleukodystrophy, Alzheimer’s disease (AD), Lewy body diseases, stroke, traumatic brain injury, epilepsy, multiple sclerosis, and autoimmune encephalidities, among others. As the science of psychosis evolves, it is increasingly clear that division of psychoses into primary and secondary types is artificial, at best. However, this division, nevertheless, remains useful for characterizing clinical phenotypes and ensuring that the underlying illness is optimally treated even when the psychosis itself must be a target of intervention.
Although phenomenology does not always reliably differentiate between primary and secondary psychoses, certain differences are generally apparent. The primary psychoses usually (although not invariably) begin in late adolescence or early adulthood and often feature a family history of phenomenologically similar psychoses. The secondary psychoses usually (although not invariably) begin in late adulthood and are associated with a known or identifiable neurological illness. Hallucinations are predominantly (although not exclusively) auditory in the primary psychoses, and delusions are often bizarre and complex. In the secondary psychoses, hallucinations are more often visual, and delusions are often simpler and more contextually or environmentally dependent (e.g., delusions of theft in a patient with AD as memory impairment and executive dysfunction develop). Treatment of the primary psychoses usually requires antipsychotic medications, whereas treating the underlying disease process may be sufficient to diminish or ameliorate delusions and hallucinations in some (but not all) of the secondary psychoses.
Schizophrenia is a common illness, affecting 0.5%–1.0% of the general population worldwide, with typical onset in late adolescence and early adulthood. The core features of schizophrenia include delusions, hallucinations (without insight), disorganized speech (e.g., frequent derailment or incoherence), grossly disorganized or catatonic behavior, and negative symptoms (i.e., diminished emotional expression or avolition). For DSM-5 criteria for schizophrenia to be met, two or more of these symptoms must be present for a significant portion of time during a 1-month period (or less if successfully treated) amid at least 6 months of continuous signs of the disturbance, and at least one of the symptoms must be delusions, hallucinations (without insight), or grossly disorganized speech. Additionally, these symptoms must be severe enough to markedly interfere with previously achieved function in one or more major areas of daily functioning (e.g., work, interpersonal relations, self-care), or, if onset occurs in childhood or adolescence, to preclude attainment of expected levels of interpersonal, academic, or occupational functioning (American Psychiatric Association 2013).
Schizophrenia has long been regarded as the archetypal primary psychotic disorder; however, DSM-5 reframed schizophrenia as one of several psychotic disorders existing on a spectrum of psychopathology. Although the schizophrenia spectrum disorders differ with respect to type, number, complexity, severity, and duration of the psychotic symptoms and associated features that define them, they all feature hallucinations, delusions, disorganized thinking (i.e., “formal thought disorder,” which is usually inferred from an individual’s speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms. Conditions on the mild end of the schizophrenia spectrum feature fewer, less complex, and shorter-duration psychotic symptoms, whereas those on the severe end entail a larger number of, more complex, severe, and persistent psychotic symptoms.
Delusions are “fixed beliefs that are not amenable to change in light of conflicting evidence” (American Psychiatric Association 2013). There are many types of delusions, some examples of which can be found in Table 24–1. Delusions are considered bizarre if they are clearly implausible and do not derive from ordinary life experience, even after the patient’s sociocultural belief system is taken into account. Examples of bizarre delusions include thought insertion (i.e., the belief that an external force is placing thoughts in one’s mind against one’s will), thought withdrawal (i.e., the belief that one’s thoughts have been removed by an outside force), and bizarre somatic delusions (e.g., the belief that key internal organs have been removed from one’s body by an outside force). In schizophrenia, delusions are often complex or systematized. For instance, a patient with schizophrenia may report that his internal organs have been secretly replaced by the military in order to spy on him.
Type |
Description |
Control |
Another person, group, or external force is controlling one’s thoughts, feelings, and/or behaviors. |
Cotard |
One does not exist or has died. |
Erotomanic |
Another person, usually of higher social status or fame, is in love with the patient (also known as De Clérambault’s syndrome). |
Grandiose |
One has exceptional abilities, wealth, fame, or power. |
Jealousy |
One’s spouse or lover is having an affair (when he or she is not doing so). |
Nihilistic |
Things, including oneself, do not exist or are unreal. |
Paranoid (persecutory) |
One is being followed, harassed, conspired against, spied on, attacked, cheated, poisoned or drugged, or otherwise obstructed in the pursuit of one’s goals. |
Phantom intruder (boarder) |
Others (usually unwelcome) are living in one’s home. |
Referential |
Otherwise mundane or innocuous gestures, comments, environmental cues, events, and so forth are directed at oneself and/or have special and personal meaning. |
Somatic |
One’s body is somehow diseased, abnormal, or changed. |
Theft |
Others are stealing or hiding one’s things. |
Thought broadcasting |
Others can hear or are aware of one’s thoughts. |
Thought withdrawal |
Another person or entity is removing thoughts directly from one’s mind. |
Thought insertion |
Another person or entity is placing thoughts directly into one’s mind. |
Verbal auditory hallucinations are thought to occur in 50%–70% of patients with schizophrenia. In 25%–30% of cases, these hallucinations are refractory to medication treatment (Brunelin et al. 2012). Voices may appear to originate from animals, from inanimate objects, or from no clear source. The patient may or may not recognize the speaker. The patient often has no voluntary control over the voices and may consider them threatening and upsetting. Sometimes the voices may issue commands or instructions to the patient that may be harmful to the patient or to others. The voices often form one aspect of a complex delusional system.
Imaging studies have found that the presence of auditory hallucinations in schizophrenia is associated with cerebral hyperactivity in the left temporal and parietal regions (Silbersweig et al. 1995). Investigators have hypothesized that decreasing cerebral activation in the left temporal and parietal regions may suppress auditory hallucinations. Brunelin et al. (2012) reported a mean reduction in auditory hallucinations of 31% using the therapeutic modality of transcranial direct current stimulation. In this study, the scalp electrode was placed in such a way that the excitability of the underlying cortex was reduced. In a meta-analysis of repetitive transcranial magnetic stimulation (rTMS) over the left temporoparietal cortex (between T3 and P3 in the 10–20 International System of Electrode Placement) for the treatment of auditory verbal hallucinations (AVHs) in schizophrenia, Slotema and colleagues (2014) reported a mean weighted effect size of 0.63 (moderate to large) for a 10-day course of 1-Hz rTMS treatment of AVHs in patients with schizophrenia. In this meta-analysis, left temporoparietal rTMS did not outperform sham with respect to other symptoms of schizophrenia, and right rTMS was no better than sham with respect to AVHs in schizophrenia. In addition to the clinical implications of these findings, they support the thesis that AVHs in schizophrenia (and, by extension, other psychoses) are associated with abnormalities of left temporoparietal function.
Hallucinations, particularly visual hallucinations, are also a common symptom of secondary psychotic disorders. Cummings and Mega (2003) hypothesized that hallucinations in the secondary psychoses could be correlated with a few basic mechanisms: 1) perceptual release, or the release of spontaneous neurological activity in the presence of decreased sensory input; 2) ictal discharges; 3) dream intrusions; or 4) neurochemical effects. The possible neurobiology of secondary psychosis is further explored later in this chapter.
Patients with schizophrenia are often characterized as being “odd” or “eccentric” in appearance and behavior. This is frequently due not to any major transgression on the part of the patient but to a more general impression of disorderliness or “off” behavior. Such an appearance may result from the patient’s lack of certain sets of social skills derived from theory of mind, which encompasses an array of cognitive processes responsible for discerning the mental states of others. Byom and Mutlu (2013) parse theory of mind into three related components: 1) knowledge of the shared social context, 2) perception of social cues, and 3) interpretation of the actions of others. An impaired theory of mind has profound implications for behavior. In their examination of subjects enrolled in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) studies, Ruocco et al. (2014) explored the ability of subjects to correctly identify facial expressions. The researchers found that schizophrenia subjects exhibited marked impairment in their ability to recognize facial expressions, especially those faces expressing fear, happiness, and sadness. A schizophrenia patient’s inability to accurately gauge another person’s cognitive or emotional state may lead to interpersonal misunderstandings resulting in others viewing the patient as odd or eccentric.
Abnormal movements have also been described in patients with schizophrenia. These movements have included withdrawn catatonia (i.e., patient awake but immobile and relatively mute), catalepsy (i.e., waxy flexibility), agitated catatonia (i.e., patient paces rapidly but remains uncommunicative), and choreic/athetoid-like movements. Peralta et al. (2010) found that 31 motor signs in drug-naive schizophrenia spectrum disorder patients fell into specific categories using factor analysis. Five of these categories—abnormal involuntary movements, hypokinesia, retarded catatonia, excited catatonia, and echo phenomenon—improved when medication therapy was initiated. One category, parkinsonism, worsened. These findings would seem to confirm that abnormal movements in schizophrenia reflect a vulnerability in the neuronal circuits linking basal ganglia to cortex and cerebellum.
Abnormal thought processes in schizophrenia have also been linked to frontal lobe dysfunction. A number of clinical features observed in schizophrenia have long been associated with dysfunction of the prefrontal lobe areas. Such clinical features have included impaired problem solving, blunted affect, social withdrawal, reduced motivation, distractibility, attentional deficits, and impaired insight (Weinberger et al. 1991). These clinical observations have been supported by functional imaging studies. Importantly, early regional blood flow studies found that hypofrontality is generally seen primarily when patients are engaged in certain cognitive tasks known to activate prefrontal cortex, such as the Wisconsin Card Sorting Task (WCST). Of further interest is the observation that drug-naive schizophrenic subjects generally demonstrate less prefrontal activation during the WCST than medicated subjects. This would suggest that antipsychotic medications may improve symptoms in part by improving frontal lobe activation (Berman et al. 1992).
More recent studies indicate that cognitive difficulties extend beyond those generally associated with frontal dysfunction. Fatouros-Bergman et al. (2014) performed a meta-analysis of cognitive performance in a large number of medication-free subjects using a standard test battery. In general, subjects scored worse in all cognitive domains but were especially impaired in the areas of verbal memory, speed of processing, and working memory. Mesholam-Gately et al. (2009) observed that memory impairment was generally more evident in subjects at risk for psychosis, while executive deficits such as those associated with frontal dysfunction were more apparent in subjects who had already transitioned to psychosis.
Early computed tomography scans of schizophrenia patients indicated ventricular enlargement. More recent magnetic resonance imaging (MRI) studies have not only confirmed this increase in ventricular volume but also further suggested reduced volume of the medial temporal structures, hippocampal formation, amygdala, and parahippocampal gyrus (Kuperberg et al. 2003). Investigators from the B-SNIP study (Padmanabhan et al. 2015) performed a cross-sectional analysis of cortical density and volume across subject groups with clinically diagnosed schizophrenia, bipolar disease, and schizoaffective disorder, as well as control subjects. Positive symptom scores correlated inversely with gray matter volume and cortical thickness of frontal and temporal areas. Negative symptoms correlated inversely with gray matter volume–cortical surface area. There was no significant interaction between illness severity and MRI structural factors.
Recent brain imaging studies have found that certain cerebral areas remain active even though control subjects are simply resting quietly. Investigators further noted that these cerebral centers then “deactivated” when subjects were asked to attend to specific types of motor or cognitive tasks. It has been argued that these centers form a unique interconnected cerebral network, “the default network” (Buckner et al. 2008). Although functions of this network have only recently been explored, one of its most crucial functions may be to support internal mentation, both related and unrelated to the immediate external environment. Such internal mentation could include conducting mental simulations based on autobiographical memory. These reflections may form the bases for self-reflective thought, judgment, and inferred emotional and social context.
Problems with the default network may underlie some of the most important symptoms of schizophrenia. Ordinarily, the dorsolateral prefrontal cortex (DLPF) is activated during certain cognitive tasks and deactivated during rest. Because the opposite pattern is seen in the default network, researchers believe there may be something of a reciprocal “anticorrelation” between the default network and the DLPF. Whitfield-Gabrieli et al. (2009) propose that because the DLPF is necessary for working memory and other cognitive tasks, cognitive deficits in schizophrenia could in part be due to hyperactivity and hyperconnectivity of the default network. In other words, patients experiencing hyperactivity of the default network may be overly attentive to internal fantasy states, rendering them unable to appropriately attend to external environmental stimuli. Among other problems, such overactivity could result in the misattribution of internal thoughts or emotional states to external situations.
Somewhat paradoxically, other studies have shown that this increased functional connectivity is accompanied by decreased structural connectivity in the same clinical samples (Fornito and Bullmore 2015). These latter findings suggest a “decoupling” of functional from structural connectivity in schizophrenia. Fornito and Bullmore (2015) speculate that schizophrenia neuropathology reflects a compromise of structural connectivity between network connector hubs located in association cortices. Loss of structural connectivity at a busy network hub might paradoxically result in an increase in functional connectivity through the hub if the signal-to-noise ratio is improved by the removal of less relevant information. Taken together, these studies suggest that hyperactivity and hyperconnectivity of the default network in schizophrenia not only may be associated with overattentiveness to internal thought but may result in impairment of frontal executive function as well.
Twin studies have demonstrated an increased risk of illness in first-degree relatives and identical twins. Cardno and Gottesman (2000) found concordance rates of 41%–65% in monozygotic twins and 0%–28% in dizygotic twins. Overall heritability was estimated at 80%–85%. In a Finnish study, Tienari et al. (2003) found that 5.3% of children adopted away from mothers with schizophrenia were eventually diagnosed with the disease, whereas only 1.74% of children adopted away from control mothers were so affected. However, when the definition was broadened to schizophrenia spectrum disorder, the rates for adopted children were 22.46% for affected mothers and 4.36% for non-affected mothers. Despite a strong genetic contribution to disease risk, no single genetic marker has been identified to explain this risk. In a recent meta-analysis, Gatt et al. (2015) found that 97 genetic variants had been studied in schizophrenia, with conflicting null studies for 27 of these variants. Some of the variants that had been the subject of a number of studies included variants of the genes for methylenetetrahydrofolate reductase, brain-derived neurotrophic factor, and catechol O-methyltransferase. Studies have suggested genetic “hot spots” that may harbor multiple structural variants associated with schizophrenia. Understanding the genetic variants associated with schizophrenia may eventually help better explain the neurobiology of the illness.
A recent genome-wide association scan in a large cohort of patients with schizophrenia and control subjects identified 108 regions of interest. One of the strongest areas of association was in the major histocompatability complex on chromosome 6. This area is also associated with genetic coding for complement factor, part of the innate immune system. Complement factor may also play a role in cerebral development perhaps explaining some of the developmental abnormalities seen in schizophrenic patients (Dhindsa and Goldstein 2016).
The task of defining “psychosis” becomes still more challenging when one is dealing with specific neurological diseases, such as epilepsy or Parkinson’s disease (PD). The two cases presented below explore the boundaries of the definition of “psychosis.”
A middle-aged woman had a long history of complex partial seizures originating in the temporal lobe. She had several hospitalizations for status epilepticus with ictal and postictal paranoid psychosis. This paranoid psychosis would resolve completely after a few weeks if her seizures were kept under control. One interesting feature of her seizure management, however, was that she would from time to time experience a period of days or weeks in which she believed that the license plate numbers on vehicles she saw on the street publicly displayed information about her personal life. Fortunately, she had the insight to contact her neurologist when she began to experience this paranoid delusion, and her anticonvulsant medications were adjusted appropriately. If her anticonvulsants had not been quickly adjusted, she would have experienced a seizure and a postictal period of severe paranoia.
An elderly man with Lewy body disease (LBD) had mild cognitive impairment but no overt dementia. On occasion, he would experience brief, nonthreatening visual hallucinations. One particular delusion/hallucination of fascination to his family and physicians alike was his belief that he could talk at will and without a phone to his sister, who lived 1,000 miles away. When asked to do so, he would stop, look up, and say, “Hello, Sadie, is that you?” He would then have a conversation for several minutes, during which observers would have the impression of listening to half of a perfectly normal telephone conversation. The patient had no insight into the extraordinary nature of these calls and merely accepted this skill at face value.
The first case raises the important question of insight. The patient experienced well-defined paranoid delusions that were likely precipitated by ictal discharges, increasing in frequency during the prodromal ictal state. However, although the delusion reoccurred, her insight was not immediately impaired. This case suggests that insight is not binary (present vs. absent), and it need not exist in lockstep with delusion.
The second case raises the question about the applicability of the term “psychosis.” The patient was not at all distressed by his “telephone skills.” Because the patient was participating in activities that were clearly impossible, and because his insight was impaired, he could be described as psychotic. However, because the patient experienced no distress due to this isolated delusion and, in fact, initiated the experience himself, one could question the applicability of the term “psychosis” in this case. In fact, his clinicians chose not to treat this particular symptom of his LBD.
Psychotic or psychotic-like behavior may occur during abnormal or normal sleep. During prolonged sleep deprivation, a patient may experience intermittent hallucinations. These hallucinations may be due to the intrusion of sleep and dream material into wakefulness. Non–rapid eye movement (non–REM) sleep parasomnias include sleepwalking and confusional arousals. Patients may exhibit prolonged bizarre behavior during these parasomnias, such as sleep eating behavior. Even violent behavior resulting in injury or death has occasionally been described (Siclari et al. 2010). Nocturnal panic attacks or night terrors may result in disturbing nighttime experiences.
It is of interest that hallucinations are more common in those dementia syndromes associated with an increased risk for sleep disorders. It is possible that there is a link between visual hallucinations and disordered sleep in these illnesses. For example, REM sleep behavior disorder (RSBD)—the failure to suppress motor tone during REM sleep—occurs with sufficient regularity prior to the onset of other clinical features of LBD that some investigators feel that RSBD should be considered a key diagnostic feature of the disorder. As in confusional arousals or sleep walking, the dream enactment behavior of RSBD may appear bizarre and psychotic.
In patients with advanced dementia or severe encephalopathy, the breakdown in the distinction between the states of wakefulness, REM sleep, and non-REM sleep may become particularly severe, resulting in status dissociatus (Mahowald and Schenck 1991). In this state, patients may appear encephalopathic, psychotic, or both. Although seen during the course of some acute withdrawal syndromes, this condition is especially problematic when it occurs during the course of severe dementia. Rather than experience brief episodes of hallucinations or confusion, patients may continue in a dreamlike state without end; they have lost the normal experience of the distinction between sleep and wakefulness.
Patients with RSBD may also at times exhibit a complex and disabling array of symptoms known as parasomnia overlap disorder (Schenck et al. 1997). These patients may exhibit features of sleepwalking, sleep terrors, and confusional arousals.
Further strengthening the association between psychosis and sleep disorder are the clinical symptoms occurring due to “top of the basilar artery” syndrome (Caplan 1980). Some patients who suffer a stroke involving the bifurcation of the basilar artery, in addition to other symptoms, may experience somnolence, vivid hallucinations, and dreamlike behavior. These symptoms are probably due to ischemia of upper midbrain and diencephalic structures, which contain anatomical neural centers and pathways for sleep regulation.
Epilepsy was one of the first disorders to be linked to psychosis, and current estimates indicate it is present in approximately 4%–10% of patients with epilepsy (Krishnamoorthy 2002). Psychosis in epilepsy can be classified based on its temporal relationship with seizures: ictal psychosis, postictal psychosis, or chronic interictal psychosis (Nadkarni et al. 2007).
Ictal psychosis, the occurrence of psychotic behavior during a seizure, is relatively rare. Patients will typically experience auditory or visual hallucinations and illusions combined with affective changes including agitation, fear, or paranoia (Nadkarni et al. 2007). When ictal psychosis occurs, the seizure focus is usually localized to the limbic system and neocortical temporal lobe and can be prolonged if the patient is in partial or partial complex status epilepticus. It can also be associated with generalized epilepsy, including absence status epilepticus.
Postictal psychosis is defined as psychosis that occurs within 1 week of a seizure and has a duration of 1 day to 3 months. It occurs in approximately 2%–7.8% of epilepsy patients but can rise to 18% in patients with medically intractable focal epilepsy (Nadkarni et al. 2007; Trimble et al. 2010). Postictal psychosis is usually associated with complex partial seizures and often follows a cluster of seizures. There is often a lucid interval during which the patient may be mildly subdued or confused although he or she displays ostensibly normal mental health and behavior. This interval may last up to 72 hours and rarely even longer. The mean duration of postictal psychosis ranges from 3 to 14 days but can last up to 90 days. During these psychotic episodes, patients often experience significant mood alterations, including depression and mania. Delusions may be present and can be paranoid, persecutory, grandiose, or religious in nature. Religious delusions, in particular, which typically come with a fear of impending death, may occur in up to 25% of patients with postictal psychosis, compared with only 2% of patients with interictal psychosis (Trimble et al. 2010). Both visual and auditory hallucinations occur. In addition, patients may become aggressive or violent. Postictal psychosis usually begins to occur after more than 10 years of epilepsy, and as its frequency increases, so does the risk of developing chronic interictal psychosis. The patient in Case 1 above was probably experiencing subclinical ictal activity, which triggered her delusions regarding the license plate numbers.
Most studies have linked postictal psychosis to medial temporal limbic structures, but the laterality is less clear. Several electroencephalographic studies have linked postictal psychosis to bilateral independent interictal and ictal foci. Imaging studies using single-photon emission computed tomography (SPECT), however, have shown increased blood flow to the right temporal lobe (Trimble et al. 2010).
The underlying mechanism of postictal psychosis is not clear. The lucid period between the associated seizure and its onset would argue against simple overstimulation and fatigue as the cause. Trimble et al. (2010) hypothesized that the mechanism of postictal psychosis could be similar to forced normalization. Forced normalization is a phenomenon in which a patient develops psychosis after his or her seizures are successfully treated with antiepileptic medications. It can develop suddenly with severe delusions, despite clear consciousness and a normal electroencephalogram.
Chronic interictal psychosis can occur in approximately 5% of patients with a long history of uncontrolled seizures (Nadkarni et al. 2007). Persecutory auditory hallucinations are common in these patients, while the negative symptoms of schizophrenia are less so. Interictal psychosis is most often associated with complex partial seizures involving the temporal lobe, perhaps with a left medial temporal predominance. It has, however, also been described with extratemporal ictal foci and generalized epilepsy. Risk factors include onset of seizures in early adolescence, female gender, left medial temporal seizure focus, left-handedness, cognitive impairment, and presence of psychic auras (Cummings and Mega 2003).
As for postictal psychosis, the underlying mechanism for interictal psychosis has yet to be fully elucidated. One hypothesis is the kindling model: frequent seizures would stimulate and alter the limbic structures leading to psychotic symptoms (Lancman 1999). An alternative hypothesis is that a single lesion that predates the onset of seizures is responsible for the development of both psychosis and epilepsy.
In 1907, Dr. Aloysius Alzheimer described a 51-year-old patient who presented with striking symptoms: inexplicable jealousy toward her husband and worsening memory loss (Strassnig and Ganguli 2005). As her disease progressed, she developed agitation, paranoia, and likely auditory hallucinations. After her death, she was found to have the now well-recognized senile plaques and neurofibrillary tangles of AD. While AD is characterized by progressive memory loss and further cognitive impairment, symptoms of psychosis are also common—just as Alzheimer’s first patient may have experienced paranoid delusions. The estimated prevalence of psychotic symptoms in AD varies, but the authors of a review of published studies from 1990 to 2003 found a median prevalence of 41.1% (range=12.2%–71.1%) (Ropacki and Jeste 2005). This would make AD the second most prevalent psychotic disorder in the United States after schizophrenia (Murray et al. 2014).
Common psychotic symptoms in AD include delusions, visual hallucinations, and misidentification syndromes. In contrast to the bizarre, complex delusions of schizophrenia, the delusions of AD are typically simple, loosely held, transient, and related to their immediate environment (Cummings and Mega 2003). For instance, patients may believe that an unwelcome stranger is coming into their house and stealing or that their spouse is unfaithful. Although visual hallucinations are the most common in AD, hallucinations are known to occur in all sensory modalities. The misidentification delusional syndromes, such as Capgras syndrome, are also common and will be discussed in a later section.
Psychosis in AD presents added difficulties beyond the psychotic symptoms themselves, as it is associated with greater cognitive impairment and a more rapid decline (Murray et al. 2014). Moreover, psychosis in AD is tied to the behavioral symptoms of agitation and aggression, along with depression and apathy. The combination of these symptoms leads to greater rates of institutionalization and mortality.
Although the pathogenesis of psychosis in AD is not yet fully understood, it does appear to be most associated with the dysfunction of the neocortex—especially the dorsolateral prefrontal cortex and the heteromodal association areas—as opposed to the medial temporal lobe structures. This has been shown with functional imaging as well as with pathological evidence, including increased neurofibrillary tangle density in the neocortex but not the medial temporal structures (Murray et al. 2014). These findings suggest that in AD, psychosis is not primarily due to limbic system dysfunction.
Researchers have found many neurotransmitter abnormalities that may be associated with AD with psychosis. For instance, AD patients with delusions have shown an increase in muscarinic acetylcholine M2 receptor density in the orbitofrontal cortex and middle temporal gyrus. There may also be an association with the density of dopamine D3 receptors in the nucleus accumbens and reduced serotonin in the ventral temporal cortex and proscubiculum. In addition, there appears to be genetically mediated risk of psychosis in AD, as the estimated heritability is 30% for a single psychotic symptom and 61% for recurrent or multiple symptoms. Although no specific genes have been definitively identified, the dopamine receptor gene DRD1 polymorphism may be associated with hallucinations and the DRD3 polymorphism with delusions. Notably, the apolipoprotein E epsilon 4 allele, which is a genetic risk factor for late-onset AD, is not associated with psychosis (Murray et al. 2014).
Parkinson’s disease is a neurodegenerative disorder characterized by movement abnormalities (resting tremors, bradykinesia, and rigidity) (see Chapter 21, “Neurocognitive Disorders With Lewy Bodies”). The pathological hallmark is the Lewy body, a cytoplasmic inclusion predominantly made up of the protein α-synuclein. Pathology of the substantia nigra in the midbrain is associated with decreased levels of the neurotransmitter dopamine, resulting in the disease’s well-known motor symptoms. Although PD is primarily a movement disorder, it can also have cognitive and behavioral features. Psychosis is common, affecting approximately one-third of patients on dopaminergic therapy (Goldman et al. 2011).
LBD shares the same Lewy body pathology as PD (see Chapter 21). The difference is one of location; whereas PD pathology is more prevalent in the brain stem, LBD has more cortical pathology. In addition, cognitive symptoms occur earlier in LBD than in PD. Psychosis is very common in LBD, occurring in 57%–76% of patients (Assal and Cummings 2002). In fact, visual hallucinations are part of the diagnostic criteria, along with parkinsonism and fluctuations in cognition.
The most common psychotic symptom in PD and LBD, again in contrast to schizophrenia but similar to AD, is visual hallucinations. These range from mild symptoms, such as illusions and passage or presence hallucinations, to more complex, well-formed hallucinations. A passage hallucination is the sensation of a person passing through one’s peripheral vision, whereas a presence hallucination is the sensation that another being is present in one’s immediate environment. The formed visual hallucinations of PD are typically of people or animals, such as children playing in the yard. These hallucinations usually last a few seconds to several minutes, and they can worsen at night. Visual hallucinations occur in about 30% of patients with PD taking dopaminergic mediations; however, they are much more common in patients with LBD (prevalence: 14%–92%) (Jellinger 2012). Hallucinations can, however, occur in other sensory domains as well. In addition, delusions occur in approximately 5%–10% of PD patients who receive dopaminergic therapy. Common delusions in PD and LBD include paranoid or persecutory delusions and the misidentification syndromes such as Capgras or Frégoli syndromes (see Table 24–2) (Jellinger 2012).
Type |
Description |
Capgras syndrome |
Belief that a spouse, family member, or other familiar individual has been replaced by an impostor who is physically, but not psychologically, identical to the replaced person |
Clonal pluralization of the self |
Belief that there are multiple copies of oneself that are identical both physically and psychologically but physically separate and distinct |
Frégoli syndrome |
Belief that different people are in fact a single person (usually a persecutor or other threatening individual) who changes appearance or is in disguise |
Intermetamorphosis syndrome |
A variant of the Frégoli syndrome in which the patient believes that others change into someone else in both external appearance and internal personality |
Mirrored self-misidentification |
Belief that one’s own appearance in the mirror is that of someone else (“mirror sign”) |
Reduplicative paramnesia |
Belief that one’s current location is actually located adjacent to (or part of) another location, usually closer to home |
Syndrome of subjective doubles |
Belief that a physical double of oneself exists (doppelgänger), although usually with different personality traits, carrying out independent actions; also known as the subjective Capgras delusion |
One might be tempted to conclude from the above that dopaminergic treatments are, if not the sole contributing factor, then one of the major contributing factors to the development of psychosis in PD. Indeed, it was hypothesized that these treatments lead to psychosis by rendering mesolimbic receptors hypersensitive. There are, however, several factors that challenge the notion that dopaminergic medications alone are the primary cause of psychosis in this disease: 1) there is evidence that the daily dose of dopamine replacement may not differ between patients with psychosis and those without; 2) high-dose intravenous levodopa does not induce psychosis (Goldman et al. 2011); and 3) there are reports of patients with PD developing psychosis prior to the advent of dopaminergic medications. What is more, there are known risk factors involved in the manifestation of psychosis in PD other than medication: 1) longer duration and severity of the disease, 2) greater cognitive impairment, 3) decreased visual acuity, and 4) greater degree of depression. The single most important risk factor, however, is dementia—and hallucinations and delusions are often a sign of progression to dementia. The estimated prevalence of psychosis among patients with PD without dementia is 7%–14% but rises to 29%–54% in patients with Parkinson’s disease with dementia (Assal and Cummings 2002).
Even if mesolimbic hypersensitivity from dopaminergic medications is not the primary cause of psychosis in PD and LBD, dopamine is clearly involved. Evidence of this is that all classes of dopaminergic enhancers are associated with inducing or exacerbating psychosis, and the removal of or decrease in these agents may improve psychotic symptoms. An alternative theory of psychosis in PD is that there is a loss of balance between the cholinergic and dopaminergic systems. In PD and LBD, there is a degeneration of the ascending cholinergic system from the basal forebrain. This loss of cholinergic activity in the presence of dopaminergic replacement may lead to psychotic symptoms. Supporting this is the fact that anticholinergic medications can induce psychosis, and increasing acetylcholine with cholinesterase inhibitors has been shown to improve these symptoms. A proposed mechanism for this is that acetylcholine enhances the neuronal signal-to-noise ratio. If acetylcholine is reduced, the noise of irrelevant internal or sensory information may reach conscious awareness (Goldman et al. 2011).
The serotonergic system is also implicated in psychosis in these disorders. In PD, there is a loss of the serotonergic raphe nucleus, with its projections to the frontal and temporal lobes, and putamen. Dopaminergic therapy lowers the serotonin-to-dopamine ratio further and may also lead to hyperstimulation of 5-HT2A receptors. Hyperstimulation of these serotonergic receptors modulates dopamine neurons in the ventral tegmentum, leading to excitation of the limbic area and inhibition of the prefrontal cortex (Goldman et al. 2011). Other studies using positron emission tomography (PET) scans have shown increased 5-HT2A receptors in the ventral visual processing pathway, dorsolateral prefrontal cortex, medial orbitofrontal cortex, and insula, all areas important for visual and cognitive processing and for behavior. A final role of serotonin is its involvement in REM sleep and the potential that visual hallucinations may be REM intrusions (see section “Psychosis and Sleep” earlier in this chapter). Further supporting the serotonergic hypothesis is the efficacy of atypical antipsychotics such as clozapine, quetiapine, and pimavanserin, all of which have high 5-HT2A activity.
The brain is organized into two visual processing streams: a ventral occipitotemporal lobe “what” visual stream and a dorsal occipitoparietal lobe “where” visual stream. Given the well-formed visual hallucinations that often involve movement in PD and LBD, it might be predicted that there would be abnormalities in both of these processing streams. In fact, hallucinations in PD are associated with both decreased volume and activation on imaging of the occipital, parietal, and temporal regions. There is also evidence that hallucinating PD patients have decreased volume of the hippocampus, limbic system, and neocortex. Finally, there is evidence that the frontal lobes have increased activation in PD with hallucinations (Goldman et al. 2011).
Nagahama et al. (2010) were able to correlate the anatomy of psychosis even further in LBD. Using SPECT imaging, they divided psychotic symptoms into visual hallucinations, delusions, and misidentification syndromes. As with PD, visual hallucinations were associated with hypoperfusion in the ventral visual stream (left ventral occipital gyrus) and dorsal stream (bilateral parietal cortices). This seems to follow Cummings and Mega’s (2003) perceptual release explanation for hallucinations. The hypoperfusion of the left ventral occipital gyrus seems to coincide with the face recognition pathway. It has been hypothesized that the decrease in cholinergic inputs from the basal forebrain and brain stem in LBD may lead to this hypoperfusion of the visual pathways. Interestingly, delusions of theft and persecution were associated with relative hyperperfusion of the frontal cortex compared with the posterior regions, but these delusions were associated with hypoperfusion when compared with the frontal lobes of control subjects. Relative hypoperfusion of frontal areas has been associated with delusions in other conditions, such as AD and schizophrenia. From these findings, Nagahama et al. (2010) hypothesize that the delusions in LBD are due to incorrect causal attributions to external people based on impaired source monitoring and insufficient episodic memory from frontal lobe dysfunction.
In 1907, Professor Arnold Pick described a 67-year-old woman with senile dementia who had developed a fixed belief that her Prague hospital and her physicians had been simultaneously duplicated and that she was being treated in her hometown rather than in Prague. This was the first description of reduplicative paramnesia. Later, in 1923, Drs. Joseph Capgras and Jean Reboul-Lachaux described a 53-year-old woman who believed everyone close to her, including her husband and daughter, had been replaced by various doubles or imposters. Later known as Capgras syndrome, this, along with reduplicative paramnesia, form part of the group of delusional misidentification syndromes, which are characterized by a misidentification or doubling of a person or place (Harciarek and Kertesz 2008). Additional common misidentification syndromes are listed in Table 24–2.
Originally thought to be due to psychiatric disorders like schizophrenia, misidentification syndromes are now commonly associated with neurological disorders. These syndromes are common in AD (15.8%) and LBD (16.6%) (Harciarek and Kertesz 2008) but have also been described in Parkinson’s disease with dementia, semantic dementia, vascular dementia, traumatic brain injury, epilepsy, stroke, pituitary tumor, multiple myeloma, multiple sclerosis, viral encephalitis, migraine, tuberous sclerosis, neurocysticercosis, and frontal lobe pathology (Cummings and Mega 2003).
The misidentification syndromes can be split into two groups based on sense of familiarity. The first group has in common that patients feel decreased familiarity for a person or place. This group includes syndromes such as Capgras syndrome and the mirror sign. The second group involves abnormally increased familiarity for a person or place. This group includes Frégoli syndrome, intermetamorphosis, and reduplicative paramnesia.
Lesions causing misidentification syndromes are strongly associated with the right hemisphere. It has been reported that in patients with reduplicative paramnesia, approximately 52% had lesions in the right hemisphere, 41% had bilateral lesions, and only 7% had left hemisphere lesions (Devinsky 2009). Similarly, in patients with Capgras syndrome, 32% had right hemisphere lesions, 62% had bilateral lesions, but only 7% had left-side-only lesions. More specifically, the right frontal lobe appears to be particularly involved in Capgras syndrome. In a study of 29 patients, 10 out of the 29 (34.5%) had exclusively frontal lobe lesions, 6 of which were bifrontal and 4 of which were right frontal only. None of the patients had lesions sparing the frontal lobes (Devinsky 2009).
Although the frontal lobes may be involved in the generation of misidentification syndromes, the temporal lobes may determine the level of familiarity a patient experiences. One study of misidentification syndromes showed that temporal lesions were present in 64% of patients who had decreased familiarity, whereas they were present in only 14% of patients who had increased familiarity (Devinsky 2009). This could indicate that if a patient has a temporal lesion, the delusional misidentification is more likely to have decreased familiarity, whereas if the patient’s temporal lobe is spared, he or she may experience increased familiarity. Of interest is the fact that the perirhinal parahippocampal cortex is activated by familiar stimuli and evokes a sense of déjà vu if electrically stimulated.
It has been hypothesized that frontal lobe dysfunction may cause misidentification syndromes through impairment of reality, memory, and familiarity monitoring. However, frontal lobe dysfunction does not always lead to misidentification. Harciarek and Kertesz (2008) did not find any misidentification syndromes in behavioral-variant frontotemporal dementia or in primary progressive aphasia, both of which are predominately associated with frontal lobe pathology. Alternatively, the misidentification symptoms could be an attempt by the impaired brain to resolve conflicting information. For example, Capgras syndrome has been described as the opposite of prosopagnosia, which is the inability to recognize faces due to lesions of the ventral visual stream (Harciarek and Kertesz 2008). Often, patients with prosopagnosia will maintain their familiarity with a person, even though they cannot recognize that person’s face. This may be due to an intact more dorsal secondary visual stream through the inferior parietal lobule connecting the occipital lobe to limbic structures. In Capgras syndrome, the opposite may occur. Because of a malfunction of the more dorsal pathway, patients may retain their recognition of the person’s face but lose the associated feeling of familiarity and emotional significance. To resolve this conflicting information, patients may conclude that the person is an impostor.
It may be that misidentification syndromes require a double-hit pathology, such as baseline generalized atrophy with a subsequent right hemisphere lesion (Devinsky 2009). Functional imaging supports the involvement of multiple areas of dysfunction. In a study of patients with AD using PET imaging, patients with misidentification syndromes had hypometabolism of the bilateral paralimbic structures (orbitofrontal and cingulate) and left medial temporal areas (Mentis et al. 1995).
Although the prevalence of a psychotic syndrome in stroke is relatively low—between 0.4% and 3.1%—it is associated with increased mortality (Hackett et al. 2014). Individual symptoms of psychosis are more common, with delusions occurring in approximately 3%–10% of patients and hallucinations in approximately 4%. Delusions and hallucinations are usually associated with lesions to the right hemisphere, whereas ideas of reference and persecution may be associated with the left hemisphere (Cummings and Mega 2003).
Delusions have accompanied strokes to the right frontal, temporal, and parietal lobes, as well as the subcortical limbic structures (Devine et al. 2014). Recently, there has been increasing evidence that the right inferior frontal gyrus may also be involved. Devine et al. (2014) used a lesion overlap analysis to associate persistent poststroke delusions with the right inferior frontal gyrus and its underlying white matter. An earlier study associated delusions with right caudate infarctions and hypometabolism of the inferior frontal gyrus (McMurtray et al. 2008). These abnormalities are similar to what is found in AD and are consistent with the hypothesis that delusions are due to a disruption of the prefrontal lobe function of reality monitoring and testing. Anton’s syndrome occurs with bilateral occipital lobe lesions and is associated with cortical blindness and confabulation of visual images; patients will report that they can see visual stimuli when they, in fact, are completely blind. Visual hallucinations can also be present with unilateral infarcts, however, and occur in 12% of occipital lobe strokes (Hackett et al. 2014). Patients may report complex visual phenomena in their blind hemifield, although patients usually recognize that their visual experiences are not real. This type of hallucination fits the perceptual-release hypothesis. Auditory hallucinations are less common, occurring in approximately 0.8% of cortical strokes (Hackett et al. 2014).
Psychosis can also be a sequela of traumatic brain injury (TBI), occurring in 0.9%–8.5% of closed-head injuries (Fujii and Ahmed 2014). There are two categories of psychotic symptoms in TBI: delusional disorder and schizophrenia-like psychosis. Patients with a delusional disorder most commonly suffer from Capgras syndrome and/or reduplicative paramnesia, each of which occurs in approximately 32% of patients. Delusional jealously is less common, occurring in 16% of patients. The schizophrenia-like psychosis of TBI is characterized by both hallucinations and delusions. Of these patients, 97% experience hallucinations, the majority of which are auditory (88%), but visual hallucinations are also present (22%). Delusions are present in 85% of cases and are often persecutory (65%). Bizarre delusions, ideas of reference, and grandiose delusions—more typical of primary psychosis—also occur (Fujii and Ahmed 2014).
Ninety-four percent of delusional disorders in TBI have structural MRI abnormalities, the most common of which are lesions in frontal (75%) and temporal lobes (56%). In contrast, patients with schizophrenia-like psychoses after TBI are less likely to have structural lesions on neuroimaging and much more likely (86% of patients) to exhibit abnormalities on functional imaging (SPECT/PET), particularly in temporal lobes. Delusional disorders tend to occur within the first year of a patient’s injury, while schizophrenia-like psychosis will typically have a more delayed onset, often somewhere in the range of 3–4 years after the injury was sustained. It is important to distinguish psychosis due to TBI from the psychotic symptoms that might occur in posttraumatic stress disorder, seizures, and substance abuse, as these all often co-occur in this patient population (Fujii and Ahmed 2014).
There are several other, secondary causes of psychosis that are worth briefly exploring. Besides AD, PD, and LBD, other degenerative diseases, such as Huntington’s disease or frontotemporal dementia (FTD), can produce psychosis. Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by chorea and behavioral changes (see Chapter 22, “Huntington’s Disease”). It has been reported that a schizophrenia-like psychosis may develop in 4%–12% of patients (Cummings and Mega 2003). Frontotemporal dementia is a neurodegenerative disorder characterized by progressive behavioral or language decline and atrophy of the frontal and anterior temporal lobes (see Chapter 23, “Frontotemporal Dementia”). It was originally believed that psychosis in FTD was rare, but recent evidence has shown that psychosis may have often gone unrecognized and is particularly prevalent in certain pathological and genetic subtypes (Shinagawa et al. 2014). The overall prevalence of psychosis in FTD has been reported at 10%–15%, but in carriers of the C9ORF72 mutation (related to TDP-43 [transactive response DNA-binding protein 43] type B pathology), the prevalence may be up to 50% (Shinagawa et al. 2014). Additional variants commonly associated with psychosis include the progranulin gene (GRN) mutation (related to TDP-43 type A pathology) and the fused in sarcoma pathology (Shinagawa et al. 2014). Imaging studies in FTD have shown an association between visual hallucinations and atrophy of the medial right temporal lobe.
Herpes simplex encephalitis is a viral infection that preferentially affects the medial temporal lobe and inferior frontal lobes. It will frequently manifest with psychosis, with auditory hallucinations and delusions as initial symptoms (Cummings and Mega 2003). Additional infections that may cause psychosis include rabies, mumps, syphilis, and HIV encephalopathy, among others.
A recently described form of autoimmune encephalitis presents with psychosis even more frequently than herpes encephalitis: anti–N-methyl-D-aspartate (anti–NMDA) receptor encephalitis. Anti–NMDA receptor encephalitis is a paraneoplastic syndrome often associated with ovarian teratomas in young women. Psychosis is a common initial symptom and in one series was present in 68% of subjects, all of whom had (typically auditory) hallucinations (Gable et al. 2009).
Additional paraneoplastic and autoimmune causes of psychosis include voltage-gated potassium channel encephalitis, Hashimoto’s encephalitis, and systemic lupus erythematosus. There are also many metabolic causes of psychosis. Psychosis may be a presenting symptom of Wilson’s disease, caused by abnormal copper metabolism. Patients with this disorder frequently present with psychiatric symptoms and may have paranoid delusions and auditory hallucinations very similar to schizophrenia (Cummings and Mega 2003). Other metabolic causes of psychosis include kidney and liver disease, electrolyte abnormalities, endocrine disturbances, nutritional deficiencies, myelin-affecting disease, genetic metabolic disorders, and medications.
Regardless of whether patients are diagnosed with primary or secondary psychosis, treatment is generally the same. Although there is an extensive literature on the treatment of schizophrenia, there have been far fewer studies examining the relative efficacy of the drugs used to treat psychosis in patients with known neurological disorders (secondary psychoses). Nevertheless, drugs used to treat schizophrenia are generally effective, although to varying degrees, in other primary and secondary psychoses—especially in treating delusions and/or hallucinations.
The efficacy of both the older first-generation antipsychotics and newer atypical drugs is largely mediated by D2 receptor antagonism, with some exceptions. Clozapine has been found to be superior in treating refractory schizophrenia, but there is a general consensus among clinicians that there are relatively few differences in efficacy between the first- and second-generation antipsychotics in the treatment of psychotic symptoms. However, the second-generation antipsychotics may be superior with respect to their effects on cognition and negative symptoms. Additionally, the second-generation antipsychotics (or at least those that are relatively modest D2 antagonists) are associated with fewer adverse motor effects and a lower risk of tardive dyskinesia.
In LBD and AD, psychotic symptoms may sometimes improve in response to treatment with acetylcholinesterase inhibitors. In LBD, antipsychotics are largely contraindicated because of increased sensitivity to side effects. Both quetiapine and clozapine, however, may be used cautiously in this condition.
New drugs are under study that may benefit cognitive function as well as psychosis (Bruijnzeel et al. 2014). Among these, a potentially important addition to the pharmacotherapies of psychosis is pimavanserin, a nondopaminergic atypical antipsychotic that acts principally through selective inverse agonism of serotonin 5-HT2A receptors. It demonstrates a 40-fold greater selectivity for the 5-HT2A receptor than for the 5-HT2C receptor and demonstrates no clinically significant activity at 5-HT2B receptors or dopamine receptors. At the time of this writing, pimavanserin is approved by the U.S. Food and Drug Administration for the treatment of some patients with psychosis due to Parkinson’s disease and is being studied as an adjunctive treatment for schizophrenia. In the latter context, pimavanserin appears to potentiate the antipsychotic effects of otherwise subtherapeutic doses of risperidone and improves the tolerability of haloperidol by reducing the development of extrapyramidal side effects. While the role of pimavanserin in the treatment of primary and secondary psychoses requires further clarification, it represents an important development in the pharmacotherapy of psychoses that may portent similar near-term advances in this area of neuropsychiatric treatment.
Behavioral therapies have also been found to be of benefit in some patients with primary psychosis, including versions of cognitive-behavioral therapy developed specifically for the treatment of psychosis (Mehl et al. 2015) and cognitive remediation and psychiatric rehabilitation strategies for persons with schizophrenia (Wykes et al. 2011). These interventions are important elements of the treatment of schizophrenia and related psychoses, but they remain underdeveloped and infrequently provided as treatments for secondary psychoses. Also, as noted earlier in this chapter, transcranial direct current stimulation and rTMS may prove useful in suppressing auditory hallucinations in patients with schizophrenia. The potential applications of psychological, behavioral, and neurostimulation interventions to the treatment of primary and secondary psychoses remain to be elucidated but appear promising as potential adjuncts and/or alternatives to the pharmacotherapy of psychosis.
Over the last 200 years, the term psychosis has either been applied broadly to the presence of a spectrum of cognitive, emotional, behavioral, or motoric symptoms or more narrowly to the presence of insight-impaired delusions often with content-congruent hallucinations. Studies of psychosis or schizophrenia largely depend on the choice of narrow or broad enrollment criteria. However, at its core, psychosis is largely identified by the presence of delusions of bizarre, strongly held beliefs that are not amenable to reason or persuasion.
Schizophrenia is a medical illness that is strongly associated with delusions and hallucinations consistent with psychosis. However, schizophrenia is often associated with a characteristic age range of onset, positive family history for psychiatric disorders, thought disorder, poor social skills, motor symptoms, and cognitive dysfunction (often with a frontal-executive pattern). However, no pathophysiological process has been identified yet as an etiology for schizophrenia.
Careful evaluation is critical to determine a possible secondary cause for psychosis. The most important secondary etiologies to consider include the following: drug effects, dementia, delirium, infection, sleep disorders, seizure disorders, or focal neurological deficits such as strokes.
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