We consider psychotic disorders to reside primarily in the domain of psychiatry. But primary care and other medical physicians almost always see these patients at some early point during their illness journey and can play a significant role in their care. By recognizing that your patient may have a psychotic disorder—or be in the process of developing one—early referral is possible. The duration of untreated psychosis is directly related to time to recovery.¹ Hence, primary care physicians play a pivotal role in reducing the duration of untreated psychosis and modifying long-term outcome.^2,3 Also, you can play a key role in co-managing, with a psychiatrist, patients’ often very prominent medical problems.

Unfortunately, there are many barriers to early recognition and treatment. First, “lack of insight,” which is perhaps the most frequent symptom of psychotic disorders, often delays seeking care by the patient.⁴ Second, self-stigma and societal stigma associated with the diagnosis of a psychiatric disorder, particularly a psychotic disorder, are prominent and difficult obstacles.⁴ Third, the customary separation of mental illness from general medicine means that medical clinicians are often unfamiliar with psychotic disorders, not considered part of their domain. Finally, substance use disorder is observed in 50% of patients presenting with early psychosis. This greatly impedes the diagnosis of a psychotic disorder, symptoms too readily ascribed to the substance use.⁵

Psychotic symptoms are experienced by 3% of the general population and up to 20% of patients seeking primary care.^6,7 Further, up to a third of the general population will at some time during their lives experience psychotic symptoms.⁸ Worldwide, schizophrenia occurs in about 1% of the population, and it is the fifth (for men) and sixth (for women) leading cause of work disability.⁹

Neurobiological Basis

Our understanding of the neurobiological basis of psychotic disorders emerged in the 1950s following the serendipitous discovery of chlorpromazine. It became the first effective antipsychotic and dramatically transformed the lives of patients from sequestration in remotely-located institutions to recovery.¹⁰ It was discovered that antipsychotic agents work by blocking postsynaptic dopamine (D₂) receptors in the mesolimbic pathway.¹⁰ The later discovery that amphetamines enhance the release of dopamine in this pathway and induce psychotic symptoms further corroborated this notion.¹¹ This led to the “dopamine hypothesis.” The observation that psychotomimetic agents such as LSD and mescaline, which are serotonin 5-HT_2A agonists, also induce psychotic symptoms, led to the “serotonin hypothesis” and the subsequent discovery of antipsychotic drugs targeting serotonin 5-HT_2A receptors. Finally, the discovery that phencyclidine (PCP) induces the full spectrum of schizophrenic symptoms (positive, negative, and cognitive) led to the “glutamate N-methyl-D-aspartate (NMDA) receptor deficit hypothesis.”¹¹

Key Symptoms

The symptoms of schizophrenia, the quintessential psychotic disorder, are generally classified as positive, negative, and cognitive, summarized in Table 9-1. The positive symptoms are those of the psychosis itself: hallucinations, delusions, illogical thinking, and disorganized behaviors and speech. The negative symptoms are deficits of normal function: poverty of ideas, flat affect, withdrawal/apathy, impoverished speech, and lack of motivation. Cognitive symptoms include deficits of attention, concentration, intellect, working memory, social cognition, and executive function. Unfortunately, negative symptoms and neurocognitive and social cognitive deficits often precede the emergence of positive psychotic symptoms by many years, obscuring the underlying diagnosis. Furthermore, the cognitive deficit symptoms may be misattributed to a depressive disorder or to attention deficit disorder and inadvertently managed with psychostimulants.¹² In addition to positive, negative, and cognitive symptoms, untreated schizophrenia is associated with a gradual decline in social, interpersonal, and occupational function.

Psychotic Spectrum Disorders

In Table 9-2, the primary psychotic disorders represent conditions in which psychotic symptoms are predominant and not explained by another disorder. They include schizophrenia, schizoaffective disorder, brief psychotic disorder, schizophreniform disorder, and delusional disorders. Secondary psychotic disorders are conditions in which psychotic symptoms are caused by another psychiatric disorder, by a neurological or physical disorder, or by a drug or substance-induced disorder.

Differential Diagnosis

Let’s now look at how to make a specific diagnosis.

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  Nonpsychiatric disorders: Acute or subacute, isolated psychotic symptoms are usually due to medical/neurologic causes or to a medication/substance cause, as summarized in Table 9-3; that is, all the secondary psychotic disorders except the “other psychiatric disorders.” Hallucinations may occur in the context of delirium, along with disturbances in attention and other cognitive problems, when the psychosis is due to a medical condition, substance abuse or withdrawal, exposure to a toxin, or a combination of causes. If psychosis is present only in the context of delirium and is demonstrated by evidence (from the history, physical examination, or laboratory findings) to be the direct physiologic consequence of a general medical condition, then the diagnosis is psychotic disorder due to another medical condition. When hallucinations or delusions develop in the context of intoxication with or withdrawal from a drug, medication, or toxin, and do not occur exclusively during the course of a delirium, then the diagnosis is substance/medication-induced psychotic disorder. Hallucinations that occur during the transition from wakefulness to sleep or the transition from sleep to waking (called, respectively, hypnagogic and hypnopompic hallucinations) are observed in narcolepsy and do not signify a psychiatric disorder.¹³ Auditory and visual hallucinations that occur in bereavement are considered as normal human experiences. These are often comforting in nature and are described as benign hallucinations.

  
  

  Generally, visual hallucinations suggest delirium, while auditory hallucinations suggest a primary psychotic disorder. Tactile hallucinations are commonly observed in drug intoxication, olfactory and gustatory hallucinations in temporal lobe epilepsy. Persecutory delusions are often observed in patients with Alzheimer and Lewy body dementia and Parkinson’s disease.

  
  
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  All psychiatric disorders: Subacute to chronic cognitive, behavioral, or emotional symptoms are the usual presentation of true psychiatric disorders—the primary psychotic disorders and other psychotic disorders due to another psychiatric disorder (such as depression or bipolar disorder). These conditions typically present with the progressive worsening of symptoms in a subacute or chronic fashion. Clinicians then differentiate primary from secondary psychiatric disorders as follows:

  
  
  
  
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    Secondary psychotic disorders

    
    
    
    
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      Major depressive disorder—See Chapter 4 for the severe, psychotic type of depression where depressive symptoms precede the onset of psychosis, the latter remitting with treatment of the depression. Auditory hallucinations and delusions occur in about 14% of patients with major depressive disorder. These are typically mood-congruent and often disparaging and commanding self-harm. In contrast to the bizarre and paranoid delusions observed in schizophrenia, the delusions observed in depression carry themes of guilt, sin, poverty, serious somatic illness, and nihilism.

      
      
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      Bipolar disorder—See Chapter 4 for bipolar I disorder, wherein psychotic symptoms often occur during the peak of a manic episode. Grandiose delusions (eg, affluence, power, physical strength, divinity) are commonly associated with mania.

      
      
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      Posttraumatic stress disorder (PTSD)—See Chapter 5 where severe PTSD flashbacks and reexperiencing of the traumatic event may cause auditory and visual hallucinations.

      
      
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      Personality disorder—With severe personality disorders, brief psychotic periods may appear, reviewed in Chapter 10. For example, patients with borderline personality disorder infrequently experience auditory hallucinations that resemble the ones observed in patients with major depression or PTSD.

      
      
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      Dissociative disorders—These disorders are rare and may appear to be experienced as psychotic. The diagnoses will require psychiatric input.

    
    
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    Primary psychotic disorders: When other etiologies have been ruled out and the symptoms are attributed to a primary psychotic disorder, careful attention is paid to the timing, the nature of the symptoms, and associated features to arrive at a diagnosis.

    
    
    
    
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      Brief psychotic disorder—This is a condition resembling schizophrenia but lasts less than a month (and at least 1 day).

      
      
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      Schizophreniform disorder—This condition resembles schizophrenia but lasts less than 6 months (and at least 1 month). It almost invariably progresses to schizophrenia.

      
      
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      Schizophrenia—Lasts more than 6 months. See discussion below.

      
      
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      Schizoaffective disorder—This combination of schizophrenia and a mood disorder (unipolar or bipolar) lasts greater than 6 months but also must have a 2-week period where psychotic symptoms are present when the mood disorder is quiescent.

      
      
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      Delusional disorders—These are psychotic disorders characterized by usually isolated delusions, that is, without hallucinations, negative or cognitive symptoms, and deterioration of social function. They last longer than 1 month.

We now expand on the primary psychotic disorders and then address their treatment, emphasizing what the medical clinician can do.

Introduction

The all-cause standardized mortality for schizophrenia is 12 times higher than in the general population.^14,15 About a third of patients with schizophrenia attempt suicide. One in every 10 dies of suicide.¹⁴ Nevertheless, medical problems, not suicides, are the major reason deaths exceed expectations. Metabolic, cardiovascular, cerebrovascular, pulmonary, and substance use disorders are more prevalent than in the general population.¹⁴ Although much is written about metabolic consequences of antipsychotic drugs,¹⁶ it is increasingly apparent that schizophrenia is independently associated with adverse health outcomes. Because of this, schizophrenia has been described as a “systemic disorder.” Adverse health outcomes are multifactorial and may relate to lifestyle (sedentary living, cigarette smoking, overeating), substance misuse, and the neuroimmune and neuroendocrine sequelae of psychosis. For instance, medication-naïve patients with schizophrenia display elevated levels of inflammatory markers such as homocysteine, C-reactive protein, interleukin-6, and tumor necrosis factor.¹⁶ The Recovery after Initial Schizophrenia Episode (RAISE) study revealed that metabolic disorders are present at disease onset and that medication-naïve patients had elevated levels of serum cortisol, total cholesterol, triglycerides, and excessive visceral adiposity compared to nonaffected age-matched individuals.¹⁷ The Clinical Antipsychotic Trials of Antipsychotic Effectiveness (CATIE) study revealed that obesity, hypertension, and dyslipidemia are twice as common among patients with schizophrenia as compared to those in the general population.¹⁸ Hence, whereas the care of patients with schizophrenia generally resides in the mental health sector, primary care physicians are consulted to manage the common physical disorders.⁷ The high frequency of comorbid substance use increases the risk of medical illnesses such as hepatic and neurologic disorders.⁸

Compounding all these risk factors is the stark reality that patients with schizophrenia are less likely to receive routine health maintenance, annual physical examinations, and recommended medical screening procedures.¹⁹ Transportation difficulties, embarrassment, and adverse health care experiences are all barriers to screening. Fear of pain and discomfort additionally interfere even though schizophrenia is associated with increased pain tolerance. Less likely to experience pain, they are less likely to seek medical care.²⁰ The lack of insight commonly observed in patients with psychotic disorders applies to physical diseases as well. This means that patients with primary psychotic disorders are just as likely to not seek treatment for physical symptoms as for psychological symptoms.¹⁹

Diagnosis

Schizophrenia is characterized by the hallmark positive, negative, and cognitive symptoms noted earlier and in Table 9-1. See Table 9-4 for the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for a diagnosis.²¹ Symptoms generally emerge during late adolescence or early adulthood. The age of onset is early to mid-20s in men and mid- to late-20s in women.²¹ The symptoms tend to occur in 3 progressive phases, which we now outline to help you make an early diagnosis in the prodromal phase.

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  Prodromal phase (mood and cognitive symptoms): Two-thirds of patients who go on to develop schizophrenia experience prodromal symptoms. These are observed for 2 to 5 years before the emergence of psychosis. Depressed mood, sleep disturbances, social withdrawal, lack of motivation, impaired attention and concentration, and attenuated psychosis are prominent.

  
  
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  Psychotic phase (positive symptoms): During a psychotic episode patients display predominantly positive symptoms: delusions, hallucinations, and/or disorganized thoughts, speech, and behavior. Erratic, risk-taking behavior and self-neglect can lead to psychiatric attention.

  
  
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  Residual phase (negative symptoms): Following the first episode of psychosis, the illness course is characterized by recurrence and gradual deterioration of social, occupational, and interpersonal function. This is accompanied by loss of gray matter volume in the cerebral cortex.^22,23 Positive symptoms generally respond to treatment, while negative symptoms respond less well. The burden of negative symptoms is cumulative, growing steadily with each successive psychotic episode. It is widely believed that prevention of relapse can diminish the negative symptom burden, preserve functional capacity, and perhaps arrest the progressive loss of gray matter volume.²³