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11. First-Episode Psychosis
Keywords
DiagnosisProdromeUltrahigh riskTransition to psychosisCourse of first-episode psychosisPhase-specific treatment goalsAntipsychotic choiceRelapse preventionPrognosisCoordinated specialty careEssential Concepts
In most cases of first-episode patients, the diagnosis is clear once the longitudinal course is reviewed: most patients have been ill for more than 6 months if the prodromal period and duration of untreated psychosis are included. Diagnostic uncertainty during the first episode of psychosis should not delay schizophrenia-specific treatment.
Using clinical staging (prodromal phase, acute and stabilization phase, stable (maintenance) phase), phase-specific treatment goals guide clinicians in the selection of the best treatment tools for each phase.
Preventing medical morbidity and mortality is important across all illness phases and needs to be taken into account in parallel to achieving symptom control and remission.
Patients at ultra high-risk for psychosis require close follow-up and integrated psychological and family interventions. Antipsychotics should not be used for the purpose of schizophrenia prevention.
First-line antipsychotics achieve a response and symptomatic remission in most first-episode patients (around 60–70%). The choice of antipsychotic is guided by side effect considerations, including extrapyramidal symptoms (EPS) and long-term metabolic safety. Avoid haloperidol and olanzapine, respectively. Anticipating maintenance treatment, consider selecting an antipsychotic that can, after initial stabilization, be given as a long-acting injectable formulation.
Treatment response to antipsychotic medications is much better in first-episode patients compared to chronic, multi-episode patients. The antipsychotic dose should be on the lower half of the dose range.
Move to clozapine as soon as treatment-resistant schizophrenia becomes apparent. The majority of first-episode patients who are treatment-resistant (70–80% of all treatment-resistant patients) are refractory from the get-go (i.e., they do not develop resistance over time); changing antipsychotics prior to a clozapine trial is of limited benefit for those patients.
A long-acting antipsychotic would keep almost 100% of patients in sustained symptom remission for 1–2 years and prevent the psychosocially toxic relapse.
While ultimately the patient and family will decide about maintenance treatment after a first psychotic episode, I always emphasize a higher risk of death during untreated illness and loss of responsiveness with each subsequent episode as key considerations in favor of maintenance treatment. At a minimum, patients should continue treatment for 18 months after full resolution of positive symptoms.
Multicomponent-coordinated specialty care can improve short-term outcomes for first-episode schizophrenia but is not widely available.
While symptomatic remission can be achieved in the majority of patients, functional recovery remains an elusive goal that is only achieved for a minority.
Currently, only about 15% of patients achieve symptomatic and functional recovery 10 years after their first episode. Extended treatment beyond 2 years of specialized services may be needed.
“Même la nuit la plus sombre prendra fin et le soleil se lèvera.”
(Even the darkest night will come to an end, and the sun will rise.)
– Victor Hugo (1802–1885), French writer of the of the Romantic period; Les Miserable [1]
In medicine, treatment during earlier disease stages, before a disease causes complications, is often more successful [2]. In psychiatry, intervening early in the course of schizophrenia, before prolonged psychosis causes wide-ranging disruption of people’s lives and before the illness becomes chronic, is a more recent and promising approach [3]. In addition, the early years after the diagnosis of schizophrenia are marred by high mortality due to accidents, drug use, and suicide [4]. The mortality risk in young first-episode patients is comparable to the risk of death in a cohort of geriatric patients over age 70. Optimal treatment of a first episode of psychosis may therefore improve some short-term and long-term outcomes, if we dedicate societal resources to it (see epigraph). In this chapter, I will outline the competent management of patients who present with a first episode of schizophrenia, with emphasis on the psychopharmacological management. I include a brief section on the prodromal (prepsychotic) period even though most psychiatrists will only encounter patients that are already in the psychotic phase. Reducing the duration of untreated psychosis, an important public health goal of schizophrenia care [5], is discussed in Chap. 9 as it represents an issue that can only be solved at a larger systems level, not by individual clinicians. First episode of psychosis and first episode of schizophrenia is used interchangeably.
Acronyms in early intervention
Terms for putatively prodromal states | |
UHR | Ultra high-risk |
CHR | Clinically high-risk |
ARMS | At risk mental state |
APS | Attenuated psychosis syndrome (DSM-5 term) [6] |
Assessment tools | |
SIPS/SOPS | Structured interview for prodromal syndromes/scale of prodromal symptoms |
CAARMS | Comprehensive assessment for at risk mental states |
Clinical states | |
DUP | Duration of untreated psychosis |
DUI | Duration of untreated illness |
Cohorts | |
NAPLS | North American Prodrome Longitudinal Study [7] |
Tipsa | Early Treatment and Intervention in Psychosis [8] |
Opusb | |
Clinical trials | |
EUFEST | European First-Episode Schizophrenia Trial [9] |
CAFÉ | Comparison of Atypicals in First-Episode Psychosis [10] |
RAISE | Recovery After an Initial Schizophrenia Episode [11] |
OPTiMiSE | Optimization of Treatment and Management of Schizophrenia in Europe [12] |
Diagnosis
The correct diagnosis of a first episode of schizophrenia hinges on the combination of typical symptoms on cross-sectional mental status exam and the longitudinal development of symptoms over time and the exclusion of “organic” factors that would explain the presentation (see Chap. 5). The onset of symptoms is usually in late adolescence or early adulthood although earlier and later onsets are possible. Many first episodes seem to be tied to the stress of leaving home for the first time (e.g., going to college or joining the military). The phenomenology of the early symptom course is discussed in greater detail in Chap. 7.
Before the onset of frank psychosis, patients experience a mixture of affective, negative, and cognitive prodromal symptoms, social withdrawal, and role failure.
A period of attenuated positive symptoms turns into first-episode psychosis once an admittedly arbitrary syndromal psychosis threshold is crossed.
The onset of frank psychosis is a late event. Once patients are psychotic, they have often been ill for many years. Both duration of untreated illness (DUI, when, in hindsight, there were signs that schizophrenia began) and duration of psychosis (DUP, when frank psychosis began) are measured in years.
Treatment initiation in first-episode patients leads to a rapid reduction in positive symptoms but an incomplete response in negative and cognitive symptoms.
Course of first-episode psychosis
The depicted course represents a prototypical course. In reality, there can be significant differences, particularly with regard to the rapidity of onset. A minority have no discernible prodromal period and a rather sudden onset of psychosis. A manic episode with psychosis or an acute and transient psychotic disorder is strong differential diagnostic consideration in such cases. Sudden onset cases indicate a good prognosis, in part because they are brought to treatment early – something is clearly wrong. In contrast, patients with a very long prodromal period characterized by slow social withdrawal and a long period of unrecognized psychosis have a worse prognosis.
Tip
A common diagnostic mistake is only counting acute psychosis and not an often clearly discernible prodromal period toward the duration of the illness. Many patients have clearly been ill for more than 6 months when you encounter them in the emergency room or during their first psychiatric hospitalization. The 6-month duration requirement in DSM-5 for a diagnosis of schizophrenia reflects illness duration, not merely active psychosis. Quite often, the duration of untreated psychosis alone is long enough to make the diagnosis.
Medical Examination
A medical examination and first-episode psychosis work-up is needed in order to achieve several goals: (1) to make sure that the psychosis is not secondary, (2) to detect medical comorbidities that may influence your treatment choice (e.g., ECG), and (3) to establish a baseline for some markers that are influenced by your treatment (e.g., weight and metabolic baseline). Refer to Table 5.1 in Chap. 5 for a proposed work-up.
Diagnostic Uncertainty
Tolerating uncertainty is hard, and communicating diagnostic uncertainty is an important clinical skill [13]. Patients and families are often left wondering if “everything was excluded.” They may focus on incidental laboratory abnormalities or pursue potentially quite dangerous treatments (e.g., for chronic Lyme disease). They wonder if drug use alone explains the psychotic episode. We need to acknowledge the distress but also tactfully explain why schizophrenia is the likely diagnosis in order to implement the correct treatment. At the same time, convey openness to changing your diagnosis as new facts become available. It is humbling to realize that our current knowledge is always incomplete and that new diseases are going to be discovered. When I attended medical school, hepatitis C was not yet discovered and known as non-A, non-B hepatitis, and NMDA receptor encephalitis was an unknown entity. For some family progress represents hope, and I encourage patients to consider participating in innovative research. Gluten-free diet may be helpful for some aspects of schizophrenia, for example, but only more clinical trials will identify those patients who can benefit from it. Some patients and families will never quite accept a psychiatric diagnosis and remain on some quest for the eventual discovery of the “real” cause of their symptoms.
Phase-Specific Treatment Goals
Phase-specific treatment goals for early course schizophrenia
Prodromal phase | Prevent progression to full syndrome |
Limit social and functional harm | |
KEY QUESTION: Use antipsychotic? | |
Acute phasea | Keep duration of untreated psychosis (DUP) short |
Prevent harm and control psychotic behavior | |
Achieve initial symptom response (reduce symptom severity) | |
KEY QUESTION: Which antipsychotic and what dose? | |
Stabilization phasea | Achieve early symptom remission (symptom resolution) |
Prevent early relapse | |
Early readjustment to community living | |
Monitor and address side effects | |
KEY QUESTION: When to switch if there is a poor response? | |
Stable (maintenance) phaseb | Achieve sustained symptom remission |
Improve function and quality of life | |
Monitor and address long-term iatrogenic morbidity | |
Monitor and address demoralization and suicidality | |
Achieve recovery (meaningful life despite illness) | |
KEY QUESTION: For how long do you treat after remission? |
(Putatively) Prodromal Phase
Great hopes have been pinned on identifying the prodromal phase prospectively in order to intervene and either delay or prevent the full syndrome of schizophrenia. Following the pioneering work of Patrick McGorry in Australia [14], many academic centers all over the world have in the last 20 years developed “early intervention” services to identify such putatively prodromal, clinically high-risk or ultra high-risk (UHR) patients, as they are called. The Australian group delineated three groups of patients that were at high-risk of transition to psychosis within 1 year: patients with attenuated psychotic symptoms, patients with stuttering psychotic experiences (also known as BLIPS, for brief limited intermittent psychotic symptoms [15]), and patients with genetic risk (a family history of schizophrenia in first-degree relatives, schizotypal features) whose function declined; this general delineation of three UHR states is still used today [16]. In German-speaking countries, a different path based on basic symptoms was taken to identify UHR patients [17]. Basic symptoms are subtle (nonpsychotic) disturbances in thinking and perception that are believed to be the subjective experiencing of the changing brain in the prepsychotic period [18]. Examples are the experience of thought pressure or interference (difficulties giving thoughts direction) or difficulties reading as words and sentences make no sense (akin to reading a foreign language where you can sound out the words but they have no meaning to you). Phenomenologically, the prodromal period is rich with anomalous experiences of the self [19].
While the idea of identifying people during the prodromal phase of schizophrenia has been fruitful and energizing for psychiatry (including the creating of a huge list of acronyms, see Table 11.1), ushering in modern preventive psychiatry, several hard lessons were learned.
Most importantly, casting a large net to identify adolescents seemingly at risk for schizophrenia will result in catching many young people with social difficulties and non-specific symptoms. It turns out that psychotic-like experiences (transient subclinical phenomena like perceptual abnormalities or delusion-like ideas) or isolated frank psychotic symptoms are surprisingly common in children and adolescents, occurring in almost 10% of adolescents, for example [20]. The field had come to grapple with the problem that many young people seeking help in specialized “early intervention” centers have attenuated syndromes that defy a clear syndromal diagnosis [21], with only a minority (one third in 3 years) moving on the schizophrenia [22]. Transition rates around 10% in current CHR cohorts are now common which hinders research into effective interventions [23]. (In comparison, in the early years of studying high-risk cohorts, one-year transition rates were as high as 40% [24].) Most help-seeking patients today are “probably at risk, but certainly ill.” Increasingly, the pleiotropic nature of clinical symptoms of developing brains is appreciated, with no direct line from high-risk states to schizophrenia. As many as one third of CHR patients completely remit within 2 years [25]. The medical “high-risk” and “transition” approach may even be misplaced and needs replacing with a trans-diagnostic public health approach that provides interventions in youth-specific settings [26].
Current high-risk criteria based on clinical symptoms are insufficient for screening in unselected populations although risk calculators to predict transition risk in identified CHR patients have been developed [27]. Efforts are underway to increase the positive predictive value of clinical risk models by including biological markers [28] as well as neuroimaging and machine-learning [29].
Perhaps the biggest disappointment in the early intervention field was the failure of the multi-site NEURAPRO trial [23] to replicate positive result from an earlier indicated prevention trial using omega-3 polyunsaturated fatty acids to prevent transition to psychosis [30]. Omega-3 fatty acids would have been an ideal medication from a prevention perspective due to their safety. Neuroprotective agents like N-acetylcysteine (NAC) remain an interesting consideration for another indicated prevention trial [31]. One of the few intervention trials in the prodromal phase with antipsychotics, conducted in the NAPLS network, was inconclusive [32]. While olanzapine reduced positive symptoms and had fewer conversions to psychosis, this trial could not answer the fundamental question if the natural course of schizophrenia was merely delayed or in any way altered. Other antipsychotic trials were similarly inconclusive, particularly as patients also received non-medication interventions that alone may be effective [33]. The role of antipsychotics in managing CHR states as primary prevention remains to be studied [34] and is currently not recommended for indicated prevention. Strengthening those cognitive weaknesses that increase the risk for transition offers one possible non-medication intervention [35].
Treatment recommendations for UHR patients
Assess and treat syndromes (anxiety, depression) |
Do not treat pseudo-ADD with stimulantsa |
Benign interventions to delay conversion |
CBT should be first-line treatment |
Integrated psychological interventions (individual plus family therapy) |
Omega-3 fatty acids are ineffective; consider N-acetylcysteine |
Education about the importance of avoiding cannabis |
Use of antipsychotics |
Use low-dose second-generation antipsychotics if clinically indicatedb |
Do not use long-term for primarily preventive purpose to delay/prevent conversionc |
Provide long-term follow-upd |
Acute Phase
Usually, but not always, initial treatment for an acute psychotic episode is provided in the hospital, where antipsychotics are initiated with the expectation of a response. In a meta-analysis, 50% of patients showed a 50% reduction in psychopathology with acute treatment for their first episode of schizophrenia, with a better treatment response in female patients, in more severely ill patients, in antipsychotic naive patients, or in patients with a shorter illness duration [40].
Key Point
The overarching treatment goal for the first episode of psychosis is the timely initiation of a first-line antipsychotic (keeping DUP as short as possible) and a timely move to clozapine in treatment-refractory schizophrenia patients. A reformulated goal would be the initiation of effective treatment.
Ancillary medications (e.g., benzodiazepines or valproate) are often prescribed to reduce the severity of the patient’s psychopathology. Create a good drug experience. All my older patients remember their first acute dystonic reaction from first-generation antipsychotics. Add-on therapies for presumed neuroinflammation or free radical production during acute psychosis are sometimes added by adventurous clinicians (e.g., N-acetylcysteine (NAC) 600 mg twice daily) [41].
Antipsychotic Choice
One seminal trial to answer the question which antipsychotic to initiate was the European First-Episode Schizophrenia Trial (EUFEST) [42]. EUFEST was a 1-year trial that compared low-dose haloperidol (mean dose 3.0 mg/d) with several second-generation antipsychotics (amisulpride (not available in the United States), ziprasidone (mean dose 110 mg/d), olanzapine (mean dose 12.5 mg/d), and quetiapine (mean dose 500 mg/d)) for the treatment of first-episode patients with minimal antipsychotic exposure. While low-dose haloperidol had the highest all-cause discontinuation rate (a common outcome measure since the CATIE trial), all antipsychotics had virtually identical symptom reduction [9]. A similar trial, CAFÉ, that compared olanzapine, quetiapine, and risperidone for first-episode schizophrenia confirmed comparable effectiveness between the three antipsychotics tested in this trial [10]. A network meta-analysis that compared all antipsychotics studied in randomized trials found little efficacy or tolerability differences between second-generation antipsychotics [43]. Haloperidol, however, was poorly tolerated. Since creating a good drug experience influenced adherence, it is prudent to avoid high-potency first-generation antipsychotics. Second-generation antipsychotics are clearly preferred today. In most patients, olanzapine could be avoided (although there are advantages on the inpatient side given its good efficacy and calming effect). There is no evidence that clozapine is advantageous for treatment-responsive first-episode patients (i.e., clozapine does not have disease-modifying properties [44]).
Key Point
The selection of the antipsychotic is guided by side effects as all first-line antipsychotics are about equally effective [43]. Given the need for maintenance treatment and comparable efficacy, a metabolically safe antipsychotic should be selected, preferentially one that is also available as a long-acting injectable. First-generation antipsychotics, particularly haloperidol, should not be used due to a higher risk of EPS.
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