Anxiety in First-Episode Psychosis: Prevalence, Clinical Significance, and Prognostic Implications

First-episode psychosis (FEP) represents a critical intervention window — the initial emergence of frank psychotic symptoms, typically occurring between ages 15 and 30, during which treatment response is strongest and long-term trajectory is most modifiable. While clinical attention in FEP has historically centered on positive symptoms (hallucinations, delusions), negative symptoms, and cognitive impairment, a substantial body of evidence now establishes that anxiety is among the most prevalent, functionally impairing, and prognostically significant comorbid phenomena in this population.

Anxiety in FEP is not simply a secondary reaction to a frightening illness experience, though that component exists. It reflects overlapping neurobiological vulnerabilities, shares genetic architecture with psychotic disorders, and independently predicts worse functional outcomes, higher relapse rates, and elevated suicidal behavior. Despite this, anxiety symptoms remain systematically underdetected and undertreated in early psychosis services, partly because they are subsumed under the psychosis diagnosis and partly because clinicians may fear that addressing anxiety will complicate antipsychotic management.

This article provides a comprehensive clinical review of anxiety in first-episode psychosis, covering epidemiological data, diagnostic challenges, neurobiological substrates, treatment evidence, and prognostic implications. The goal is to move beyond the recognition that "anxiety is common in FEP" toward a clinically actionable understanding of when it matters, what drives it, and how to intervene.

Estimates of anxiety comorbidity in FEP vary considerably depending on measurement approach — structured diagnostic interview versus self-report scale — and the specific anxiety construct being assessed. However, the weight of evidence consistently places anxiety as the most common comorbid domain in early psychosis, exceeding rates of depression, substance use disorders, and obsessive-compulsive disorder when each is considered individually.

Overall Anxiety Prevalence

A systematic review and meta-analysis by Achim and colleagues (2011) examining anxiety disorders across the psychosis spectrum found that approximately 38% of individuals with psychotic disorders meet criteria for at least one comorbid anxiety disorder, with rates notably higher in first-episode and early-phase samples compared to chronic schizophrenia populations. More recent estimates from the EU-GEI (European Network of National Schizophrenia Networks Studying Gene-Environment Interactions) study and other large FEP cohorts place the point prevalence of any anxiety disorder in FEP between 30% and 50%, depending on the sample and diagnostic methodology.

Disorder-Specific Estimates

When parsed by specific anxiety disorder, the following prevalence estimates emerge from pooled data across major FEP studies:

• Social anxiety disorder (SAD): 15–25% of FEP patients, making it the single most common specific anxiety diagnosis. The TIPS (Early Treatment and Intervention in Psychosis) study and the ÆSOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study both found SAD rates in FEP exceeding general population prevalence by approximately 3–5 fold.
• Generalized anxiety disorder (GAD): 10–18% of FEP samples, often co-occurring with depressive symptoms in a mixed anxious-depressive presentation.
• Panic disorder: 8–15%, with some studies finding rates as high as 20% in FEP samples with prominent persecutory delusions.
• Obsessive-compulsive disorder (OCD): 8–13%, with additional OCD symptom emergence (de novo) occurring in 5–10% of patients following initiation of second-generation antipsychotics, particularly clozapine.
• Post-traumatic stress disorder (PTSD): 12–20%, reflecting both pre-morbid trauma exposure and the psychosis experience itself acting as a traumatic event. Emerging evidence from the AESOP-10 follow-up suggests that PTSD related to the psychotic episode ("psychosis-related PTSD") may occur in 25–40% of FEP patients and is an independent predictor of relapse.

Subthreshold Anxiety

Beyond categorical diagnoses, elevated anxiety symptoms that do not meet full diagnostic thresholds are present in 50–65% of FEP patients at the time of first presentation. This subthreshold anxiety is clinically meaningful: studies using the Beck Anxiety Inventory (BAI) and the Hamilton Anxiety Rating Scale (HAM-A) in FEP samples show that even moderate anxiety levels are associated with reduced medication adherence, delayed help-seeking, and poorer engagement with early intervention services.

Temporal Course

A critical clinical observation is that anxiety symptoms in FEP often predate psychosis onset. In the North American Prodrome Longitudinal Study (NAPLS), anxiety disorders were present in approximately 50% of clinical high-risk (CHR) individuals, and baseline anxiety severity predicted subsequent conversion to full psychosis. In FEP cohorts, retrospective assessments consistently find that anxiety symptoms preceded psychotic symptom onset by 2–5 years in 40–60% of patients, suggesting shared vulnerability rather than purely reactive anxiety.

The high co-occurrence of anxiety and psychosis is not coincidental. These conditions share overlapping neural substrates at multiple levels of analysis — from molecular genetics to large-scale circuit dysfunction. Understanding these shared mechanisms is essential for rational treatment selection and for appreciating why anxiety in FEP is not simply an epiphenomenon.

Amygdala–Prefrontal Circuit Dysfunction

The amygdala–prefrontal cortex (PFC) circuit is the canonical neural substrate of anxiety, governing threat detection, fear conditioning, and emotion regulation. In FEP, structural and functional neuroimaging studies consistently show amygdala hyperactivation to threatening stimuli combined with reduced prefrontal regulatory capacity, a pattern that mirrors findings in anxiety disorders without psychosis. Specifically:

• Functional MRI studies in FEP demonstrate exaggerated amygdala blood-oxygen-level-dependent (BOLD) response to fearful faces, correlating with self-reported anxiety severity (r = 0.35–0.45 across studies).
• Structural MRI data from the ENIGMA Schizophrenia Working Group show reduced gray matter volume in the ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) in FEP — regions critical for top-down regulation of amygdala reactivity.
• Disrupted functional connectivity between the amygdala and the dorsolateral PFC (dlPFC) has been documented in FEP patients with comorbid anxiety, with connectivity strength inversely correlated with anxiety severity.

Dopaminergic Mechanisms

The aberrant salience hypothesis of psychosis, formulated by Kapur (2003), proposes that dysregulated mesolimbic dopamine activity leads to the inappropriate assignment of motivational significance to neutral stimuli — a process that underlies both paranoid ideation and anxiety. Elevated presynaptic dopamine synthesis capacity in the striatum, consistently demonstrated in FEP using [18F]-DOPA PET imaging, may drive both psychotic symptoms and the heightened threat sensitivity that manifests as anxiety. This shared dopaminergic substrate explains why anxiety and paranoia frequently co-occur and why anxiety may partially improve with antipsychotic-mediated D2 blockade, albeit incompletely.

GABAergic and Glutamatergic Dysfunction

Gamma-aminobutyric acid (GABA) interneuron dysfunction is a well-established finding in schizophrenia-spectrum disorders, particularly deficits in parvalbumin-positive (PV+) interneurons in the PFC and hippocampus. This GABAergic deficit produces cortical disinhibition and impaired gamma oscillations. Importantly, GABAergic deficits also represent a core neurobiological mechanism in anxiety disorders, where reduced GABA-A receptor availability in the amygdala and insula has been demonstrated via PET and MRS (magnetic resonance spectroscopy) studies. The convergence of GABAergic deficiency in both conditions suggests a shared vulnerability pathway.

Similarly, glutamatergic excess — specifically, NMDA receptor hypofunction leading to compensatory glutamate overflow — has been proposed as a mechanism linking psychosis to anxiety. Elevated glutamate levels in the ACC, measured via proton MRS, have been found in both FEP and GAD samples, and glutamate levels in this region correlate with anxiety symptom severity in FEP patients.

Serotonergic System

The 5-HT (serotonin) system is centrally implicated in anxiety regulation, particularly via 5-HT1A and 5-HT2A receptors. PET studies in FEP show reduced 5-HT1A receptor binding in the raphe nuclei, hippocampus, and cortex — a pattern shared with panic disorder and GAD. The 5-HT2A receptor, which is a primary target of second-generation antipsychotics (e.g., risperidone, olanzapine, quetiapine), is also relevant: 5-HT2A antagonism may contribute to the anxiolytic effects of atypical antipsychotics, providing a mechanistic rationale for why some SGAs show differential effects on comorbid anxiety.

Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysregulation

FEP is associated with HPA axis hyperactivation, including elevated baseline cortisol levels and blunted cortisol awakening response. These findings parallel HPA abnormalities in anxiety disorders and are particularly pronounced in FEP patients with childhood trauma histories. Cortisol levels at FEP presentation correlate with anxiety severity (r = 0.25–0.35 across studies) and predict hippocampal volume reduction over the following 12 months, suggesting a neurotoxic pathway linking chronic anxiety-related HPA activation to brain structural changes in early psychosis.

Genetic Architecture

Genome-wide association studies (GWAS) and polygenic risk score (PRS) analyses reveal significant genetic overlap between schizophrenia and anxiety-related traits. The Brainstorm Consortium analysis (2018), which examined genetic correlations across psychiatric disorders using summary statistics from major GWAS, found a genetic correlation (rg) of 0.21–0.24 between schizophrenia and anxiety disorders, indicating shared heritable liability. Specific loci in the CACNA1C (L-type calcium channel) and ANK3 (ankyrin-G) genes have been implicated across both schizophrenia and anxiety phenotypes. Additionally, COMT Val158Met polymorphism, which modulates prefrontal dopamine catabolism, influences both psychosis risk and anxiety vulnerability, with the Met/Met genotype associated with higher anxiety in FEP samples.

Accurately diagnosing anxiety in the context of FEP is more difficult than it may initially appear. Multiple diagnostic confounds exist, and failure to navigate them leads to both underdiagnosis and misattribution of anxiety symptoms.

DSM-5-TR and ICD-11 Considerations

The DSM-5-TR permits comorbid anxiety disorder diagnoses alongside schizophrenia-spectrum diagnoses, provided the anxiety symptoms are not better explained by the psychotic illness itself. The ICD-11 similarly allows dual coding. However, in practice, this distinction is challenging to operationalize. Key diagnostic pitfalls include:

• Diagnostic overshadowing: The most pervasive problem. Clinicians attribute anxiety symptoms to the psychotic episode ("Of course they're anxious — they're hearing voices") rather than recognizing a comorbid anxiety disorder with independent treatment implications. Research consistently shows that clinicians detect anxiety in FEP at roughly half the rate that structured diagnostic interviews reveal it.
• Symptom overlap between anxiety and psychosis: Hypervigilance in PTSD can mimic persecutory ideation. Obsessional intrusive thoughts can be difficult to distinguish from thought insertion. Social withdrawal driven by social anxiety is frequently misclassified as a negative symptom of schizophrenia (avolition, asociality). Panic attacks with depersonalization or derealization can be mistaken for incipient psychotic episodes.
• Medication-induced anxiety: Akathisia, a common side effect of antipsychotic medications, produces subjective restlessness that is frequently misdiagnosed as anxiety. The Barnes Akathisia Rating Scale (BARS) should be administered when anxiety symptoms emerge or worsen after antipsychotic initiation. Conversely, antipsychotic-induced OCD symptoms (particularly with clozapine due to potent 5-HT2C antagonism and serotonergic modulation) represent genuine de novo psychopathology rather than a side effect per se.
• Substance-induced anxiety: Cannabis use, present in 30–50% of FEP samples, can independently produce anxiety symptoms. Stimulant use, alcohol withdrawal, and nicotine dependence further complicate the picture.

Assessment Recommendations

Best clinical practice in FEP assessment includes systematic anxiety screening using validated instruments. Recommended tools include:

• Structured Clinical Interview for DSM-5 (SCID-5) anxiety modules for diagnostic classification
• Social Interaction Anxiety Scale (SIAS) for social anxiety, which has been validated in FEP populations
• PTSD Checklist for DSM-5 (PCL-5) to screen for trauma-related symptoms
• Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) for OCD symptoms, particularly important when prescribing clozapine
• Barnes Akathisia Rating Scale (BARS) to differentiate akathisia from anxiety

Longitudinal assessment is essential. Anxiety that persists beyond acute psychotic symptom resolution (typically 6–12 weeks after treatment initiation) is more likely to represent a genuine comorbid anxiety disorder rather than symptom-phase anxiety. The RAISE-ETP (Recovery After an Initial Schizophrenia Episode–Early Treatment Program) study protocol recommended anxiety reassessment at 3, 6, and 12 months as a standard component of early psychosis care.

Anxiety in FEP rarely occurs in isolation. It clusters with other comorbid conditions in patterns that influence treatment selection, functional outcomes, and overall clinical complexity.

Anxiety and Depression in FEP

Depression co-occurs in 40–60% of FEP patients, and when anxiety is also present, the combination creates a mixed anxious-depressive presentation that is associated with the worst functional outcomes across all FEP subgroups. Data from the UK National EDEN (Evaluating the Development of Early Intervention Networks) study found that patients with comorbid anxiety and depression at FEP baseline had significantly lower social functioning scores (GAF scores averaging 8–12 points lower) and were 2.3 times more likely to be unemployed at 12-month follow-up compared to those with psychosis alone.

Anxiety and Substance Use Disorders

Substance use disorders are present in approximately 25–40% of FEP patients, with cannabis being the most common substance. Comorbid anxiety may drive self-medication behaviors: FEP patients with social anxiety disorder report cannabis use as a coping strategy at approximately twice the rate of non-anxious FEP patients. This creates a vicious cycle, as cannabis use exacerbates both psychotic and anxiety symptoms and is associated with earlier relapse.

Anxiety and Suicidality

The relationship between anxiety and suicidal behavior in FEP is among the most clinically urgent findings in this literature. Anxiety at FEP presentation is an independent predictor of suicidal ideation and suicide attempts, even after controlling for depression severity. The OPUS trial (Denmark) found that FEP patients with comorbid anxiety disorders had a suicide attempt rate of approximately 15% over 2 years, compared to 7% in non-anxious FEP patients. Panic attacks, in particular, have been identified as an acute risk factor for suicidal behavior in psychosis, possibly due to the overwhelming subjective distress they generate.

Anxiety and Trauma Exposure

Childhood trauma (physical, sexual, or emotional abuse; neglect) is present in approximately 50–70% of FEP patients, substantially exceeding general population rates. Trauma exposure is a potent risk factor for comorbid anxiety in FEP, and it mediates the relationship between childhood adversity and psychosis severity. The Traumatic Experiences Screening Instrument (TESI) and the Childhood Trauma Questionnaire (CTQ) reveal that FEP patients with both high trauma exposure and comorbid anxiety have more severe positive symptoms, more persistent negative symptoms, and poorer treatment engagement.

Anxiety and Cognitive Impairment

Cognitive deficits are a core feature of schizophrenia-spectrum disorders, but their interaction with anxiety in FEP is underappreciated. Moderate anxiety can paradoxically impair cognitive performance through attentional resource allocation toward threat monitoring (as described by Eysenck's attentional control theory), worsening the already-compromised processing speed and working memory that characterize FEP. Studies show correlations between anxiety severity and poorer performance on the MATRICS Consensus Cognitive Battery (MCCB) subtests of attention/vigilance and working memory, with effect sizes in the small-to-medium range (d = 0.25–0.45).

The treatment of anxiety in FEP is complicated by limited direct evidence — most trials of anxiolytic agents excluded patients with psychotic disorders, and most FEP trials did not measure anxiety as a primary or secondary outcome. Clinical practice therefore relies on extrapolation from broader schizophrenia and anxiety literature, supplemented by a growing number of FEP-specific studies.

Antipsychotics and Anxiety Reduction

Second-generation antipsychotics (SGAs) vary in their anxiolytic properties, largely based on their receptor-binding profiles:

• Quetiapine has the strongest evidence for anxiety reduction in psychosis, likely due to its combined 5-HT2A antagonism, histamine H1 antagonism (producing sedation), and norquetiapine metabolite activity at the norepinephrine transporter. In the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) trial, quetiapine showed the largest reductions in anxiety/depression PANSS subscale scores compared to other antipsychotics, though this was a secondary analysis in a chronic schizophrenia sample, not an FEP sample.
• Olanzapine also demonstrates anxiolytic effects, again through multi-receptor antagonism including 5-HT2A and 5-HT2C. However, its metabolic side effect burden (weight gain of 6–10 kg in the first year of treatment, metabolic syndrome risk) limits its desirability as a first-line agent in FEP.
• Aripiprazole and risperidone, commonly used first-line agents in FEP, have more modest anxiolytic effects. Aripiprazole, a dopamine D2 partial agonist, can paradoxically increase anxiety and akathisia in some patients during early treatment, though this typically resolves within 2–4 weeks.

Importantly, while antipsychotics reduce global psychopathology including anxiety, residual anxiety symptoms persist in 40–60% of FEP patients even after adequate antipsychotic treatment, indicating the need for additional interventions.

Selective Serotonin Reuptake Inhibitors (SSRIs) in FEP

SSRIs are the first-line pharmacological treatment for anxiety disorders in the general population, but their use in FEP has been cautious due to theoretical concerns about serotonergic-dopaminergic interactions. The available evidence, however, is generally reassuring:

• A systematic review by Bosanac and Castle (2015) found that SSRI augmentation of antipsychotics for anxiety in schizophrenia was effective in most studies, with response rates of 50–65% for comorbid social anxiety and OCD symptoms.
• Sertraline and fluvoxamine have the most data in psychosis populations. Fluvoxamine is notable for its sigma-1 receptor agonism, which may provide additional neuroprotective and pro-cognitive effects, but it also inhibits CYP1A2, potentially elevating clozapine and olanzapine levels.
• The main clinical concern — that SSRIs might worsen psychotic symptoms — has not been borne out in controlled studies. A meta-analysis by Sepehry and colleagues (2007) found no significant increase in positive symptom scores with SSRI augmentation in schizophrenia.

Clinicians should be aware that pharmacokinetic interactions exist: fluoxetine and paroxetine are potent CYP2D6 inhibitors, and fluvoxamine inhibits CYP1A2 and CYP3A4, potentially altering antipsychotic blood levels. Sertraline and escitalopram have the fewest clinically significant drug interactions in this context.

Benzodiazepines

Benzodiazepines are frequently prescribed for acute anxiety in FEP — often as PRN (as-needed) medications during initial stabilization. Short-term use (up to 2–4 weeks) is reasonable for severe acute anxiety or agitation. However, routine or long-term benzodiazepine use in FEP is discouraged by most guidelines, including NICE (National Institute for Health and Care Excellence) and the PORT (Schizophrenia Patient Outcomes Research Team) recommendations. Concerns include cognitive impairment (compounding the cognitive deficits of FEP), dependence risk, disinhibition, and evidence from observational studies linking chronic benzodiazepine use in psychosis to worse long-term outcomes and increased mortality.

Other Pharmacological Options

• Buspirone (5-HT1A partial agonist): Limited evidence in FEP specifically, but a reasonable option for generalized anxiety given its favorable side effect profile and lack of dependence risk. Response rates in the general GAD population are approximately 50–60%, with NNT of approximately 5–8, but these figures have not been confirmed in FEP samples.
• Pregabalin: Effective for GAD in the general population (NNT approximately 5–7), with some evidence for anxiolytic effects in schizophrenia. However, concerns about misuse potential and CNS depression limit its use in FEP.
• Beta-blockers (propranolol): Useful for somatic anxiety symptoms (tremor, tachycardia, sweating) and performance anxiety, and also help manage antipsychotic-induced akathisia. Limited evidence for broader anxiety reduction in FEP, but a reasonable adjunct when somatic symptoms predominate.

Psychological treatments for anxiety in FEP have a stronger emerging evidence base than is commonly appreciated, and they address a gap that pharmacotherapy alone cannot fill.

Cognitive-Behavioral Therapy for Psychosis (CBTp)

CBTp is the most extensively studied psychological intervention in early psychosis, and meta-analyses consistently demonstrate benefits for anxiety symptoms as a secondary outcome. The NICE guideline for psychosis (CG178, updated 2014) recommends CBTp for all individuals with FEP, noting its benefits for emotional distress including anxiety. Key findings include:

• A Cochrane review of CBT for schizophrenia (Jones et al., 2018) found small-to-medium effect sizes for anxiety and distress reduction (g = 0.30–0.45), though heterogeneity across trials was significant.
• The SUPEREDEN3 trial, which examined long-term CBTp outcomes in an early psychosis sample, found sustained benefits for anxiety and depression at 18-month follow-up.
• When CBTp specifically targets anxiety maintenance mechanisms — safety behaviors, threat appraisals, avoidance — rather than focusing exclusively on psychotic symptoms, anxiety outcomes improve further. Freeman and colleagues (2015) demonstrated that targeting worry in psychosis with CBT produced significant reductions in both persecutory delusions and anxiety, with medium effect sizes (d = 0.47 for worry reduction).

Disorder-Specific Anxiety Interventions in FEP

A growing body of evidence supports the delivery of standard evidence-based anxiety treatments (adapted for the FEP context) rather than relying solely on transdiagnostic CBTp:

• CBT for social anxiety in psychosis: Pilot RCTs by Michail and colleagues (2017) demonstrated feasibility and preliminary efficacy of a modified Clark and Wells model CBT protocol for social anxiety in FEP, with large within-group effect sizes (d = 1.2 for SIAS scores). The therapy required adaptation (shorter sessions, simplified formulations, integration of psychosis-related safety behaviors) but used the same core mechanisms as standard SAD treatment.
• Trauma-focused therapies in FEP: Eye Movement Desensitization and Reprocessing (EMDR) and trauma-focused CBT have been piloted in FEP with promising results and, crucially, without exacerbation of psychotic symptoms — a common clinical fear. A meta-analysis by Sin and Spain (2017) found that trauma-focused interventions in psychosis reduced PTSD symptoms with a large effect size (d = 0.88) and also improved positive symptoms of psychosis.
• Mindfulness-based interventions: Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Cognitive Therapy (MBCT) have been adapted for psychosis populations. A meta-analysis by Louise et al. (2018) found small-to-medium effects on anxiety (g = 0.34) and distress in psychosis, with no evidence of adverse effects including psychotic symptom exacerbation.

Comparative Effectiveness: Pharmacology vs. Psychotherapy

No head-to-head trials directly compare SSRIs to CBT for anxiety specifically in FEP. However, extrapolating from the general anxiety literature and from CBTp meta-analyses, the following synthesis is reasonable:

• For mild-to-moderate anxiety in FEP, psychological interventions (CBTp with anxiety focus, or adapted disorder-specific protocols) should be offered first, consistent with NICE guidance prioritizing psychological treatments and shared decision-making.
• For moderate-to-severe anxiety that is functionally impairing or not responding to therapy, SSRI augmentation of the existing antipsychotic is appropriate, with sertraline or escitalopram preferred due to minimal drug interactions.
• Combined treatment (SSRI + CBT) is likely most effective for severe or persistent anxiety, though this has not been tested in FEP specifically. In the general anxiety disorder literature, combined treatment outperforms either modality alone, with NNTs for combined versus monotherapy typically in the range of 6–10 depending on the disorder.

Anxiety in FEP is not merely a source of subjective distress — it carries measurable prognostic weight. Understanding its predictive significance allows clinicians to risk-stratify patients and allocate resources accordingly.

Functional Outcome

Anxiety at FEP baseline is consistently associated with worse social and occupational functioning at follow-up. The Social Functioning Scale (SFS) and Global Assessment of Functioning (GAF) scores at 1, 2, and 5 years are significantly lower in FEP patients with comorbid anxiety, with effect sizes in the medium range (d = 0.40–0.55). Social anxiety, in particular, predicts social isolation, unemployment, and reduced educational attainment — outcomes that persist even when positive psychotic symptoms remit.

Relapse Risk

Data from the OPUS trial and the AESOP-10 follow-up study indicate that anxiety at FEP presentation is associated with 1.5–2.0 times the risk of psychotic relapse within the first 2 years, independent of medication adherence and substance use. This may be mediated by HPA axis hyperactivation, increased dopamine release under chronic stress, and avoidance behaviors that reduce treatment engagement.

Duration of Untreated Psychosis (DUP)

Paradoxically, comorbid anxiety in FEP is associated with both longer and shorter DUP in different studies. Panic-level anxiety may precipitate earlier help-seeking, while social anxiety may lead to avoidance of healthcare systems and longer DUP. Öngür and colleagues have suggested that the type of anxiety matters: distress-related anxiety shortens DUP, while avoidance-related anxiety lengthens it.

Suicidal Behavior

As noted above, comorbid anxiety in FEP is an independent risk factor for suicide attempts. This relationship is strongest in the first 12 months following FEP onset — the period of highest suicide risk in psychotic disorders overall (lifetime suicide rate in schizophrenia: approximately 5%, with approximately 50% of lifetime attempts occurring in the first 5 years of illness). Anxiety contributes to suicidality through hopelessness amplification, agitation, and insomnia — each of which independently elevates acute suicide risk.

Positive Predictive Factors

Not all anxiety in FEP predicts poor outcomes. Some evidence suggests that acute, distress-related anxiety that motivates treatment engagement may be associated with better outcomes than either chronic avoidance-based anxiety or the absence of anxiety (which may reflect blunted emotional processing or anosognosia). Patients with FEP who report anxiety about their illness and actively seek help show better medication adherence and therapeutic alliance scores. This aligns with the broader finding that some preserved emotional reactivity in FEP is a positive prognostic sign.

Several landmark studies have shaped our understanding of anxiety in FEP and early psychosis. Clinicians and researchers should be familiar with the following:

• OPUS Trial (Denmark): A randomized controlled trial of intensive early intervention versus standard treatment for FEP, which included anxiety assessment as a secondary measure. The trial demonstrated that comprehensive early intervention reduced anxiety and depression symptoms more effectively than standard care at 2-year follow-up, though anxiety benefits attenuated by 5 years when intensive intervention was discontinued. This highlighted the need for sustained anxiety-focused treatment beyond the initial intervention period.
• RAISE-ETP and RAISE-NAVIGATE (USA): The Recovery After an Initial Schizophrenia Episode studies implemented the NAVIGATE coordinated specialty care model for FEP. Anxiety was not a primary outcome but was measured as part of the Quality of Life Scale. The NAVIGATE model — combining antipsychotic management, CBT, supported employment, and family education — showed superior outcomes to community care on multiple measures, and subgroup analyses suggested greater benefit for patients with comorbid anxiety and depression.
• NAPLS (North American Prodrome Longitudinal Study): This landmark prospective study of the clinical high-risk (CHR) state established that anxiety disorders are present in approximately 50% of CHR individuals and that anxiety severity predicts conversion to psychosis, providing strong evidence for anxiety as a vulnerability marker rather than merely a consequence of psychotic experience.
• AESOP and AESOP-10 (UK): The Aetiology and Ethnicity in Schizophrenia and Other Psychoses study and its 10-year follow-up provided critical long-term outcome data, including evidence that psychosis-related PTSD at baseline predicted persistent symptoms and functional impairment over a decade. The AESOP-10 follow-up is among the longest prospective FEP studies with comprehensive comorbidity data.
• Achim et al. (2011) Meta-Analysis: The most frequently cited meta-analysis of anxiety prevalence in psychosis, establishing the approximately 38% pooled prevalence estimate and highlighting the significant heterogeneity across studies — heterogeneity that underscored the need for standardized anxiety assessment in psychosis research.

Despite growing recognition of anxiety as a critical clinical target in FEP, substantial gaps remain in the evidence base.

Limitations

• Exclusion from trials: Most pivotal antipsychotic trials (including CATIE and RAISE) either excluded patients with prominent anxiety disorders or did not measure anxiety as a primary outcome. Most SSRI efficacy trials excluded patients with psychotic disorders. This mutual exclusion has created an evidence gap specifically at the intersection of anxiety and psychosis treatment.
• Measurement heterogeneity: Studies use widely varying definitions of anxiety in FEP — from PANSS anxiety item scores to structured diagnostic interviews to self-report questionnaires — making cross-study comparison difficult.
• Short follow-up periods: Most FEP studies follow patients for 1–2 years. The long-term trajectory of anxiety in psychosis — whether it persists, remits, or transforms — is poorly characterized beyond the AESOP-10 dataset.
• Racial and ethnic diversity: The majority of FEP studies have been conducted in predominantly White European samples. Anxiety expression, help-seeking patterns, and treatment response may differ across cultural contexts, but data on these differences in FEP are limited.

Emerging Research Directions

• Transdiagnostic computational models: Computational psychiatry approaches — particularly predictive processing models — offer a unified framework for understanding anxiety and psychosis as disorders of precision-weighted prediction error. Under this framework, both conditions reflect abnormal precision weighting of sensory signals relative to prior beliefs, with anxiety reflecting excessive precision on threat-related prediction errors. This could inform novel pharmacological targets, particularly at glutamatergic synapses.
• Digital phenotyping: Smartphone-based ecological momentary assessment (EMA) is being used in FEP research to capture real-time fluctuations in anxiety, paranoia, and their interaction. Early findings from the EMPOWER trial suggest that momentary anxiety predicts subsequent paranoid ideation with a lag of 30–60 minutes, supporting a causal role for anxiety in psychotic symptom generation.
• Anti-inflammatory interventions: Elevated peripheral inflammatory markers (CRP, IL-6, TNF-α) are found in both FEP and anxiety disorders. Clinical trials of anti-inflammatory agents (celecoxib, minocycline, omega-3 fatty acids) in FEP are underway, with some evidence suggesting greater benefit for patients with elevated inflammatory profiles and comorbid anxiety.
• Personalized treatment matching: Efforts to develop clinical prediction models that match FEP patients to optimal treatments based on anxiety subtype, symptom profile, and biomarkers are in early stages. Machine learning approaches applied to RAISE and OPUS datasets have identified anxiety-related symptom clusters that predict differential response to coordinated specialty care versus standard treatment.

Based on the current evidence, the following clinical recommendations can be made for managing anxiety in first-episode psychosis:

• Screen systematically: All FEP patients should be screened for anxiety disorders using structured instruments at baseline and at 3, 6, and 12 months. Do not rely on clinical impression alone — diagnostic overshadowing is the rule, not the exception.
• Differentiate anxiety from akathisia: Always administer the Barnes Akathisia Rating Scale before attributing restlessness or inner tension to anxiety, particularly after antipsychotic initiation or dose changes.
• Assess trauma history: Given the high prevalence of trauma exposure in FEP and its mediating role in anxiety, systematic trauma assessment (e.g., with the CTQ or ACE questionnaire) should be standard practice.
• Prioritize psychological intervention: CBTp with an explicit anxiety focus should be offered to all FEP patients with significant anxiety. For identified social anxiety, PTSD, or OCD, consider disorder-specific adapted protocols delivered by therapists with both anxiety and psychosis competencies.
• Use SSRIs judiciously: When anxiety is moderate-to-severe and persistent beyond acute stabilization, SSRI augmentation (sertraline or escitalopram preferred) is supported by available evidence. Monitor for pharmacokinetic interactions with the co-prescribed antipsychotic.
• Minimize benzodiazepine use: Limit to short-term acute management (2–4 weeks maximum) when necessary. Long-term prescribing carries clear risk and limited benefit.
• Consider anxiety in risk assessment: Comorbid anxiety in FEP elevates suicide risk. Include anxiety severity in routine risk formulations, particularly during the first 12 months of illness.
• Address anxiety as a barrier to recovery: Social anxiety and avoidance directly impede vocational rehabilitation, social reintegration, and engagement with early intervention services. Treatment plans should explicitly target these barriers.

Anxiety in first-episode psychosis is not peripheral to the psychotic process — it is mechanistically intertwined with it, prognostically significant, and therapeutically accessible. Recognizing and treating anxiety in FEP is not a luxury; it is a clinical imperative that meaningfully alters the trajectory of early psychotic illness.