Generalized anxiety and panic disorder in schizophrenia

Chapter 6 Generalized anxiety and panic disorder in schizophrenia

KEY POINTS

• Schizophrenia and anxiety disorders occur together much more commonly than would be expected by chance.

• There is evidence that generalized anxiety disorder (GAD) and panic disorder (PD) are particularly prevalent in the prodrome to first episode psychosis.

• Anxiety is also a common early warning sign of psychotic relapse.

• Cognitive models of delusional beliefs feature anxiety.

• Biological explanations for the higher than expected comorbidity include genetic predisposition and the impact of shared environmental factors.

• Treatment of GAD and PD in people with schizophrenia has very little specific direct evidence.

• Cognitive behavioural therapy for psychosis (CBTp) is often focused on reducing delusional distress and anxiety.

• Antidepressant medication is safe to use as adjunct with antipsychotic medication and may be worth an individual patient trial.

There is strong evidence of the common occurrence of panic and generalized anxiety symptoms in schizophrenia, at both the symptom and disorder level. Anxiety symptoms are also prominent in the prodrome of first episode psychosis (FEP) and feature heavily as early warning signs of psychotic relapse. Psychological models of the development of positive symptoms such as persecutory delusions are based on information processing or prediction errors which are related to enhanced ‘threat to self’ appraisals. Genetic overlaps between risk for schizophrenia and a range of affective and anxiety disorders are becoming clearer with genome-wise association studies, and there is some tantalizing evidence that targeting anxiety may reduce the incidence of psychosis onset or relapse. This all points to anxiety symptoms being an underrecognized area of potentially significant treatment, which may also have wider secondary outcomes. This chapter outlines biological and psychological explanations for the increased incidence of panic and generalized anxiety and provides guidance on its recognition and potential management.

Prevalence of generalized anxiety and panic disorder in schizophrenia

Achim et al. (2009) conducted a systematic review and meta-analysis of all anxiety disorders in schizophrenia, and reported lifetime prevalence rates of up to 24% for generalized anxiety disorder (GAD) and 12% for panic disorder (PD)—considerably higher than the general population (Achim et al. 2009). Rates varied widely, with the level of disorder generally derived from cross-sectional studies that assess symptoms reaching a level of significance for a disorder to be diagnosed. The lifetime prevalence of symptoms of anxiety and panic are likely to be much higher still; in one report up to 65% of patients with schizophrenia experienced panic attacks at some point in their illness (Goodwin et al. 2002).

Symptoms of anxiety have been described in patients with schizophrenia for many decades, including in Bleuler’s first descriptions of evolving schizophrenia (Buckley et al. 2009). With increasing recognition of a staged model of psychosis and developing mental health disorders in young people (McGorry et al. 2006), psychopathological variability in early phase disorders has also become clear. The ultra-high risk (UHR) phase of psychosis is often accompanied by generalized anxiety and panic: in a recent systematic review, Wilson and colleagues suggest that the prevalence of anxiety in UHR and FEP stages is considerably underestimated (Wilson et al. 2020). Categorical anxiety disorders are likely to represent just one component of a broader continuum of anxiety symptoms that are particularly prevalent in the early stages, when diagnostic fluidity is more apparent; when psychosis is developing in relapse; and when symptoms fluctuate across the course of the disorder.

In terms of PD specifically, Hofmann and colleagues (2000) put forward a number of hypotheses to explain the co-occurrence with schizophrenia, including that autonomic hyperactivity associated with panic may serve as a stressor to induce or exacerbate psychotic symptoms, again reinforcing the idea that anxiety symptoms may be most relevant in the development and maintenance of psychopathology (Hofmann et al. 2000).

In psychotic relapse, the identification of early warning signs has become established practice, with their successful identification linked with the ability of individuals and their clinical teams to alter treatment plans, reduce environmental pressures, or alter pharmacological regimes prior to the full manifestation of psychotic relapse (Birchwood et al. 2000). Early warning signs are now recognized to include both psychosis precursors such as thought disorganization, low-level paranoid ideation and social withdrawal, and ‘neurosis’ factors, such as anxiety and depression (Bustillo et al. 1995). Norman and Malla (1995) highlighted the importance of such non-psychotic symptoms, suggesting that they may be useful to identify psychotic relapse and also they are related to early and subtle signs of psychosis (Norman and Malla 1995).

What are the causes of an increased occurrence of anxiety in schizophrenia?

If anxiety symptoms are present in UHR phases, and prior to psychotic relapse, there follows a likelihood that they may be a precursor to schizophrenia. Anxiety symptoms are prominent in cognitive models of positive symptoms of psychosis. Population-based studies such as the Avon Longitudinal Study of Parents and Children (ALSPAC) indicate that young people with high levels of anxiety are more likely to experience psychotic symptoms, with symptoms representing a manifestation of a unitary, latent continuum of common mental disorder, with psychotic experiences conveying information about the more severe end (Stochl et al. 2015). This conclusion is in keeping with the hierarchical model outlined in Chapter 3, whereby in the presence a more severe illness, symptoms common in other ‘less severe’ syndromes such as GAD are to be expected (Foulds and Bedford 1975). As PD is also common in the UHR phase (Rapp et al. 2012; Tien and Eaton 1992), people with panic symptoms are unsurprisingly more likely to seek help early than those without panic disorder (Goodwin et al. 2002).

The ALSPAC cohort also demonstrated that a high polygenic risk score for schizophrenia is expressed in the increased likelihood of broadly occurring anxiety symptoms as well as positive symptoms of psychosis (Jones et al. 2016). Similarly, the Edinburgh High Risk Study of schizophrenia showed that anxiety and mood symptoms preceded the onset of psychotic symptoms in those who went on to develop a psychotic disorder (Owens et al. 2005). Understanding causal mechanisms and developing targeted interventions would be needed to elucidate whether the common symptoms of anxiety are simply harbingers of more severe psychopathology or are indeed causally related to schizophrenia. Longitudinal studies demonstrating the temporal relationship between GAD and PD and risk for schizophrenia give important information. However, psychosis itself is a stressful life event for many people, and GAD and PD are equally likely to be precipitated by this experience; therefore models should take into account the anxiety-provoking consequences of psychosis, as well as how these experiences may precipitate psychotic relapse.

Cognitive models of generalized anxiety and psychosis

A number of psychosis risk factors—including minority status, childhood trauma, and migration—increase the risk of anxiety disorders. These non-specific factors of poor mental health may also be precursors to substance misuse, depression, and other mental health outcomes. However, heightened anxiety can bias both perception and cognition and may contribute to the development of positive psychotic symptoms and their perceived distress and need for care.

Freeman and Garety have developed robust models of persecutory delusions based on the premise that worry and the process of anxiety are essential for the development and maintenance of delusional distress (Freeman and Garety 2003; Garety and Freeman 1999). General anxiety, worry, and meta-cognitive processes were found to be related to the development of delusional thinking. The content of persecutory delusions is conceptualized as threat beliefs, and then maintained by confirmatory ‘evidence’, with heightened threat to self-appraisals not allowing disconfirmatory evidence to enter the equation. However, in contrast to individuals with GAD and no psychosis, psychotic individuals are more likely to look out for threat (Freeman et al. 2002), whilst worry in people with persecutory delusions is associated with more perseverative thinking, catastrophizing, and intolerance of uncertainty (Startup et al. 2007). These models form the basis of cognitive behavioural therapy for psychosis (CBTp). Although not without controversy (Jauhar et al. 2019), evidence suggests CBTp can be effective in terms of reducing delusional distress and improving acute symptoms for transitory periods (Lewis et al. 2002), and although studies that make no attempt to mask group allocation are likely to inflate effect sizes, positive results appear to be seen to some extent also for secondary outcomes, including anxiety (Wykes et al. 2008).

In terms of auditory hallucinations, distress and anxiety are strongly linked with the experience of anomalous perceptions and the need for care. Clinical voice hearers are more likely to report negative beliefs, worry, and lack of control than non-clinical voice hearers and it may be the distress itself leads to help-seeking (Hill and Linden 2013). Woods et al. (2015) reported that around a third of voice hearers have anxiety as a core part of the experience (Woods et al. 2015). A systematic review also highlighted the high frequency of insecure or anxious attachment in people who manifest psychotic symptoms: insecurely attached individuals were more likely to develop maladaptive coping strategies for processing social information, mentalization, and developing social relationships (Korver-Nieberg et al. 2014). Social isolation may be a pathway to anxiety-driven psychotic phenomenology in vulnerable individuals.

Biological models

As detailed in Chapter 1, schizophrenia is a highly heritable condition, with genomic factors explaining around 65–80% of the variance in risk (Purcell et al. 2009; Sullivan et al. 2012). However, this risk is shared amongst many common risk alleles, each of small effect; combined together these risk alleles at an individual level can be used to generate a polygenic risk score (PRS). Schizophrenia PRSs correlate with schizophrenia status, but also with other disorders including bipolar disorder and depression (Richards et al. 2019). Regarding anxiety disorders, Jones et al. (2016), using the ALSPAC cohort, demonstrated that PRS was associated with anxiety and negative symptoms in adolescents (Jones et al. 2016); and other researchers using the same cohort showed that the PRS for schizophrenia conferred risk specifically for GAD and PD, and this extended into adulthood as well as adolescence (Richards et al. 2019). This has been replicated in a separate cohort, from New Zealand, with odds ratios (ORs) for PRS for schizophrenia and GAD being 1.5 and for PD 1.3. These findings suggest the co-occurrence of schizophrenia and GAD/PD is driven at least in part by common biological antecedents.

Increased release of presynaptic dopamine remains the prevailing model of positive symptoms of schizophrenia (Howes and Kapur 2009), compatible with the efficacy of antipsychotic medications that act as dopamine antagonists. However, it should be noted that antipsychotic medications when first produced were labelled as ‘major tranquillizers’ and the vast majority of first and second generation antipsychotics have sedative effects secondary to histaminergic function. Thus anxiety, in the broadest sense, may well be treated serendipitously when positive symptoms are targeted. Whilst dopamine may be a final common pathway for positive symptoms, other non-dopaminergic pathways are active and may well be relevant when considering comorbidities, including glutaminergic and immune mechanisms (see Chapter 3). Thus, understanding and recognizing GAD and PD comorbidity is important not only for treating an underrecognized comorbidity, but also for driving the development of novel treatments.

Recognition of GAD and PD in schizophrenia

Recognition of GAD and PD in people with schizophrenia requires careful consideration and elucidation of positive, negative, and general symptoms (Box 6.1). Anxiety can present as secondary to explicit threat from perceived persecutors as part of fully formed delusions or be present in the prodrome. It can also manifest as part the phenomenology associated with the development of primary delusions, manifesting as uncomfortable feelings or delusional mood. Negative symptoms such as amotivation and avoidance may be secondary to avoidance of anxiety-provoking situations. GAD and PD may be a reactive manifestation to external circumstances or as a discrete comorbid condition. In all scenarios, they can have profound negative effects on prognosis, functional recovery, and quality of life (Buckley et al. 2009).

Box 6.1 Features of schizophrenia comorbid with GAD and PD