INTRODUCTION — Anxiety is frequently observed among patients with schizophrenia. Anxiety may present as a component of schizophrenia (particularly during an acute psychotic episode), a result of an underlying organic condition, a medication side effect, or a symptom of a co-occurring anxiety disorder. A thorough psychiatric examination, including a medical history and physical examination, and possibly intervention trials, may be needed to arrive at an accurate diagnosis. Treatment is based on this determination.
Posttraumatic stress disorder, which was redefined as a trauma-related disorder in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), was previously studied in patients with co-occurring schizophrenia along with the anxiety disorders and is included in this topic.
The epidemiology, clinical manifestations, diagnosis, and treatment of anxiety in patients with schizophrenia are discussed here. Anxiety disorders and schizophrenia as individual, noncomorbid conditions are discussed separately.
●(See "Social anxiety disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)
●(See "Schizophrenia in adults: Clinical manifestations, course, assessment, and diagnosis".)
EPIDEMIOLOGY — A meta-analysis of 52 studies with a total of 4032 patients with a schizophrenia spectrum disorder found that 38.3 percent suffered from a comorbid anxiety disorder [1]. Schizophrenia spectrum disorders include schizophrenia, schizoaffective, schizophreniform and delusional disorders, and psychosis not otherwise specified. Mean prevalence rates were as follows:
●Social anxiety disorder (social phobia) – 14.9 percent
●Posttraumatic stress disorder – 12.4 percent
●Obsessive-compulsive disorder (OCD) – 12.1 percent
Disorder rates across studies were markedly heterogeneous, largely due to use of different samples, diagnostic tools, and symptom-rating instruments. Mean rates were higher than those found for anxiety disorders in the general population. A study that included 327 patients with a chronic psychotic illness found that rates of an anxiety disorder were substantially higher among subjects diagnosed with schizoaffective disorder compared with schizophrenia (30.1 versus 16.7 percent) [2].
High levels of anxiety symptoms or the presence of an anxiety disorder have been associated with more severe positive symptoms of schizophrenia, social withdrawal, depression, hopelessness, increased suicide rates, and poorer functioning [3,4].
Studies suggest that individuals with an early age of schizophrenia onset have a higher prevalence of anxiety than individuals with later onset. An analysis of data from the Epidemiologic Catchment Area study found that the presence of OCD, social phobia, or panic attacks were associated with a 2.6 to 3.5 increased odds of developing schizophrenia [5]. The presence of anxiety disorders in patients with first episode psychosis has been associated with poorer initial outcomes [6,7].
PATHOGENESIS — Little is known regarding the pathophysiology of anxiety in schizophrenia. Imaging and postmortem studies suggest that dysregulation of the major neurotransmitters, such as dopamine, glutamate, and serotonin may contribute to the presence of anxiety symptoms in schizophrenia [8]. A study identified gray matter volume decreases in patient with schizophrenia as compared with patients with schizophrenia and anxiety comorbidity, mostly noticeable in the dorsolateral prefrontal cortex. Patients with schizophrenia and anxiety had volumes comparable to controls in this sample [9].
Familial aggregation of obsessive-compulsive-associated disorders (ie, obsessive-compulsive disorder [OCD], obsessive-compulsive personality disorder, and schizophrenia with comorbid obsessive symptoms) has been reported, such that relatives of schizophrenia patients with OCD have higher rates of anxiety disorders than relatives of schizophrenia probands without OCD [10]. This provides support for the validity of the OCD as a discrete comorbid entity [3,4]. However, these findings are derived from small samples, and no comparable studies have been done for other anxiety disorders.
CLINICAL MANIFESTATIONS — The term “anxiety” can be used to describe several different mental phenomena: an affect, a symptom, or one of several syndromes. As an affect, anxiety performs an important signal function, alerting a person to danger. An example is the anxiety that alerts a person to look both ways before crossing the street. Anxiety is described as a symptom if it is experienced as unduly severe, in the absence of a sufficient cause, or lasts longer than is reasonable. In these cases, the unpleasant aspect of the anxious feeling has crossed a threshold that may lead a person to complain about it. Several syndromes, which can occur in patients with and without schizophrenia, present with anxiety in combination with other symptoms and associated impairment.
Symptoms of anxiety in patients with schizophrenia can be secondary to schizophrenia or independent of the psychotic disorder. Anxiety as a secondary symptom presents as an integral part of an active psychotic process. An example is a patient experiencing anxiety induced by terrifying hallucinations and delusions. Anxiety secondary to psychosis tends to improve as psychosis improves (eg, in response to antipsychotic treatment).
Anxiety may be present prior to the occurrence of schizophrenia or may persist in the absence of psychosis. Anxiety is often a feature in the prodrome leading to schizophrenia [11]. Studies suggests that anxiety is more prevalent in individuals with an earlier rather than later age of schizophrenia onset. (See 'Epidemiology' above.)
Anxiety can persist in the form of a syndrome or disorder that co-occurs independently from schizophrenia. Anxiety disorders and their distinguishing features [12] are described below. Symptoms must occur to a degree causing significant distress or impairment for a disorder to be diagnosed. The DSM-5 diagnostic criteria for each disorder are provided later in the topic. (See 'Anxiety disorders' below.)
●Obsessive-compulsive disorder (OCD) – Obsessions are persistent thoughts, ideas, or images that are perceived as senseless and intrusive; compulsions are urges or impulses for repetitive intentional, stereotyped behavior performed to alleviate the anxiety of the obsessions
●Panic disorder – Sudden onset of intense apprehension, fear, or terror accompanied by the abrupt development of specific affective, cognitive, and somatic symptoms (eg, palpitations, shortness of breath).
●Posttraumatic stress disorder – Intrusive thoughts, nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance, exaggerated startle response and sleep disturbance.
●Specific phobia – Marked, irrational, and persistent fears of an object, activity, or situation, which is actively avoided or endured with intense anxiety or distress.
●Social anxiety disorder – Unreasonable fear of embarrassment and humiliation in social or performance situations, leading to avoidance or intense anxiety.
●Generalized anxiety disorder – Excessive anxiety and worry, fatigue, muscle tension, memory loss, and/or insomnia.
Specific anxiety disorders can present with different degrees of overlap with the psychotic symptoms of schizophrenia, conceptually and possibly clinically. As examples, panic and paranoia both involve extreme states of fear. It has been proposed that the affective storm of anxiety during a panic attack can spur a patient with schizophrenia to scan their environment for danger that would justify the anxiety [13]. A paranoid individual may experience an exaggerated perception of danger in their environment as a complement to the extreme anxiety of the panic attack. Obsessions in OCD can overlap conceptually with delusions in schizophrenia. It can be the inability of a patient to get a delusional thought off their mind, rather than the incorrectness of the thought, which causes much of the patient’s suffering and functional impairment [14].
COURSE — Patients with anxiety predating schizophrenia have been found to have worse outcomes compared with patients with anxiety that developed as part of the psychotic process [15,16]. Studies of patients with co-occurring schizophrenia and anxiety disorders have found that patients with anxiety disorders had increased service utilization and hospitalization rates compared with patients without an anxiety disorder [17].
ASSESSMENT AND INITIAL MANAGEMENT — In patients with schizophrenia presenting with anxiety, the assessment and management of the anxiety are closely intertwined.
Differential diagnosis — Assessment and management are guided by the differential diagnosis. The clinician needs to determine the source of the anxiety or anxiety-like symptoms:
●A product of an underlying medical condition
●A side effect of antipsychotic or other medication
●An understandable psychological reaction to transpiring events
●A constituent of schizophrenia
●An essentially distinct, co-occurring syndrome
Assessment of anxiety can prove daunting when attempted in a single cross-sectional evaluation. It often requires meticulous history taking and clinical examination, optimally repeated over an extended period. This allows the clinician to determine, for example, whether the anxiety symptoms preceded or occurred independent of the psychotic symptoms.
Diagnosis of anxiety as a component of schizophrenia or an anxiety disorder is a diagnosis of exclusion, requiring the clinician to rule out organic factors, including medication side effects, as possible causes. Treatment interventions can be used to identify or rule out possible diagnoses.
Organic factors — Many medical conditions can generate or mimic anxiety symptoms in patients with schizophrenia, including current medical illnesses, medication side effects, and substance use disorders, including withdrawal. See tables for medical conditions (table 1) and medications (table 2) that can cause anxiety or symptoms that can be mistaken for anxiety. Individuals with schizophrenia have higher rates compared with the general population of such medical conditions, including cardiovascular and pulmonary disease [18] and substance use disorders [19,20]. (See "Co-occurring schizophrenia and substance use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment and diagnosis".)
A medical history, physical examination, review of the patient’s medications and adherence, and laboratory testing are indicated to identify organic factors contributing to anxiety in patients with schizophrenia. A reasonable initial screening evaluation should include complete blood count and complete metabolic panel, a calcium level and thyroid function tests. If panic attacks are part of the differential diagnosis, concern about a potential pheochromocytoma or arrhythmia can prompt referral to a medical generalist or specialist.
Side effects of antipsychotics — Anxiety and anxiety-like symptoms can occur as side effects of antipsychotic drugs, as in akathisia and obsessive-compulsive symptoms.
Akathisia — Akathisia, an extrapyramidal symptom, may present with fidgetiness and marked internal angst akin to that reported in primary anxiety. Akathisia usually presents as motor restlessness with a compelling urge to move and an inability to sit still. Individuals with milder akathisia can describe a subjective feeling of restlessness but not show restless motor behavior. Additional information about akathisia, including interventions, is discussed separately. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Akathisia'.)
In cases where the diagnosis is uncertain, a trial of an intervention may be helpful to identify or rule out akathisia. (See 'Side effects of antipsychotics' above and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Side effects'.)
Obsessions and compulsions — De novo obsessive and compulsive symptoms can accompany initiation of a second-generation antipsychotic drug [21]. Data suggest that the symptoms increase with antipsychotic dose. A temporal association between medication initiation (or dose increase) and symptom onset can help to identify these side effects. However, the symptoms may develop weeks or months after medication initiation. The side effects are thought to be caused by the 5-HT2a antagonism of most second-generation antipsychotics.
The initial treatment of antipsychotic-induced obsessive and compulsive symptoms would be to decrease the antipsychotic medication, if this can be done without exacerbating the psychotic disorder. If this is not feasible or results in an inadequate response, the clinician should consider switching antipsychotics, possibly to one with less serotonin antagonism, such as haloperidol.
A change in antipsychotic medication may not be an option when the patient is taking clozapine, because this drug is typically used in patients with schizophrenic symptoms refractory to other antipsychotics. Case reports have suggested that selective serotonin reuptake inhibitors (SSRIs) may reduce clozapine-induced obsessive and compulsive symptoms [22-24]. However, it should be noted that controlled studies are lacking, and the risks of additional side effects should be weighed against potential benefits of adding an SSRI. Some SSRIs (especially fluvoxamine) interact with clozapine, leading to toxic clozapine levels in some individuals [25]. Fluvoxamine should be avoided in patients receiving clozapine. Other SSRIs should be used with caution and accompanied by monitoring of clozapine drug levels. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)
Symptoms of schizophrenia — To distinguish between anxiety as a symptom of schizophrenia and a distinct anxiety disorder, the clinician should be attuned to signs of temporal and clinical independence between the anxiety and psychotic symptoms. Examples follow:
●In a patient presenting with panic attacks, untriggered attacks are suggestive of a panic disorder, while panic accompanying the persecutory delusions of schizophrenia does not suggest an independent anxiety disorder.
●A patient avoiding social situations may have a comorbid social anxiety disorder, suggested by the presence of discomfort with social exposure, or may lack interest in social situations, a common negative symptom of schizophrenia. Social avoidance can also be due to active positive symptoms. As an example, a patient might avoid social interaction for delusional fear of persecution. Such cases should be distinguished from comorbid social anxiety disorder.
The presence of anxiety with an acute psychotic episode can increase the severity of the patient’s clinical status and the difficulty of clinical management. In these cases, suggested steps are as follows:
●Evaluate the level of environmental and intrapsychic stress to which the patient is exposed.
●In cases where specific situations or interpersonal interactions are identified as closely related to the onset of anxiety, the patient may benefit from supportive therapeutic techniques, building of the patient’s coping skills, or family interventions. A single observational trial was conducted of a short-term psychoeducational intervention provided to 46 family members of inpatients treated for schizophrenia [26]. Significant reductions were seen in patient anxiety, family burden, and patient-family relationship difficulties. (See "Psychosocial interventions for schizophrenia in adults".)
●If psychosocial interventions are not an option, due to availability or patient preference, acute treatment with benzodiazepines (eg, lorazepam 1 to 6 mg/day orally in two to three divided doses) can be beneficial and safe. The need for the medication for anxiety should be reevaluated once the psychotic exacerbation has improved.
The phenomenological distinction between symptoms of anxiety disorders and psychotic symptoms can be often difficult to determine. During acute psychotic breaks it can be close to impossible. Examples of diagnostic challenges follow:
●Symptoms of schizophrenia involving fearfulness or having “bad thoughts” can mimic core features of agoraphobia, panic disorder, and obsessive-compulsive disorder (OCD).
●The avoidance inherent in social anxiety can overlap phenomenologically with negative symptoms of schizophrenia (eg, a lack of interest in social activities).
●Obsessions in OCD can overlap with delusions in schizophrenia [14]. It can be the inability of a psychotic patient to get delusional thoughts off their mind, rather than the content of the thought itself, that causes much of the patient’s suffering and functional impairment.
Trials of treatment can be useful in determining the diagnosis. Initiating an antipsychotic medication, or increasing an existing dose, is indicated to manage escalating anxiety and psychosis. If the anxiety resolves along with the psychosis, the response suggests that the anxiety was a symptom of schizophrenia.
Anxiety disorders — A co-occurring anxiety disorder can be diagnosed in patients with schizophrenia if the patient fully meets DSM-5 diagnostic criteria for the disorder and if the alternative possibilities, described above, have been ruled out [12]. While this may be clear cut in some cases, it may be more ambiguous in others. DSM-5 criteria require that the current anxiety symptoms are “not better accounted for by another mental disorder.” This judgment is left to the individual clinician and may be less than obvious in some cases. The individual anxiety disorders are listed below:
●Posttraumatic stress disorder (see "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis")
●Generalized anxiety disorder (see "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis")
●Panic disorder (see "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis")
●Social anxiety disorder (see "Social anxiety disorder in adults: Epidemiology, clinical manifestations, and diagnosis")
●Phobic disorders (see "Specific phobia in adults: Epidemiology, clinical manifestations, course and diagnosis" and "Agoraphobia in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis")
TREATMENT FOR CO-OCCURRING ANXIETY DISORDERS — For most patients with an anxiety disorder co-occurring with schizophrenia, treatment of the anxiety disorder should be cautiously based on the treatment recommendations for the anxiety disorder in the noncomorbid population. Information on the efficacy, safety, and administration of treatment for individual anxiety disorders in patients with co-occurring schizophrenia is provided below.
Pharmacotherapy — Treatments for comorbid anxiety disorders have not been extensively studied in patients with schizophrenia. Small randomized trials, open trials, and case reports have suggested varying levels of support for selective serotonin reuptake inhibitors (SSRI) for individual disorders.
Obsessive-compulsive disorder — Two small randomized trials have found the serotonergic antidepressants clomipramine and fluvoxamine to reduce obsessive-compulsive disorder (OCD) symptoms in patients with schizophrenia compared with placebo [27]. These findings have been supported by case reports suggesting efficacious treatment with fluoxetine, fluvoxamine, paroxetine, and sertraline. (See "Pharmacotherapy for obsessive-compulsive disorder in adults".)
Clinical trials and case reports have not reported adverse effects beyond what is typical in patients without schizophrenia. One case report described the apparent efficacy of intravenous clomipramine in a patient unresponsive to oral clomipramine and fluoxetine [28]. The SSRI fluvoxamine should be avoided in patients treated with clozapine. (See "Guidelines for prescribing clozapine in schizophrenia" and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects" and "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)
SSRIs should be started at low doses, eg, 5 to 10 mg of paroxetine or 25 mg of fluvoxamine. However, doses necessary to treat OCD are frequently higher than those needed to treat depression. A switch in medication or augmentation with another agent should be considered after 8 to 13 weeks of an initial adequate medication trial. It should be noted that SSRIs can result in potentially relevant changes in antipsychotics’ blood levels.
Panic attacks — Case reports and open trials have reported reductions in panic attacks in patients with comorbid schizophrenia and panic disorder treated with alprazolam, diazepam, and imipramine [29-31]. A few case reports have suggested panic attacks respond to changes from a first- to second-generation antipsychotic [32,33]. No studies were found of SSRIs for panic in schizophrenia. (See "Management of panic disorder with or without agoraphobia in adults".)
Social anxiety disorder — A small open trial suggested that aripiprazole may be effective for patients with schizophrenia and social phobia [34]. Sixteen patients had their existing antipsychotics cross titrated with aripiprazole and were then followed for two months. The change to aripiprazole was associated with a reduction of social anxiety after three weeks of treatment. These results have not been replicated. (See "Pharmacotherapy for social anxiety disorder in adults".)
Other anxiety disorders — No published trials or case reports are available to evaluate the efficacy of pharmacotherapy for posttraumatic stress disorder (PTSD), generalized anxiety disorder, or phobias other than social anxiety in patients with schizophrenia. (See "Generalized anxiety disorder in adults: Management" and "Pharmacotherapy for specific phobia in adults" and "Management of posttraumatic stress disorder in adults".)
A clinical trial of 54 subjects with schizophrenia and anxiety compared pregabalin with placebo for treatment of anxiety [35]. After eight weeks treatment, no difference was seen in change of anxiety symptoms between groups.
Cognitive-behavioral therapy — Specific cognitive-behavioral therapies (CBTs) have been developed with efficacy in one or more anxiety disorders. (See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies" and "Psychotherapy for social anxiety disorder in adults" and "Psychotherapy for panic disorder with or without agoraphobia in adults" and "Cognitive-behavioral therapies for specific phobia in adults" and "Psychotherapy and psychosocial interventions for posttraumatic stress disorder in adults".)
For patients with co-occurring panic disorder, social anxiety disorder, or PTSD who have not responded adequately to medication, we suggest a trial of adjunctive CBT.
Limited evidence suggests that CBT may be efficacious in reducing symptoms of anxiety disorders in patients with co-occurring schizophrenia, including two small trials of patients with social anxiety disorder [36,37] and a small open trial of patients with panic disorder [38]. Stronger evidence supports the use of CBT for PTSD in patients with schizophrenia [39,40].
A clinical trial found two CBTs, prolonged exposure therapy and eye movement desensitization and reprocessing (EMDR) therapy, to reduce PTSD symptoms in patients with co-occurring PTSD and a psychotic disorder (90 percent with schizophrenia or schizoaffective disorder) [40]. The trial randomly assigned 155 patients to receive eight 90-minute sessions of one of the two interventions, or to a waiting list control group that received treatment as usual. At the end of the treatment period and at six-month follow-up, groups who received exposure therapy or EDMR therapy experienced less severe PTSD symptoms and had lower rates of participants continuing to meet PTSD diagnostic criteria compared with the control group (57 and 60 versus 27 percent). Participants receiving exposure, but not those receiving EMDR, were more likely to meet criteria for full remission of PTSD compared with the control group (28.3 and 16.4 versus 6.4 percent). There were no differences in severe adverse events among groups.
Although not empirically tested in schizophrenia and varying by anxiety disorder, combined therapy with medication and CBT may be more effective than either of the individual modalities. (See "Management of panic disorder with or without agoraphobia in adults" and "Psychotherapy for social anxiety disorder in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psychotic disorders".)
SUMMARY AND RECOMMENDATIONS
●Co-occurring anxiety disorders are a common occurrence among patients with schizophrenia. Higher levels of anxiety are associated with more prominent positive symptoms of schizophrenia and poorer functioning. (See 'Epidemiology' above.)
●The differential diagnosis of anxiety in a patient with schizophrenia includes (see 'Assessment and initial management' above):
•Anxiety or anxiety-like symptoms due to a medical condition, medication, or substance use disorder (table 1 and table 2)
•Side effects of antipsychotic medications such as akathisia or obsessions/compulsions (see "Schizophrenia in adults: Maintenance therapy and side effect management")
•Anxiety that is a component of schizophrenia (see 'Symptoms of schizophrenia' above)
•An independent, comorbid anxiety disorder (see 'Anxiety disorders' above)
●Specific anxiety disorders that can co-occur with schizophrenia include (see 'Clinical manifestations' above):
•Obsessive-compulsive disorder (see "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis")
•Posttraumatic stress disorder (PTSD) (see "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis")
•Generalized anxiety disorder (see "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis")
•Panic disorder (see "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis")
•Social anxiety disorder (see "Social anxiety disorder in adults: Epidemiology, clinical manifestations, and diagnosis")
•Phobic disorders (see "Specific phobia in adults: Epidemiology, clinical manifestations, course and diagnosis" and "Agoraphobia in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis")
●A medical history, physical examination, review of the patient’s medications and adherence, and laboratory testing are indicated to identify organic factors contributing to anxiety in patients with schizophrenia. A basic screening evaluation should include complete blood count, complete metabolic panel, calcium, and thyroid function tests. (See 'Organic factors' above.)
●Treatment for anxiety or anxiety-like symptoms is typically based on the cause or diagnosis of the symptoms:
•A medical condition causing anxiety requires treatment of the underlying condition. A patient experiencing significant distress or impairment may benefit from short-term treatment with a low dose of a benzodiazepine (eg, lorazepam 1 to 6 mg/day orally divided into two to three divided doses). (See 'Organic factors' above.)
•Anxiety secondary to an acute psychotic episode typically improves in response to antipsychotic medication treatment of the psychosis. (See 'Symptoms of schizophrenia' above.)
•For most patients with an anxiety disorder co-occurring with schizophrenia, treatment of the anxiety disorder should be cautiously based on treatment recommendations for the anxiety disorder in the noncomorbid population. (See 'Pharmacotherapy' above and 'Cognitive-behavioral therapy' above and "Psychotherapy for obsessive-compulsive disorder in adults" and "Psychotherapy and psychosocial interventions for posttraumatic stress disorder in adults" and "Psychotherapy for panic disorder with or without agoraphobia in adults" and "Generalized anxiety disorder in adults: Management" and "Pharmacotherapy for social anxiety disorder in adults" and "Psychotherapy for social anxiety disorder in adults" and "Pharmacotherapy for specific phobia in adults" and "Cognitive-behavioral therapies for specific phobia in adults" and "Management of posttraumatic stress disorder in adults".)
•For schizophrenia patients with co-occurring panic disorder, social anxiety disorder, or PTSD who have not responded adequately to treatment with medication, we suggest a trial of adjunctive cognitive-behavioral therapy (Grade 2C). (See "Psychotherapy for panic disorder with or without agoraphobia in adults" and "Psychotherapy and psychosocial interventions for posttraumatic stress disorder in adults" and "Psychotherapy for social anxiety disorder in adults".)
