Treating Comorbid Anxiety Disorders in Patients With Schizophrenia: A New Pathway

The presence of anxiety disorders in persons with psychotic disorders is gaining increased attention. The evolution of the diagnostic criteria in the different editions of DSM has contributed to an increased awareness of these comorbidities. For instance, in DSM-III an anxiety diagnosis could be given only if anxiety was clearly “not due to” another Axis I disorder, while in DSM-III-R and DSM-IV, diagnosis was allowed if anxiety was “unrelated to” or “not better accounted for by” the main diagnosis, respectively. While such criteria allow a comorbid anxiety disorder diagnosis in persons with schizophrenia, overlaps between the symptoms of anxiety disorders and those of psychosis may complicate the application of these hierarchical rules.

While the diagnostic criteria have not changed significantly from DSM-IV to DSM-5, the latest revision of DSM provided an opportunity to discuss the potential benefits of a dimensional approach rather than a categorical approach to diagnosis. While the implementation of such a dimensional approach was judged premature given its potential impact on clinical practice, these discussions emphasized that patients can present with symptoms that cross the established diagnostic boundaries.

[[{"type":"media","view_mode":"media_crop","fid":"31087","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_3999622129050","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"3283","media_crop_rotate":"0","media_crop_scale_h":"265","media_crop_scale_w":"125","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image"}}]]Using a meta-analysis, we identified high rates of anxiety disorders in patients with schizophrenia-38.3% of patients presented with at least one anxiety disorder.¹ The mean prevalence for individual anxiety disorders ranged from 5.4% for agoraphobia to 14.9% for social anxiety disorder.

Another striking finding from this meta-analysis was the puzzling variations in rates reported between studies. For instance, rates for obsessive-compulsive disorder (OCD) varied from 0.6% to 55%. While some partial explanations for these variations were uncovered, they remained largely unexplained. Nonetheless, the meta-analysis allowed us to highlight several factors that could contribute to increased detection of anxiety disorders in schizophrenia. For example, social anxiety disorder, OCD, and panic disorder were more often identified in outpatients than in inpatients. This finding suggests that these disorders are easier to assess and to distinguish from symptoms of psychosis once acute symptoms have abated.

Comorbid anxiety disorders were typically more prevalent in studies that assessed diagnoses with the Structured Clinical Interview for DSM (SCID) and those that supplemented the SCID with additional scales that targeted the anxiety symptoms. The latter method of assessment had a significant effect, particularly for social anxiety disorder, OCD, and PTSD.

In a recent study, we used a comprehensive semistructured interview that included all SCID-IV questions as well as the questions from the Liebowitz Social Anxiety Scale and from the Yale-Brown Obsessive Compulsive Scale to identify anxiety symptoms in outpatients with recent-onset psychosis (M. A. Roy, MD, MSc, et al, unpublished data, 2014). The study comprised 80 outpatients with recent onset of a schizophrenia spectrum disorder, 53% of whom also had a current anxiety disorder; the lifetime prevalence was 60%.

In 48% of patients, DSM-IV criteria for a social anxiety disorder were met; however, 41% of these patients had not spontaneously reported social anxiety symptoms when asked using the SCID gate questions about social anxiety (unpublished results). These cases were only detected when questions from the Liebowitz Social Anxiety Scale were added. This supports the idea that asking more specific questions can uncover some unsuspected anxiety symptoms. Anxiety comorbidity may be overlooked when basic clinical methods are used, but identification of anxiety symptoms and anxiety comorbidity may be facilitated by using targeted questions, such as those of anxiety scales, and may also be facilitated in stabilized patients.

It is increasingly recognized that positive outcome for patients with schizophrenia should not be limited to controlling the positive and negative symptoms of the disorder, but should aim to help patients achieve good functioning and quality of life. Identifying comorbid anxiety disorders as potential treatment targets may contribute to more positive outcomes. For instance, an increase in the rate of suicide attempts and poorer functioning have been reported for schizophrenia patients who present with comorbid anxiety disorders.²

Pharmacotherapy >

Pharmacotherapy

In schizophrenic patients with comorbid anxiety, antipsychotics are typically supplemented with medications that target anxiety; alternatively, in some patients, a switch is made to another antipsychotic. Data that support the efficacy of these treatments are limited and consist mainly of small open-label trials and case reports. We are aware of only one randomized controlled study by Reznik and Sirota,³ which included 30 inpatients with schizophrenia who exhibited symptoms of OCD. The patients received fluvoxamine in addition to their current antipsychotic. They had a significant decrease in symptoms, without any significant psychotic relapse. Similar findings for fluvoxamine were also seen in 2 case reports.^4,5 Nowadays, in clozapine-treated patients, other SSRIs would be favored, given the strong interaction between clozapine and fluvoxamine caused by cytochrome P-450 inhibition, which may lead to toxic blood levels of clozapine.

Clomipramine as a supplement to antipsychotic medication has been successful in reducing symptoms of OCD, but it has been associated with an exacerbation of psychosis in some patients.⁶ Other add-on medications that improve symptoms of OCD in schizophrenia include lamotrigine; milnacipran; and SSRIs other than fluvoxamine, such as escitalopram, sertraline, and fluoxetine.

Although most studies have focused on comorbid symptoms of OCD, in patients who exhibit social anxiety symptoms, switching the current antipsychotic to aripiprazole improved symptoms of social anxiety and psychosis and also improved functioning.⁷ Adding alprazolam or imipramine to an antipsychotic or switching the current antipsychotic to quetiapine has been shown to reduce panic symptoms in patients who present with schizophrenia and comorbid panic disorder.⁸

CASE VIGNETTE

Christian is a 21-year-old who is seen a few months after experiencing a first psychotic break. He has responded well to monotherapy with 15 mg/d of olanzapine, but he is convinced that some of his thoughts have been put into his head by an unknown outside force. His psychiatrist asks him about the origins of this preoccupation. Christian describes a silly, repetitive sentence that kept popping into his mind-a sort of mantra-that happened before his psychotic break: he was aware that it originated with him and tried to resist it. During the psychotic episode, he developed a delusional belief about the origin of this mantra.

On further questioning, he described signs of an undiagnosed Tourette disorder during his adolescence, a condi-tion closely related to OCD. After an explanation that this repetitive thought could be an obsession, he agreed to citalopram supplementation, titrated to 30 mg/d. Shortly thereafter, the repeti-tive thought and its delusional explanation disappeared.

Anxiety symptoms as a consequence of antipsychotics >

Anxiety symptoms as a consequence of antipsychotics

Pharmacotherapy for anxiety symptoms in patients with schizophrenia presents unique challenges: antipsychotic treatment may play a role in the exacerbation of anxiety symptoms in these patients. Such an association has been reported with antiserotonergic antipsychotics, primarily clozapine.⁹

An observational study of 543 patients reported a higher prevalence of OCD in patients treated with clozapine (38.9%) than in those treated with olanzapine (20.1%) or risperidone (23.2%), or than in those not taking antipsychotics (19.6%).¹⁰ The study similarly showed that symptoms of OCD were even more prevalent when clozapine was taken for 6 months or longer. OCD may also be particularly prevalent in patients with schizophrenia who receive higher doses of clozapine, or in those who present with symptoms after the initial administration of the drug.^9,11

While some symptoms of OCD have been identified as related to the introduction of an antipsychotic medication, it is unlikely that drug effects fully account for the higher rates of OCD or other anxiety disorders in patients with schizophrenia for the following reasons:

• An increased prevalence of anxiety disorders, particularly OCD, predates the neuroleptic era

• Symptoms of OCD can be present before the onset of psychosis

• Anxiety disorders are frequent in clinical high-risk samples and can predict psychosis, which suggests that the anxiety was present before the introduction of medication

Since patients treated with clozapine differ from those treated with other drugs on a broad array of indicators of severity, it is premature to conclude that clozapine is a genuine causative factor for OCD. Given the well-proven efficacy of clozapine in decreasing psychotic symptom severity in treatment-resistant patients, combining treatment with aripiprazole or sertraline may be warranted to control anxiety symptoms.^12,13

Nonpharmacological approaches >

Nonpharmacological approaches

Cognitive-behavioral therapy (CBT) can be effective in reducing anxiety symptoms in patients with schizophrenia. An open-label trial and a case study, which focused on psychological treatments for OCD in patients with schizophrenia, reported improvement following CBT.^14,15 The efficacy of group CBT for social anxiety in patients with schizophrenia is supported by 2 randomized controlled studies.^16,17 In these studies, the researchers randomly assigned schizophrenia patients with social anxiety disorder either to group CBT or to a waitlist. They documented significantly greater improvements of social anxiety for the CBT group.

One randomized controlled study reported improvement of PTSD symptoms following CBT in a large group of patients with major mental disorders and PTSD (N = 108).¹⁸ Four open-label trials also support the efficacy of CBT for improving PTSD symptoms in patients with schizophrenia.^19-22 Finally, promising results were reported for improvement of panic disorder in patients with schizophrenia using CBT.^23,24

A variety of other nonpharmacological approaches have also been proposed for the management of anxiety in patients with schizophrenia (eg, yoga, meditation, relaxation), but they have not specifically targeted comorbid anxiety disorders. Thus, the extent to which these results may apply to anxiety stemming from psychosis or comorbid anxiety disorders is unknown. These approaches may require some adaptations for their use in patients with psychotic syndromes.

Our clinical experience, illustrated in the following case vignette, suggests that simple psychoeducation, particularly if given shortly after the onset of symptoms, may prevent full-blown OCD.

CASE VIGNETTE

Felix is an 18-year-old with psychotic symptoms that warranted a diagnosis of schizophrenia, because the symptoms persisted during an inpatient stay of several weeks despite recreational drug abstinence (verified with regular urine checks). Because of an insufficient response to 2 antipsychotics, clozapine was introduced. His symptoms and his functioning both improved. However, Felix asks for a dosage increase because his “crazy ideas are coming back.” He describes having homosexual urges whenever he meets one of his close friends and fears that his friend may become aware of these ideas.

He is advised not to try to resist the thoughts; rather, he should accept that they are there. Eventually he agrees that if he does not appear worried, nobody will have a clue about these thoughts. During the following 3 months, he reports some recurrences of the thoughts, but they rapidly vanish when he ignores them.

Conclusion

Given the limited empirical evidence from randomized trials, it is difficult to make strong recommendations about either pharmacological treatment or psychological treatment for comorbid anxiety disorders in patients with schizophrenia. However, given the impact of these comorbid conditions on health outcomes, addressing them can certainly be beneficial for patients.

The accumulating evidence warrants an individualized approach-adding an SSRI or another drug while carefully monitoring the results. CBT also seems to provide interesting advantages to control anxiety symptoms, with strong evidence for social anxiety and emerging evidence for other disorders. although there are basic guidelines for treatment strategies, taking into account the patient’s specific needs is fundamental in treating these comorbidities.