Anxiety in Patients with Schizophrenia: Epidemiology and Management (2015)

I’m still using pregabalin augmentation of aripiprazole (combined with 375mg/day venlafaxine) for anxiety and it’s a decent approach but there’s room for improvement. Since I struggle with a dual diagnosis, it’s also been really effective at tackling alcohol cravings [1, 2].

Here’s a recent article that looks interesting.

Anxiety symptoms can occur in up to 65 % of patients with schizophrenia, and may reach the threshold for diagnosis of various comorbid anxiety disorders, including obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). We review the clinical presentation, diagnosis, neurobiology, and management of anxiety in patients with schizophrenia, with a particular focus on pharmacotherapy. The prevalence of any anxiety disorder (at syndrome level) in schizophrenia is estimated to be up to 38 %, with social anxiety disorder (SAD) being the most prevalent. Severity of positive symptoms may correlate with severity of anxiety symptoms, but anxiety can occur independently of psychotic symptoms. While anxiety may be associated with greater levels of insight, it is also associated with increased depression, suicidality, medical service utilization, and cognitive impairment. Patients with anxiety symptoms are more likely to have other internalizing symptoms as opposed to externalizing symptoms. Diagnosis of anxiety in schizophrenia may be challenging, with positive symptoms obscuring anxiety, lower levels of emotional expressivity and communication impeding diagnosis, and conflation with akathisia. Higher diagnostic yield may be achieved by assessment following the resolution of the acute phase of psychosis as well as by the use of screening questions and disorder-specific self-report instruments. In schizophrenia patients with anxiety, there is evidence of underactive fear circuitry during anxiety-provoking stimuli but increased autonomic responsivity and increased responsiveness to neutral stimuli. Recent findings implicate the serotonin transporter (SERT) genes, brain-derived neurotropic factor (BDNF) genes, and the serotonin 1a (5HT1a) receptor, but are preliminary and in need of replication. There are few randomized controlled trials (RCTs) of psychotherapy for anxiety symptoms or disorders in schizophrenia. For pharmacotherapy, data from a few randomized and open trials have shown that aripiprazole and risperidone may be efficacious for obsessive-compulsive and social anxiety symptoms, and quetiapine and olanzapine for generalized anxiety. Older agents such as trifluoperazine may also reduce comorbid anxiety symptoms. Alternative options include selective serotonin re-uptake inhibitor (SSRI) augmentation of antipsychotics, although evidence is based on a few randomized trials, small open trials, and case series, and caution is needed with regards to cytochrome P450 interactions and QTc interval prolongation. Buspirone and pregabalin augmentation may also be considered. Diagnosis and treatment of anxiety symptoms and disorders in schizophrenia is an important and often neglected aspect of the management of schizophrenia.

“In people with an established diagnosis of schizophrenia and acute anxiety symptoms or anxiety disorders, or in patients experiencing a first episode of psychosis, one strategy is to consider adjunctive/add-on treatment with an SSRI. Whereas most evidence for the use of SSRIs in schizophrenia is extrapolated from studies in patients with anxiety without schizophrenia, some evidence for the efficacy of SSRIs in people with SZ-CA is available from a few randomized trials (clomipramine for comorbid OCS, fluvoxamine for comorbid OCS, and sertraline for anxiety), small open trials and case series for fluoxetine in SAD and OCS, escitalopram in OCD, and fluvoxamine in OCS. For cases of severe and distressing delusions or hallucinations, most clinicians will wait for at least 2–4 weeks for a reduction to occur in the severity of positive psychotic symptoms and, if anxiety symptoms continue despite a reduction in psychotic symptoms, consider the addition of an SSRI. This is due to the low risk of psychotic symptoms worsening with SSRI treatment due to overactivation. In fact, a systematic review and a meta-analysis of trials investigating the use of antidepressant augmentation of antipsychotics for negative symptoms has shown the risk for adverse effects and worsening of symptoms to be quite low, with improvements in global clinical response and negative symptoms in patients treated with antidepressant augmentation”

“Alternative or potential second-line treatments following failure with SSRI treatment may include treatment with the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine for patients with SAD and generalized anxiety. In cases where treatment with SSRIs is unsuccessful, initiation of certain tricyclic agents such as imipramine in PD and clomipramine in OCD may be considered as second-line treatments, bearing in mind the increased risk of QTc prolongation with tricyclics. Addon therapy with mirtazapine (noradrenergic and serotonergic specific antagonist [NaSSa]) to antipsychotics has demonstrated improvements in negative symptoms in schizophrenia and, although its efficacy is less well researched in anxiety disorders, it could be considered as an alternative for patients with comorbid PTSD, PD, and SAD. Mirtazapine augmentation is also associated with significantly fewer extrapyramidal side effects such as akathisia, but increased propensity to weight gain may be a trade-off.”

“In patients with GAD, an alternative strategy may include the initiation of glutamate-modulating alpha-2-delta (a2d) ligands such as pregabalin. In a recent case series, the addition of pregabalin in patients with schizophrenia treated with a variety of antipsychotics led to a significant reduction in HAM-A ratings for anxiety. At least one controlled trial of pregbalin is underway investigating anxiety as a primary outcome in patients with schizophrenia”

“Alternative options in case of GAD may also include haloperidol augmentation with buspirone, a 5HT1a receptor partial agonist . A meta-analysis of buspirone augmentation of various antipsychotics (amisulpride, clozapine, olanzapine, risperidone, quetiapine) in schizophrenia showed significantly greater improvement in overall psychopathology and positive, but not negative, symptoms of
psychosis compared with placebo augmentation”


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