2013 issue 2


Volume 29, issue 2

Review article

The pharmacological treatment of anxiety disorders co-occurring with bipolar disorder

Wiesław Jerzy Cubała1
1. Klinika Chorób Psychicznych i Zaburzeń Nerwicowych Katedry Chorób Psychicznych, Gdański Uniwersytet Medyczny
Farmakoterapia w Psychiatrii i Neurologii, 2013, 2, 89–96
Keywords: bipolar disorder, anxiety disorders, pharmacotherapy, co-occurrence


Bipolar disorder (BD) is characterised by the high complexity of its symptomatology and frequent co-occurrence of psychiatric disorders. Anxiety disorders are among the most commonly co-occurring psychiatric conditions, and have a negative impact on the course of the disease and its prognosis. The treatment of anxiety disorders comorbid to BD employs a wide array of non-pharmacological interventions, including psychoeducation and cognitive-behavioural psychotherapy. The choice of an adequate pharmacological approach is crucial in the planning and management of the treatment, as specific concerns regarding its efficacy and safety arise in this subpopulation of patients. The first line of pharmacological intervention should be focused on the assessment of the adequacy of mood stabilizing treatment. Pseudoresistance to pharmacological agents and their dosing needs to be excluded at the outset. In patients with BD and any other comorbid anxiety disorder, there is evidence of the effective use of valproate, quetiapine, olanzapine, and lamotrigine. There is also mounting evidence for specific lithium resistance in BD patients, with regard to its mood stabilizing properties and the lack of therapeutic impact as such on the accompanying anxiety disorders. The use of antidepressants, particularly selective serotonin reuptake inhibitors, may pose the risk of an induction into a more severe course of bipolar disorder, and has shown poor therapeutic efficacy. Therefore in patients with comorbid bipolar and anxiety disorders, the initial goals of treatment should aim, above all, at mood stabilization and the selection of thymoleptic agents, which are efficient in the treatment of the co-occurring anxiety disorder.


Comorbidity of anxiety disorders with bipolar disorder

Bipolar disorder (BD) is characterized by a great diversity of its clinical features. A variety of clinical manifestations of mood disorder within the bipolar spectrum is further complicated by its frequent co-occurrence with other psychiatric disorders, among which anxiety disorders occupy a prominent place (Grabski 2012; El-Mallakh and Hollifield, 2008; Merikangas et al., 2007).
Epidemiological studies indicate that in a group of outpatients with bipolar disorder, comorbidity of anxiety disorders reaches 74.9% (a study by the U.S. National Comorbidity Survey - Replication) (Merikangas et al., 2007). Research in the Polish population estimates comorbidity of anxiety disorders with BD at the level of 63% (Grabski 2012).
The presence of anxiety disorders in BD implies specific clinical problems relating to possible responses to treatment and long-term prognosis. This group of patients is particularly inflicted by (Grabski 2012; Merikangas et al., 2007; Provencher et al., 2011; Kauer-Sant'Anna et al., 2009):

  • Higher risk of suicidal behaviour
  • Worse response to pharmacotherapy
  • More frequent rapid-cycling course of illness
  • Higher occurrence of depressive and mixed episodes
  • More severe depressive episodes
  • Longer period needed to achieve remission in the treatment of acute depression
  • Shorter euthymic periods
  • Increased general morbidity
  • Lower quality of life
  • Worse social functioning
  • Increased risk of harmful use or dependence on psychoactive substances
  • Earlier onset of illness

Despite frequent comorbidity of anxiety disorders with bipolar disorder there are few research results available regarding therapeutic strategies in these kinds of cases, and most of the literature on the subject is in the form of expert studies.

Treatment strategies for anxiety disorders comorbid with bipolar disorder

Anxiety disorders comorbid with BD are characterised by broad diversity. In order to specify the best treatment it is necessary to produce diagnosis which will not only take into the account a specific character of the anxiety disorder but also evaluate its severity and degree of dysfunction it causes (Kauer-Sant'Anna et al., 2009; Landowski and Cubała 2012).
It is particularly important to pay specific attention to anxiety disorders of low severity, as any modification of pharmacotherapy due to anxiety disorder may have a negative impact on the overall treatment of bipolar disorder. In fact, short and low intensity anxiety disorders at the presence of psychosocial stressors often remit spontaneously. The procedure of choice should, in such cases, be psychological support and psychoeducation, whereas more comprehensive approach to treatment is required in case of an anxiety disorder with dysfunctional severity (long, with intense safety behaviour) (Provencher et al., 2011; Landowski and Cubała 2012).
Proper diagnosis is certainly very important for the successful treatment of anxiety disorders comorbid with bipolar disorder. Treatment should take into account preferences of the patient, severity of dysfunction, as well as intensity and chronicity of anxiety disorder, the presence of other mental or somatic disorders with their accompanying treatment, and the availability of specific treatment methods.
Monitoring of the efficacy of treatment of patients suffering from anxiety disorders, with the use of psychometric tools specific to a given disorder (e.g. Hamilton Anxiety Scale – HAM-A for the assessment of generalized anxiety disorder) is also essential, as it helps choosing treatment based on the therapeutic response, and introducing modifications in case of the lack of response. It is also an indicator for the treatment of residual symptoms. It is important to remember that specific anxiety disorders include cognitive, emotional, physiological and behavioural dimensions of anxiety, and that treatment should be aimed at achieving full and permanent remission of anxiety symptoms and at psychosocial rehabilitation. Effects of therapy should be systematically assessed at every stage of treatment, independently of the type of procedure used. With this goal in mind, therapeutic cooperation should be undertaken in terms of psychoeducation regarding bipolar disorder (Provencher et al., 2011; Kauer-Sant'Anna et al., 2009; Landowski and Cubała 2012; Schaffer et al., 2012).
There are four main therapeutic methods applied in the treatment of anxiety disorders comorbid with bipolar disorder, i.e.
1. Self-help (including bibliotherapy)
2. Psychoeducation
3. Psychotherapy
4. Pharmacotherapy

Non-pharmacological approaches to the treatment of anxiety disorders comorbid with bipolar disorder

Self-help may prove to be an essential complementary provision in the treatment of anxiety disorders comorbid with BD. This should be primarily rooted in bibliotherapy whose choice and effectiveness should be monitored by a professional (Landowski and Cubała 2012).
Psychoeducation features permanently in the treatment of anxiety disorders and BD, with its role being more prominent in case of their co-occurrence. It is based on teaching the patient about the illness and the overall mental health hygiene. Psychoeducation often significantly reduces anxiety disorders and have positive impact on long-term prognosis in BD (Provencher et al., 2011; Grabski and Mączka 2012).
Psychotherapy is a key ingredient in the treatment of anxiety disorders; when they co-occur with BD it is treated as the first-line treatment for its efficacy and safety of use (El-Mallakh and Hollifield 2008; Provencher et al. 2011). Psychotherapy is also essential in the treatment of drug-resistant residual symptoms, which usually surrender to effective psychotherapeutic interventions (Landowski and Cubała 2012). The effectiveness of cognitive-behavioural therapy (CBT) in the treatment of anxiety disorders comorbid with BD has been particularly broadly discussed. Research in the group of patients who have undergone CBT indicates high efficacy of psychotherapeutic interventions in relation to comorbid anxiety disorders, also in relation to pharmacotherapy. Psychotherapeutic interventions not only reduce symptoms more rapidly, but are also understood to facilitate the effective long-term remission (El-Mallakh and Hollifield 2008; Provencher et al., 2011). It is important to take into account the specificity of comorbid bipolar disorder during cognitive-behavioural psychotherapy, because it requires modification of the protocol in terms of mood disorders, with particular emphasis on psychoeducation supporting the mood stabilizing therapy (Provencher et al., 2011).

Pharmacotherapy of anxiety disorders in bipolar disorder

Autonomous pharmacological treatment of anxiety disorders in bipolar disorder

Pharmacological treatment of anxiety disorders requires special attention in case of BD patients. In spite of high comorbidity of these two disorders there is little data available on the efficacy and safety of pharmacological treatment, which makes it hard to choose the right procedure. Some of the few studies available point us to the direction of high comorbidity of more than one anxiety disorder. Studies on the effectiveness of pharmacotherapy of anxiety disorders in BD, often refer to the anxiolytic effect in its symptomatic rather than syndromic dimension (Kauer-Sant'Anna et al., 2009), which is their major drawback. An initial assessment of mood stabilizing treatment is necessary when choosing the right medication, followed by considering its possible modification (Kauer-Sant'Anna et al., 2009). Therapeutic decisions in relation to this group of patients are also motivated by its specific character in terms of efficacy and safety of pharmacotherapy. Clinical research demonstrates that resistance to mood stabilizing effects of lithium is frequent, as is an inefficiency in the treatment of anxiety symptoms. (Kauer-Sant'Anna et al., 2009; Young et al., 1993).
The use of antidepressants of the selective serotonin reuptake inhibitor (SSRI) type, which is a treatment of choice in the absence of comorbid bipolar disorder is unjustified in case of comorbidity, as it can adversely affect the course of BD and is of no therapeutic value. (Kauer-Sant'Anna et al., 2009).

General guidelines for choosing pharmacotherapy of anxiety disorders occurring in bipolar disorder

When choosing pharmacotherapy of anxiety disorders present in bipolar disorder, it is above all necessary to focus on the mood stabilizing treatment. A review of such therapy should involve an assessment of the choice of medication, its doses, evaluation of the therapeutic concentration in the peripheral blood plasma for some mood stabilizers, discussion of therapeutic cooperation in order to achieve euthymia and detecting a possible pseudo-drug resistance. In case of anxiety disorders of subliminal severity it should be particularly noted that anxiety may be an element of the affective episode, one of its symptoms, and anxiety symptoms will withdraw with the remission of BD. Due to the complexity of the clinical features and therapeutic difficulties, in this group of patients treatment is usually based on polytherapy, which should always involve medication with proven therapeutic efficacy and established safety profile for bipolar disorder (Kauer-Sant'Anna et al., 2009).
In monotherapy, valproate, a classic mood stabilizer, is the treatment of choice in anxiety disorders comorbid with BD (Calabrese and Delucchi 1990; Davis et al., 2005). In spite of the lack of data regarding systematic clinical research into the efficacy of valproate in the therapy of anxiety occurring in BD, there are many reports on its therapeutic efficacy in the treatment of anxiety disorders. Valproate is regularly included in international therapeutic guidelines as a justified choice in the treatment of comorbidity discussed in this paper (Kauer-Sant'Anna et al. 2009). A randomized double-blind, placebo-controlled trial demonstrated the effectiveness of valproate in the reduction of anxiety symptoms in bipolar depression (Davis et al. 2005).
A number of studies have also confirmed the therapeutic efficacy and safety of selected atypical antipsychotics in the treatment of anxiety disorders co-occurring with BD. Monotherapy with quetiapine, and olanzapine adjunct to lithium or fluoxetine have also shown therapeutic effect (Kauer-Sant'Anna et al., 2009). Atypical antipsychotics are also effective in the long-term prophylactic of bipolar disorder. Therapeutic effect of quetiapine used in monotherapy in the treatment of anxiety disorder with panic attacks and generalised anxiety disorder was demonstrated in a randomized double-blind, placebo controlled study. The sustained release quetiapine, at an average dose of 186.4 ± 100.3 mg/day, resulted in a significant reduction of anxiety disorder symptoms after 8 weeks of treatment. The study also indicated the therapeutic advantage of quetiapine over valproate and over the placebo in reducing the severity of anxiety symptoms (Sheehan et al., 2013). The results of exploratory studies using the BOLDER I and BOLDER II psychometric scales demonstrated the anxiolytic effect of quetiapine (in relation to anxiety symptoms occurring in the course of bipolar depression). These studies, however, did not assess the comorbidity with anxiety disorders, and the assessed severity of anxiety was related to the assessment of the depth of the dimensions of bipolar depression. It is significant that a similar anxiolytic effect was observed for the dose of 300mg/day and 600mg/day (Lydiard et al., 2009; Hirschfeld et al., 2006). Analogous effects in the treatment of bipolar depression show the effectiveness of olanzapine (5-20mg/day and) and olanzapine adjunct with fluoxetine (6-12mg/day and 25-50mg/day respectively) in the reduction of anxiety symptoms within the 8 weeks of treatment (Tohen et al. 2007). An interventional study involving a double-blind, randomized, placebo-controlled trials, in which the primary measure of assessment was the reduction of anxiety symptoms in the course of generalized anxiety disorder or anxiety disorder with panic attacks, showed no therapeutic efficacy of risperidone in a dose of 0.5-4 mg/day in monotherapy after 8 weeks of treatment (Sheehan et al. 2009; Seo et al. 2013).
The use of lamotrigine in the treatment of anxiety disorders comorbid with bipolar disorder appears to be justified in combination with another mood stabilizer. Lamotrigine was
effective in general reduction of anxiety symptoms and in the reduction of specific disorders relating to posttraumatic stress disorder (PTSD) comorbid with BD (Kauer-Sant'Anna et al., 2009; Maina et al., 2008, Singh and Zarate 2006). It seems, however, that the therapeutic efficacy of lamotrigine is linked with a specific phenotype of BD, characterized by the comorbidity of anxiety disorder with panic attacks and harmful use of psychoactive substances, and also in rapid-cycling BD. Studies comparing the therapeutic efficacy of lamotrigine and lithium demonstrated the advantage of the former in the subpopulation of patients with the prevalence of major depression, schizoaffective disorder and a confirmed anxiety disorder with panic attacks in the family history (Passmore et al. 2003).
Therapeutic guidelines and few clinical reports mention the effectiveness of gabapentin combined with another mood stabilizer (Schaffer et al. 2012; Perugia et al., 2002), although mostly in the treatment of anxiety disorder with panic attacks.
As lithium is potentially less therapeutically effective as mood stabilizer and anxiolytic in the treatment of bipolar patients, it seems unjustified to use it in monotherapy (Kauer-Sant'Anna et al. 2009). Lithium is still treated as the mood stabilizer of choice in pharmacotherapy of BD. It is possible that the therapeutic efficacy of lithium is linked with a specific phenotype of BD. Lower therapeutic efficacy of lithium has been observed in case of high intensity of specific features of the affective temperament, such as anxiety and depression, which corresponds with clinical observations of patients with bipolar depression comorbid with anxiety disorder (Rybakowski et al. 2013). Patients suffering from active anxiety disorder in euthymia, who received lithium, and were additionally prescribed olanzapine or lamotrigine, benefited from an effective reduction of anxiety symptoms. The therapeutic effect of olanzapine and lamotrigine was also balanced after 12 weeks' therapy, whereas the improvement was faster in the group of patients who received olanzapine. Lithium was used in therapeutic concentration whereas the dozes of olanzapine and lamotrigine were 7.7 ± 4.2 mg/day and 96.7 ± 467 mg/day respectively. However these were the results of a pilot study; a randomized single-blind experiment conducted on a sample of 47 patients without placebo control, so they cannot be treated as conclusive (Maina et al. 2008).
Reports on the effectiveness of benzodiazepines in the treatment of high severity anxiety disorders comorbid with bipolar disorder demonstrate the usefulness of this class of drugs. Yet we must remember that apart from the classic regulations associated with the use of benzodiazepines, there have been also reports of mania induced by these drugs, particularly by alprazolam. The benzodiazepines of choice are: clonazepam and lorazepam (Kauer-Sant'Anna et al., 2009, Schaffer et al., 2012, Reddy et al., 1996; Goodman and Charney 1987).
There are also various reports available on the effectiveness of carbamazepine, topiramate, and oxcarbazepine in reducing symptoms of selected anxiety disorders (Kauer-Sant'Anna et al., 2009, Schaffer et al., 2012; Perugia and Akiskal, 2002). However, due to the nature of these reports (case studies) the drugs cannot be recommended as the treatment of choice in the therapy of anxiety disorders comorbid with bipolar disorder.

The use of antidepressants in the pharmacotherapy of anxiety disorders comorbid with bipolar disorder

Selective serotonin reuptake inhibitors and clomipramine are the drugs of choice in pharmacotherapy of anxiety disorder. When used in cases of comorbidity with BD they are associated with the risk of relapse as a consequence of induced hypomania, mania or mixed episodes and temporary change into rapid-cycling BD. There is also an increased risk of impulsive, especially suicidal, behaviours. Mood stabilizers seem to partially prevent these adverse effects, however the problem lies in a long-term use of antidepressants required in the treatment of anxiety disorders, which extends the period of exposure to higher risk linked with this type of treatment (Kauer-Sant'Anna et al., 2009; Schaffer et al., 2012; Himmelhoch 1998).
If the treatment with the drug of the serotonin reuptake inhibitor type is required, paroxetine seems to be an optimal choice (Schaffer et al. 2012; Young et al. 2000; McElroy et al. 2010), as it seems to effectively reduce anxiety symptoms in the course of bipolar depression (McElroy et al. 2010), and is also more generally effective in the therapy of anxiety disorders (Nemeroff et al. 2001; Sachs et al. 2007). However, its use in BD is linked with a clinically confirmed increased risk of adverse effects (McElroy et al. 2010; Young et al. 2010).
Before a decision on the use of antidepressants in bipolar disorder is made, it is therefore advisable to reassess the use of mood stabilizers and only then consider an optional treatment with alternative therapeutic strategies.

Guidelines regarding the choice of pharmacotherapy in selected anxiety disorders occurring in bipolar disorder

Patients suffering from anxiety disorder with panic attacks comorbid with BD comprise 20.1% of all patients with comorbidity of anxiety disorders (Merikangas et al., 2007). In this group the treatment of choice is cognitive-behavioural psychotherapy (Provencher et al., 2011). In case of pharmacotherapy, the first step is monotherapy with valproate, following which, treatment with quetiapine should be considered in the dose of 50–300 mg/day in monotherapy or in adjunctive treatment with valproate (Sheehan et al., 2013) or lamotrigine (Passmore et al., 2003).
Patients who suffer from generalized anxiety disorder comorbid with BD comprise 29.61% of all patients with comorbidity of anxiety disorders (Merikangas et al. 2007). Also in this group, cognitive-behavioural psychotherapy is the preferred method of treatment. Pharmacological approach recommends monotherapy with quetiapine as the first step, in the dose of 50–300 mg/day (Sheehan et al. 2013).
Patients with obsessive-compulsive disorder (OCD) comorbid with BD are exceptionally demanding, and they comprise 13.6% of all patients with comorbidity of anxiety disorders (Merikangas et al. 2007). This group is characterized by less favourable prognosis as compared to other types of comorbidity discussed here, associated with a higher risk of harmful use or dependence on psychoactive substances and a higher risk of suicide. None of the mood stabilizing drugs have proven to be effective in the treatment of obsessive-compulsive disorder. The drug of choice suggested in therapeutic guidelines is valproate. Naturalistic studies and case reports indicate that pharmacological treatment of these patients is based on a combination therapy using a mood stabilizer and an SSRI in the therapeutic dose for obsessive-compulsive disorder. Such treatment requires constant monitoring, as there is a significantly increased risk of the change of the BD phase, with SSRI-induced mania. The risk seems to be lower in case of BD/OCD comorbidity than in other BD comorbidities or in their absence (Schaffer et al. 2012; Perugi et al. 2002).
There is no systematic data on the specific strategies of pharmacological treatment of BD comorbid with social phobia, simple phobia or PTSD. In these cases the choice of pharmacotherapy needs to be highly individualized (Provencher et al. 2011; Kauer-Sant'Anna et al., 2009; Landowski and Cubała 2012; Schaffer et al., 2012).


Comorbidity of anxiety disorder with BD is high, and it presents a significant clinical problem. With a scarcity of systematic studies indicating the preferred methods of pharmacological treatment, in cases of comorbidity of specific anxiety disorders, most data originates in the exploration information available on the reduction of anxiety in bipolar depression or in case studies. When planning and maintaining pharmacotherapy of anxiety disorder comorbid with BD it is important to remember that mood stabilization is of primary importance and therapeutic relevance. Therefore the aim is the pharmacological treatment based on the drugs of proven mood stabilizing record. Table 1 presents a summary of the elements of key recommendations for the treatment of this group of patients.


Table 1. Pharmacotherapy of anxiety disorder comorbid with bipolar disorder – primary recommendations

• Before starting the therapy - review the diagnosis of specific anxiety disorder and evaluate possible comorbidity and severity of dysfunctions
• Before starting pharmacological treatment – consider the possibility of using psychotherapy, especially cognitive-behavioural psychotherapy
• Treat mood stabilization as an absolute priority
• Use psychoeducation which plays a key role in the treatment of anxiety disorder comorbid with bipolar disorder
• Use psychoeducation as a key element of the treatment of mild and short anxiety disorder co-occurring with bipolar affective illness
• Use medication recommended in the treatment of anxiety disorder comorbid with BD, i.e.: valproate, quetiapine, olanzapine and lamotrigine.
• Monitor your patient's response to treatment.
• Reduce the use antidepressants and benzodiazepines to absolute minimum


Conflict of interest
In the past three years, Wiesław Jerzy Cubała has been employed as a consultant and a lecturer. He has received a research grants and signed commercial contracts with the following institutions: Adamed, Angelini, AstraZeneca, BMS, Cephalon, GedeonRichter, GSK, GWPharmaceuticals, Lekam, Lundbeck, Novartis, Otsuka, Sanofi and Servier.



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