Chapter 33 Bipolar disorder with psychotic symptoms
EPIDEMIOLOGY, AETIOLOGY AND CLASSIFICATION
Bipolar disorder (BD) is a heritable mental illness. Approximately 1% of US adults experience persisting mood swings and fulfill criteria for a DSM-IV diagnosis of BD.1 First-degree relatives of bipolar individuals are significantly more likely to develop the disorder than the population at large. Bipolar illness in one identical twin corresponds to a 70% risk that the other twin will also have the disorder and the concordance risk is estimated at 15% in non-identical twins.2 Recent findings from genetic studies suggest that decreased expression of RNA coding for mitochondrial proteins results in dysregulations of energy metabolism in the brain, and especially in the hippocampus.3 Dysregulations in hypothalamic circuits involved in maintaining normal circadian rhythms probably cause the affective and behavioural symptoms described in Western psychiatric nosology as bipolar disorder I and bipolar disorder II. It has been suggested that both phases of BD may be manifestations of chronic folate deficiency;4 however, the aetiology of BD is varied and complex. Acutely manic patients frequently have abnormal EEG activity which may predict responsiveness to conventional pharmacological treatments.5
According to conventional Western psychiatric nosology, mania is a complex symptom pattern that may encompass disparate affective, behavioural and cognitive symptoms, including pressured speech, racing thoughts, euphoric or irritable mood, agitation, inflated self-esteem, distractibility, excessive or inappropriate involvement in pleasurable activities, increased goal-directed activity, diminished need for sleep and, in severe cases, psychosis.6 According to the DSM-IV-TR,6 a manic episode is diagnosed when elevated or irritable mood persists for at least 1 week, is accompanied by at least three of the above symptoms, is associated with severe social or occupational impairment, and cannot be adequately explained by a pre-existing medical or psychiatric disorder or the effects of substance abuse. In contrast to frank mania, the diagnosis of a hypomanic episode requires sustained irritable or euphoric mood lasting at least 4 days but does not cause severe impairment in social or occupational functioning; three or more of the above symptoms; and exclusion of medical or psychiatric disorders that may manifest as these symptoms. According to the DSM-IV, bipolar I is diagnosed when an individual has experienced one or more manic episodes, while one or more hypomanic episodes are required for a diagnosis of bipolar II disorder. Bipolar I disorder can be diagnosed after only one manic episode; however, the typical bipolar I patient has had several manic episodes, and at least 80% of patients who experience mania will have recurring manic episodes.7 According to the DSM-IV, a history of depressive episodes is not required for a formal diagnosis of bipolar I disorder. In contrast, bipolar II disorder can be diagnosed only in cases when at least one hypomanic episode and at least one depressive episode have been documented. In both disorders moderate or severe depressive episodes typically alternate with manic symptoms; however, in ‘mixed mania’ symptoms of mania and depressed mood overlap. Another variant called rapid cycling is diagnosed when at least four complete cycles of depressed mood and mania occur during any 12-month period. A mild variant of bipolar disorder is called cyclothymic disorder. Cyclothymic disorder is diagnosed when several hypomanic and depressive episodes take place over a 2-year period in the absence of severe manic, mixed or depressive episodes. It is estimated that individuals diagnosed with bipolar I disorder are symptomatic approximately 50% of the time. Bipolar patients experience depressive symptoms three times more often than mania, and five times more often than rapid cycling or mixed episodes.8
Distinguishing between transient episodes of mania and acute agitation caused by a medical or psychiatric disorder can pose diagnostic challenges. A careful history is needed to establish a persisting pattern of mood changes fluctuating between depression and mania or hypomania. Conventional laboratory tests and functional brain imaging studies are used to rule out the presence of medical disorders that can mimic symptoms of depressed mood or mania including, for example, thyroid disease, strokes (especially in the right frontal area of the brain), multiple sclerosis, (rarely) seizure disorders, and other neurological disorders. Irritability or euphoria alternating with periods of depressed mood is also associated with chronic abuse of stimulants, marijuana or other drugs. It is often difficult to establish a primary diagnosis of bipolar disorder after ruling out pre-existing psychiatric or medical disorders because of the variety of symptoms that can take place during a manic episode. For example, symptoms of irritability, agitation and emotional lability are frequent concomitants of chronic drug or alcohol abuse, psychotic disorders and personality disorders. Ongoing debate over the construct validity of BD will probably result in new diagnostic criteria in the next edition of the DSM, which is scheduled for completion in 2012.9 For example, it has been suggested that the ‘rapid cycling’ variant of bipolar disorder may more accurately correspond to a severe personality disorder than BD or other mood disorders.
RISK FACTORS
Several risk factors contribute to the rate of relapse and response to treatment in patients diagnosed with BD. A diagnosis of BD is one of the largest risk factors for suicide.10 Fewer than half of patients who take conventional maintenance treatments following an initial manic episode report sustained control of their symptoms.11 Furthermore, as many as 40% of bipolar patients who adhere to pharmacological treatment experience recurring manic or depressive mood swings while taking medications at recommended doses.11 As many as one-quarter of bipolar I patients attempt suicide, and many eventually succeed. Treatment of bipolar disorder should be maintained on a consistent, long-term basis to reduce the rate of re-hospitalisation and increase chances of full remission.12 Failure to initiate effective treatment that is well tolerated in the early stages of illness significantly increases the risk of relapse with associated increased risk of suicide.13 In patients with diagnosed BD, stressors, seasonal change, reduced sleep and stimulants or recreational drug use may provoke an episode of hypomania or mania (although sometimes the trigger may not appear to have a cause).14 Regular exercise, good nutrition, a strong social support network and a predictable, low-stress environment help reduce relapse risk.15,16
CONVENTIONAL TREATMENT
Medication management
The American Psychiatric Association endorses the use of different conventional pharmacological agents, including mood stabilisers (e.g. lithium carbonate and valproate), antidepressants, antipsychotics and sedative-hypnotics, to treat BD.17 Antipsychotics are used to treat agitation and psychosis, which occur frequently in acute mania. Sedative hypnotics are prescribed for the severe insomnia that accompanies mania as well as for daytime management of agitation and anxiety.18 A significant percentage of bipolar patients must rely on conventional antidepressants to control depressive mood swings. Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment of both the acute manic phase and the depressive phase of bipolar disorder and does not risk mania induction; however, findings of controlled trials to date are highly inconsistent.19 Mania associated with psychosis is approached differently to a mixed episode that includes both manic and depressive symptoms. Conventional antipsychotics are appropriate first-line treatments of the auditory hallucinations that occur during an acute manic episode, while mixed episodes are often managed using a combination of two mood stabilisers or a mood stabiliser and antipsychotic.14
Psychotherapy and psychosocial interventions
Psychotherapy and psychosocial interventions in stable bipolar patients may potentially reduce relapse risk by providing psychological support, enhancing medication adherence, and helping patients address warning signs of recurring depressive or manic episodes before more serious symptoms emerge.20 A review of randomised studies on adjunctive psychotherapy and psychosocial interventions in bipolar patients concluded that adjunctive psychotherapy reduces symptom severity and improves functioning.20 Family therapy and interpersonal therapy were most effective in preventing relapse when started following an acute manic or depressive episode. Cognitive behavioural therapy and group psychoeducation were effective strategies for relapse prevention when initiated during stable periods. Psychotherapies and psychosocial interventions emphasising medication adherence and early recognition of mood symptoms were more effective in preventing recurrences of mania, and cognitive and interpersonal approaches had greater success in preventing depressive relapses. A specialised psychological intervention called ‘enhanced relapse prevention’ is aimed at recognising and managing the early warning signs of depressive or manic episodes by improving patients’ understanding of BD, enhancing therapist–patient relationships, and optimising ongoing treatment. A study using qualitative interviews found that both therapists and their bipolar patients believe that enhanced relapse prevention increases awareness of early warning signs of recurring illness, leading to effective changes in medication management and fewer relapses.21
INTEGRATIVE MEDICAL DIAGNOSIS AND TREATMENT OPTIONS
INTEGRATIVE MEDICAL TREATMENT AIMS
A significant percentage of individuals diagnosed with bipolar disorder use non-pharmacological modalities together with prescription medications; however, there is relatively little evidence for the safety and efficacy of most non-conventional treatments.22,23 The most appropriate and effective integrative treatment approach is determined by the type and severity of symptoms, the presence of comorbid medical or psychiatric disorders, response to previous treatments, patient preferences and constraints on cost and availability of treatments. When prominent symptoms of anxiety, psychosis or agitation are present, effective integrative strategies should prioritise treatment of those symptoms. For example, reasonable integrative approaches when managing an acutely manic patient who is agitated and extremely anxious include an initial loading dose of valproic acid or another conventional mood stabiliser, high potency benzodiazepines, an antipsychotic that is sedating (at bedtime), and possibly also amino acids known to have calming or sedating effects, such as L-tryptophan, 5-HTP or L-theanine.
While CAM interventions appear to have limited activity in treating the hypomanic or manic phase of BD, they may have benefit in treating BD depression as monotherapies or as adjuvant treatments with synthetic antidepressants.24
Nutritional medicines
Adding L-tryptophan 2–3 g/day or 5-HTP 25 to 100 mg up to three times a day may have beneficial effects on anxiety associated with mania.25,26 L-tryptophan 2 g can be safely added to mood stabilisers at bedtime and may improve sleep quality in agitated manic patients. Doses as high as 15 g may be required when insomnia is severe (although this should be closely monitored, and this dosage may be restricted in some countries).27 When added to sedating antidepressants (such as trazodone) taken at bedtime L-tryptophan 2 g may accelerate antidepressant response and improve sleep quality.28 Serious adverse effects have not been reported using this protocol. L-theanine reduces state anxiety by increasing alpha activity and increasing synthesis of GABA.29,30 Noticeable anxiety reduction is generally achieved within 30 to 40 minutes and effective doses range between 200 mg and 800 mg/day.
Countries where there is high fish consumption have relatively lower prevalence rates of BD.31 A systematic review of controlled trials on omega-3 fatty acids in BD that used rigorous inclusion criteria identified only one study in which omega-3s used adjunctively with a mood stabiliser showed a differential beneficial effect on depressive but not manic symptoms.32 The reviewers cautioned that any conclusions about the efficacy of omega-3 fatty acids in bipolar disorder must await larger controlled studies of improved methodological quality. Large doses of omega-3 fatty acids may be more effective in the depressive phase of the illness.33 Rare cases of increased bleeding times, but not increased risk of bleeding, have been reported in patients taking aspirin or anti-coagulants together with omega-3s. Some studies suggest that the omega-3 essential fatty acid EPA at doses between 1 and 4 g/day may have beneficial adjuvant effects when added to certain atypical antipsychotics;34,35 however, one placebo-controlled trial did not confirm an adjuvant effect.36 In contrast, the appropriate management of a severely depressed bipolar patient might include an integrative regimen that combines a mood stabiliser with an antidepressant and omega-3 fatty acids. Gradually titrating stable bipolar patients on a proprietary nutrient formula (see Table 33.1 for review of the evidence) while continuing them on their conventional mood stabiliser may result in improved outcomes, reductions in therapeutic doses in some cases, lower adverse effects rates and improved treatment adherence.
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