Diagnosis and treatment of mixed states

Abstracts

Estados mistos (EM) são descritos na literatura usando-se diferentes definições, o que resulta em diferentes descrições das características demográficas e clínicas do quadro, mas sempre como uma forma de transtorno bipolar de pior prognóstico e mais prevalente do que descrito no passado. O objetivo do artigo é apresentar estas diferentes definições e seu impacto no estudo dos estados mistos. O tratamento farmacológico será discutido.

Estados mistos; Transtorno bipolar; Mania mista; Mania depressiva; Mania disfórica

Diagnosis and treatment of mixed states

Angela Schwartzmann^I; Beny Lafer^II

^IInstitute of Psychiatry of the Clinical Hospital of Medical School of the University of São Paulo - HC-FMUSP. Assistance and Research Project on Bipolar Disorder - PROMAN

^IIDepartment of Psychiatryc of the Clinical Hospital of Medical School of the University of São Paulo - HC-FMUSP. Assistance and Research Project on Bipolar Disorder of the Clinical Hospital of Medical School of the University of São Paulo (PROMAN)

^{Correspondence}

ABSTRACT

Mixed States are described in the literature using based on different definitions resulting in different descriptions of the clinical and demographic characteristics, of these episodes, but although they are always asdeemed a severe form of Bipolar disorder with worse prognosis and more prevalent than previously described. The aim of this article is to present a review of these different definitions and their impact on the study of mixed states. Pharmacological treatment is also discussed.

Keywords: Mixed states; Bipolar disorder; Mixed mania; Depressive mania; Dysphoric mania

Introduction

Mania and depression are seen as clinical syndromes of opposite polarities. It is known, according to the observations described by Kraepelin,¹ that the association of manic or hypomanic symptoms with depressive ones is not infrequent, especially among patients who have BD conditions deemed severe. Besides, their treatment is more difficult due not only to the mixed symptomatology, but also to the instability of their presentation. Most currently studied mixed episodes are mixed manias, also called dysphoric manias, in which depressive symptoms are associated in higher or lesser degree with a manic or hypomanic condition. Besides them, the literature on mixed states (MS) describes mixed depressions, characterized by a predominantly depressive condition associated in a lesser degree with manic symptoms.

Concept

Kraepelin¹ defined MS as a combination of manic and depressive symptoms in three domains: mood, psychomotor activity and ideation. He considered that it occurred in more advanced stages of the disease. He described 6 types of mixed states, based on the several combinations of polarity of these 3 spheres or domains:

1. Excited depression

2. Depression with flight of ideas

3. Depressive-anxious mania

4. Inhibited mania

5. Mania with poverty of thoughts

6. Manic stupor

Campbell² describes the 'constant change and fluidity of emotions present in these episodes'. Himmelhoch et al3 describe better depressive, manic and psychotic symptoms.

Viena's⁴ research criteria define stable mixed states (simultaneous presence of manic and depressive symptoms) and instable mixed states (rapid oscillation of symptoms), the latter corresponding to the concept of rapid cycling studied by Dunner et al⁵ and Maj et al.⁶ All of them described a syndrome of rapid alternance of opposite affective states, depression, anxiety, hostility or rapid alternation from inhibition toward behavioral agitation, aggressiveness and always with sleep disturbances.

Goodwin and Jamison⁷ define MS as the simultaneous presence of any number of depressive and manic symptoms, highlighting their high prevalence.

The RDC, Research Diagnostic Criteria,⁸ used in many researches, defines MS as a period in which manic, hypomanic and depressive symptoms occur simultaneously, or when the subject cycles rapidly to a period of opposite polarity.

The DSM III R⁹ requires the simultaneous presence of full criteria for mania and depression (except for the two-week duration) or their alternance within days with prominent depressive symptoms for at least one day.

The ICD-10¹⁰ defines MS as the combination or rapid alternance of depressive, manic and hypomanic symptoms, with prominent symptoms for at least one week.

The definition of mixed states by the DSM IV¹¹ is shown in Table 1.

In the clinical practice it is difficult to find both full syndromes simultaneously, and due to this McElroy et al¹² define mixed or dysphoric mania based on Cincinatti's criteria as seen in Table 2.

Perugi et al¹³ define MS in a more comprehensive way, emphasizing that the symptoms of opposite polarity may occur simultaneously or alternating.

What can be seen in all these attempts to define mixed symptoms is that its concept becomes more or less comprehensive according to the duration of symptoms, inclusion or not of rapid cycling and the minimal number of depressive symptoms considered.

Mixed depressions have been less studied and are not specifically contemplated by the DSM-IV or the ICD-10. The concept derives from involutive melancholy (agitated) from the 19^th century and is coincident with Kraepelin's¹ concept of agitated depression. Koukopoulos et al¹⁴ and Benazzi et al,¹⁵ authors who have been dedicated to the study of these conditions, admit that the simultaneous presence of at least two symptoms of mania in a depressive episode suffices to define agitated or mixed depression.

Clinical or epidemiological characteristics

1. Mixed mania

Mixed mania is generally referred to in the literature as a state of severe mania, more frequently developed by women and adolescents, associated with suicide, irritability, psychotic symptoms, substance abuse, neuropsychiatric abnormalities with chronic course, poor evolution in the short- and long-term, poor response to lithium and better to anticonvulsant stabilizers and ECT and higher family predisposition to depression.^16,24 Some patients show higher frequency of this type of episode than others.

Prevalence: In the literature the prevalence of these episodes ranges from 5 to 70%²⁴ of manias. McElroy et al¹² found a mean prevalence of 31%. Therefore, it is frequent the association of depressive symptoms with mania during the disease's course.

Gender: Mixed mania is more frequently among women, especially when the criterion includes higher depression rates.^13,17-19

Family history: The mixed pattern of mania is associated with family history of depression, besides bipolar disorder (BD), suggesting a double inheritance in MS.¹⁹ These data are not consensual in the literature.^13,20-21

Age of manifestation: Kraepelin¹ noted that MS had late onset, what would represent a worsening of the condition. Dell'Osso et al²⁰ and Strakowski et al²² confirm this information. As to the disease's onset, it does not change when there is occurrence of MS or pure mania in the patients' history.^13,19,22 Mc Elroy et al²³ found higher incidence of mixed symptomatology among adolescents.

Symptomatology, course and prognosis: the higher severity of the disease among patients who have MS is proved not only by its symptomatology, but also by the higher presence of comorbidities and worse prognosis. As noted by Kraepelin, more recent studies show a worse prognosis and higher severity in the short- and long-term, considering the longer duration of episodes, although they occur in lower number along the disease.^{13,19-20,24-26} They also describe worse recovery from episodes, longer duration of the disease, higher presence of psychotic symptoms, higher number of hospitalizations, worse treatment outcomes, higher comorbidity rates with disorders such as obsessive-compulsive disorder and panic disorder, altered basic mood, substance abuse, use of antidepressants and precedent stressor.^{13,17,19,24,31,38} It seems that some bipolar patients show a predominantly mixed pattern: onset of disease with mixed episode predicts a course with predominance of this type of phenomenology.^{19-20,24,27-29} Psychotic symptoms and irritability seem to be constantly present in episodes with mixed symptomatology.^{7,16,24,29-33} MS are associated with higher rates of impulsiveness and suicidality (suicide ideation, attempts and act).^34-37 Therefore, the disease with this pattern shows higher morbidity and mortality.

The ethiopathogeny of this condition has been debated by several authors, among them.Swann et al.^39,26 When studying the noradrenergic activity, hypothalamic-hipophyseal axis, they concluded that MS is an overlap of a biological condition of mania and depression. These data are not always coincident with previous studies.

2. Mixed depression (MD)

The studies on mixed depressions are scarce: Himmelhoch et al³ studied agitated psychotic depression, conceptualizing it as bipolar depression, associated with manic or hypomanic symptoms and psychotic symptoms.

MD is associated with hyperthymic mood,¹⁷ predominance of bipolar II disorder,¹⁵ atypical symptoms of depression,^15,41 predominance of females⁴¹ and use of antidepressants.¹⁴ Koukopoulos¹⁴ considers that mixed depression is an MS for showing characteristics common to mixed mania, such as treatment response, symptoms instability, great incidence on females. Tandon et al⁴⁰ obtained different biochemical findings for mixed depression from those described for mixed mania.

Differential diagnosis

The differential diagnosis of MS is a very difficult issue in the clinical practice. The main ones are:

1. Anxious depression: there is no acceleration of thought or increase of the libido.

2. Borderline personality: mood lability is common to both pathologies, but there is no cycling as in BD, as well as no previous history of BD.

3. Agitated depression, defined by the RDC⁸ as a full depressive episode associated with symptoms of psychomotor agitation such as agitation of inferior members or finger tapping. There is no acceleration of thought, increase of libido or of risk activities.

4. Fast cycling pictures may hamper the diagnosis and it must be reminded that they may be present concomitantly to MS. The DSM IV¹¹ describes rapid cycling as a course specifier, in which at least 4 different episodes occur in a 12-month period. Kräemilinger and Post⁴² define ultra-rapid and ultra-ultra rapid (ultradian) cycling as BD courses which undergo sudden changes within weeks or a few days, and in the first case with the change occurring in up to 24 hours. The instability of these episodes is the common trait and should be the initial concern of the treatment.

Treatment

The response to traditionally efficient treatments for acute mania have presented worse results for MS both in the short- and in the long-term (Prien et al.⁴³ , Goldberg et al.⁴⁴ and Montgomery et al.⁴⁵). The first step in the treatment of MS is the withdrawal of all mood-increasing substances⁴⁶. The association of more than one mood stabilizer or of one mood stabilizer and one antipsychotic is more efficient than using it in monotherapy.^45-48

1. Lithium

MS is a predictor of bad response to lithium,^43,46-47 and it fails to treat manic symptoms and improves depressive and cognitive symptoms.²⁷ Poor response does not seem to be related to the severity of the condition, but to the presence of mixed characteristics.^43,45

2. Anticonvulsivants

Divalproate and valproic acid: Response to divalproate does not seem to differ in mixed and classical mania, being much higher than placebo, what is not related to severity or gender, but only to the presence of depressive symptoms.^45,48 Calabrese et al⁴⁹ reported good prophylactic response to valproate.

Carbamazepine: high rates of dysphoria (irritability) in MS were related by Post and Uhde⁵⁰ to better response to treatment with carbamazepine, but not regarding depressive symptoms. Dilsaver et al⁵¹ reports better response to depressive symptoms when associated to manic ones than when isolated.

3. Other anticonvulsivants

There are no controlled studies for MS with gabapentine, lamotrigine, topiramate, for patients with diagnosis of MS, only for mania (Pande et al⁵² and Chengappa et al^46,53-54 ).

ECT: It is a good treatment for acute episode (Small et al,⁵⁵ Dilsaver et al^47,51). Devanand et al⁵⁶ comparing bipolar subjects in mania versus depression, versus MS, found good response in the 3 groups, but MS patients had longer hospitalization and needed a higher number of applications than bipolar depressed patients, a discordant finding from Ciaparelli et al's.⁵⁷

Antipsychotics: studies were not always performed exclusively with mixed patients, being studies on mania with or without depressive symptoms.

*Typical: they were much used in combination with lithium or alone in acute mania and MS. According to several authors, the treatment with this class of antipsychotics reduces the time of response of manic symptoms.^46,74 Extrapyramidal side-effects and late dyskinesia restrict their use.^58-59

*Atypical:

Olanzapine: its use in monotherapy is efficient in MS and pure mania, with reduction of time of response of depressive and manic symptoms.^60-61 Associations with lithium or divalproate seem to be more efficient than the use of one of these stabilizers alone, including in the long-term (49-week follow-up).^60,62 If associated with 2 stabilizers, whose response was partial, it provides advantages (lithium+valproate and lithium+ carbamazepine).⁶³

Risperidone: Studies include pure and mixed mania, and the results are not specified. Studies with bipolar patients show the efficacy of using risperidone on BD in mania, acting on depressive and manic symptoms.^64-65 If associated with other stabilizers (lithium, carbamazepine, valproate) it offers advantages to treat manias in general.^66-68 When associated with lithium, it has an action comparable to the association of lithium with haloperidol.⁶⁴

Quetiapine and Aripiprazol were not specifically studied for MS, although there are good results in the treatment of pure mania.^69-72

Clozapine: Suppes et al⁷³ report improvement in the symptomatology in one study on 6 patients with MS.

Conclusion

Mixed states represent an acute condition of bipolar disorder with more difficulty in diagnosis, more severe course and prognosis and therefore more difficult to be treated. When not identified, the use of antidepressants alone worsens not only the episode, with higher suicide risk, but also the disease's course. The patient's and the family history should be investigated not only for the presence of mood disorders, but also for suicide and comorbid psychiatric disorders. Mixed symptomatology in patients who complain of depression with irritable mood, acceleration of thought, increase of energy and aggressiveness should be always specifically investigated and treated. The correct explanation of the disease and its most severe forms to the patient has been an efficient way of improving the prognosis, and the quality of life of these individuals.⁷⁴

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Publication Dates

• Publication in this collection
  18 Oct 2006
• Date of issue
  Oct 2004