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Meeting report Bipolar depression: What are we doing? Paradoxically, despite Mania being the concept which defines bipolar disorders, it is depression itself which is the most important quantitative aspect in this illness and the one that is associated with higher levels of disability and residual sub-threshold symptoms (Judd and Akiskal, 2003). 1. Detection According to the criteria of DSM IV, the prevalence of bipolar depression is 0.6% for Bipolar Disorder I and 1.7% for Bipolar Disorder II, whereas for Unipolar Depression it is 21%. In contrast, according to the Zurich epidemiological cohort studies, with strict criteria for the length of hypomania, the prevalence remains in 0.6% for Bipolar Disorder I and around 20% for Unipolar Depression, but it is 5.3% for Bipolar Disorder II. Also, in the same cohort and taking into account wider criteria (which means including hypo- manias of one day length), the prevalence remains for Bipolar Disorder I and Unipolar Depression but increases significantly for Bipolar Disorder II reaching up to 11% (Angst et al., 2003). In two studies (Ghaemi et al., 1999, 2000) it was shown that 40% of bipolar patients had been diagnosed as Unipolar Depression, whereas in an Argentinean study the figure was 66% (Strejilevich et al., 1999). According to Akiskal et al., 2003 one of the main reasons for the inconsistency in the diagnosis is the underlying cyclothymic disregulation, leading to a clinical condition of a labile-variable nature that might be confusing in an analysis done at a par- ticular moment. The occurrence of misdiagnoses will lead not only to higher switch over possibilities, cycling increase, a higher risk of relapse and evolution to chronicity, but also into more psychosocial consequences and a higher risk of suicide. That is why it is important to determine if there are clinical characteristics during the current depressive episode that can help us identify, in an accurate way, its condition, either Bipolar or Unipolar as this is a key differentiator between Bipolar Depression (mostly in Bipolar Disorder II) and Unipolar Depression and one of the major challenges in daily clinical practice. The validated differential features observed in Bi- polar Depression rather than Unipolar Depression are the history of mania and hypomania, the cyclothymic behaviour, the similar gender distribution, the early and sudden onset, the higher amount of episodes, the higher frequency of postnatal and psychotic episodes; and the presence of hypersomnia and psychomotor retardation (Akiskal, 2005). Apart from asking the patient's family members and friends one useful strategy that has been proven is the use of semi-structured interviews which reduce the possibility of leaving symptoms undetected. It is important to take into consideration the difference between hyperactivity and euphoria or irritability by asking about the present time and looking for clues that will let us consider the Bipolar Spectrum. In this case Ghaemi's criteria (Ghaemi, 2002) might be used. One of the most difficult issues related to Bipolar Depression is the existence of Mixed Depressions, which usually consists of a complex evolution, a stron- ger relation with Bipolar Disorder II rather than Bipolar Disorder I, and the difficulty of confirming a diagnosis despite of its high frequency (70% of Bipolar Depres- sions at least have one manic or hypomanic symptom). 2. Diagnosis Regarding the diagnosis three or more hypomanic or manic symptoms in one Major Depressive Episode; this would be a specific and sensitive marker of family history of Bipolar Disorder I or II. Either Benazzi's excitation factor or Henry's emo- tional hyperactivity factor are constantly found, the high percentage of psychotic symptoms, suicides and suicide attempts and the similarity between anxious or agitated depression. Journal of Affective Disorders 98 (2007) 169 171 www.elsevier.com/locate/jad doi:10.1016/j.jad.2006.08.002

Bipolar depression: What are we doing?

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Journal of Affective Disorders 98 (2007) 169–171www.elsevier.com/locate/jad

Meeting report

Bipolar depression: What are we doing?

Paradoxically, despiteMania being the concept whichdefines bipolar disorders, it is depression itself which isthe most important quantitative aspect in this illness andthe one that is associated with higher levels of disabilityand residual sub-threshold symptoms (Judd and Akiskal,2003).

1. Detection

According to the criteria of DSM IV, the prevalenceof bipolar depression is 0.6% for Bipolar Disorder I and1.7% for Bipolar Disorder II, whereas for UnipolarDepression it is 21%. In contrast, according to theZurich epidemiological cohort studies, with strictcriteria for the length of hypomania, the prevalenceremains in 0.6% for Bipolar Disorder I and around 20%for Unipolar Depression, but it is 5.3% for BipolarDisorder II. Also, in the same cohort and taking intoaccount wider criteria (which means including hypo-manias of one day length), the prevalence remains forBipolar Disorder I and Unipolar Depression butincreases significantly for Bipolar Disorder II reachingup to 11% (Angst et al., 2003). In two studies (Ghaemiet al., 1999, 2000) it was shown that 40% of bipolarpatients had been diagnosed as Unipolar Depression,whereas in an Argentinean study the figure was 66%(Strejilevich et al., 1999). According to Akiskal et al.,2003 one of the main reasons for the inconsistency in thediagnosis is the underlying cyclothymic disregulation,leading to a clinical condition of a labile-variable naturethat might be confusing in an analysis done at a par-ticular moment.

The occurrence of misdiagnoses will lead not only tohigher switch over possibilities, cycling increase, ahigher risk of relapse and evolution to chronicity, butalso into more psychosocial consequences and a higherrisk of suicide. That is why it is important to determine ifthere are clinical characteristics during the currentdepressive episode that can help us identify, in an

doi:10.1016/j.jad.2006.08.002

accurate way, its condition, either Bipolar or Unipolar asthis is a key differentiator between Bipolar Depression(mostly in Bipolar Disorder II) and Unipolar Depressionand one of the major challenges in daily clinical practice.

The validated differential features observed in Bi-polar Depression rather than Unipolar Depression arethe history of mania and hypomania, the cyclothymicbehaviour, the similar gender distribution, the early andsudden onset, the higher amount of episodes, the higherfrequency of postnatal and psychotic episodes; and thepresence of hypersomnia and psychomotor retardation(Akiskal, 2005). Apart from asking the patient's familymembers and friends one useful strategy that has beenproven is the use of semi-structured interviews whichreduce the possibility of leaving symptoms undetected.

It is important to take into consideration the differencebetween hyperactivity and euphoria or irritability byasking about the present time and looking for clues thatwill let us consider the Bipolar Spectrum. In this caseGhaemi's criteria (Ghaemi, 2002) might be used.

One of the most difficult issues related to BipolarDepression is the existence of Mixed Depressions,which usually consists of a complex evolution, a stron-ger relation with Bipolar Disorder II rather than BipolarDisorder I, and the difficulty of confirming a diagnosisdespite of its high frequency (70% of Bipolar Depres-sions at least have one manic or hypomanic symptom).

2. Diagnosis

Regarding the diagnosis three or more hypomanic ormanic symptoms in one Major Depressive Episode; thiswould be a specific and sensitive marker of familyhistory of Bipolar Disorder I or II.

Either Benazzi's excitation factor or Henry's emo-tional hyperactivity factor are constantly found, the highpercentage of psychotic symptoms, suicides and suicideattempts and the similarity between anxious or agitateddepression.

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Misdiagnosis leads to a lack of treatment and, asKupfer shows, (Kupfer et al., 2002) patients without anytreatment more frequently commit suicide and they arealso more likely to suffer from cancer, diabetes and otherchronic illnesses.

3. Treatments

The main treatment offered consists of Mood Sta-bilizer drugs. In Bipolar Depression, Lithium was shownto be effective in 8 out of 11 studies (Zornberg and Pope,1993). Lamotrigine was also effective at 200 mg qd dose(Calabrese et al., 1999). and should be considered aprimary option in patients with Bipolar Depression andin Bipolar II patients with rapid cycling (Singh et al.,2005). The effectiveness of Carbamazepine and Valpro-ate is still not confirmed. Also there is no effectivenessyet shown for Gabapentin, Topiramate or Oxcarbaze-pine. More than 8 mEq/l of Lithium is as effective asParoxetine or Imipramine (Nemeroff et al., 2001).

While there is now sufficient evidence to establishthe importance of Mood Stabilizers as one of the mostimportant pharmacotherapeutic resources, the use ofantidepressants remains a subject of controversy. We doknow there is evidence that these molecules may causeswitching and increase the cycling, turning the patientinto a rapid cycler and making the prognoses of theillness even worse (Ghaemi et al., 2004), but equallythere are at least three studies that conclude that therelationship between destabilisation and the use of anti-depressants may not be so direct and simple as originallythought (Altshuler et al., 2003; Gijsman et al., 2004;Visser et al., 2005).

According to a study by Post et al., 2003 the risk ofswitching is 18% in 10 weeks and 35% in 1 year, andthere are no differences in the risk of switching amongthe different antidepressants. If we take into consider-ation that the estimated risk of suicide in these patients is30 times higher than in the general population (Goodwinand Jamison, 1990) the balance between the risks ofswitching versus the risk of committing suicide becomesa dilemma. With reference to this topic, Altshuler et al.,2003 concludes that we must maintain antidepressantsbecause protracted manias are not observed, thoughcontinuing them led to less relapses and a better prog-noses. In terms of efficacy, this would be similar for allantidepressants. The recommended usage should be totreat them carefully and only in the short term, always incombined with Mood Stabilizers.

Regarding Mixed Depressions, although there is noagreement on treatment, it is suggested that extreme careshould be exercised when using antidepressants due to

the risk of switching that might lead to Mixed Mania,increasing the risk of suicide and psychotic episodes.Valproate seems to have better efficacy than Lithium inMixedMania or mania associated with depressive symp-toms and is recommended as a first-line pharmacologicoption in mixed manic patients (Singh et al., 2005).Atypical antipsychotics are also effective. Electrocon-vulsive Therapy may benefit the most severe cases and ithas shown its importance in resistant depression withpsychotic symptoms and high suicide risks. The remis-sion percentage in refractive patients is 67% and the riskof switching to mania is only 3.4%.

Creating accurate guidelines giving recommenda-tions regarding the combinations of these agents andwhen and how to use them is predominantly related to“Experience” rather than “Evidence” Based Medicine.

There is not enough evidence of the effectiveness ofTranscranial Magnetic Stimulation, whereas sleep dep-rivation has been shown to be more effective in BipolarDepression than Unipolar Depression.

Psychotherapy is effective in the intensive treatmentbut not in relapse prevention or hospitalisation; in thiscase psycho-education is a must, so that the patientgets to know the main features of his/her disease, andlearn to recognise the symptoms that lead into episodes.A therapeutic and close relationship with bipolar pa-tients encourages adherence and gives better therapeuticresults.

References

Akiskal, H.S., Hantouche, E.G., Allilaire, J.F., 2003. Bipolar II withand without cyclothymic temperament: “dark” and “sunny”expressions of soft bipolarity. J. Affect. Disord. 73, 49–57.

Akiskal, H.S., 2005. The dark side of bipolarity: detecting bipolardepression in its pleomorphic expressions. J. Affect. Disord. 84,107–115.

Altshuler, L., Suppes, T., Black, D., Nolen, W.A., Keck Jr., P.E., Frye,M.A., McElroy, S., Kupka, R., Grunze, H., Walden, J., Leverich,G., Denicoff, K., Luckenbaugh, D., Post, R., 2003. Impact ofantidepressant discontinuation after acute bipolar depressionremission on rates of depressive relapse at 1-year follow-up. Am.J. Psychiatry 160, 1252–1262.

Angst, J., Gamma, A., Benazzi, F., Ajdacic, V., Eich, D., Rossler, W.,2003. Diagnostic issues in bipolar disorder. Eur. Neuropsycho-pharmacol. 13 (Suppl 2), S43–S50.

Calabrese, J.R., Bowden, C.L., Sachs, G.S., 1999. A double-blindplacebo controlled study of lamotrigine monotherapy in out-patients with bipolar I depression. Lamictal 602 study group.J. Clin. Psychiatry 60 (2), 79–88.

Ghaemi, S.N., Sachs, G.S., Chiou, A.M., Pandurangi, A.K., Goodwin,F.K., 1999. Is bipolar disorder still underdiagnosed? Areantidepressants overutilized? J. Affect. Disord. 52, 135–144.

Ghaemi, S.N., Boiman, E.E., Goodwin, F.K., 2000. Diagnosingbipolar disorder and the effect of antidepressants: a naturalisticstudy. J. Clin. Psychiatry 61, 804–808.

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Ghaemi, SN., 2002. “Cade's disease” and beyond: misdiagnosis,antidepressant use, and a proposed definition for Bipolar SpectrumDisorder. Can. J. Psychiatry 47, 125–134.

Ghaemi, S.N., Rosenquist, K.J., Ko, J.Y., Baldassano, C.F., Kontos, N.J.,Baldessarini, R.J., 2004. Antidepressant treatment in bipolar versusunipolar depression. Am. J. Psychiatry 161, 163–165.

Gijsman, H.J., Geddes, J.R., Rendell, J.M., Nolen,W.A., Goodwin, G.M.,2004. Antidepressants for bipolar depression: a systematic review ofrandomised, controlled trials. Am. J. Psychiatry 61, 1537–1547.

Goodwin, F.K., Jamison, K.R., 1990. Manic-Depressive Illness.Oxford University Press, New York.

Judd, L.L., Akiskal, H.S., 2003. The prevalence and disability ofbipolar spectrum disorders in the US population: re-analysis of theECA database taking into account subthreshold cases. J. Affect.Disord. 73 (1–2), 123–131.

Kupfer, D.J., Rucci, P., Frank, E., Kostelnik, B., Fagioline, A.,Mallinger, A.G., Swartz, H.A., Thase, M.E., Siegel, L., Wilson, D.,2002. Suicide attempts in patients with Bipolar I Disorder duringacute and maintenance phases of intensive treatment withpharmacotherapy and adjunctive psychotherapy. Am. J. Psychiatry159 (7), 1160–1164.

Nemeroff, C.B., Evans, D.L., Gyulai, L., Sachs, G.S., Bowden, C.L.,Gergel, I.P., Oakes, R., Pitts, C.D., 2001. Double-blind, placebo-controlled comparison of imipramine and paroxetine in thetreatment of bipolar depression. Am. J. Psychiatry 158 (6),906–912.

Post, R.M., Leverich, G.S., Nolen, W.A., Kupka, R.W., Altshuler,L.L., Frye, M.A., Suppes, T., McElroy, S., Keck, P., Grunze, H.,Walden, J., 2003. Stanley foundation Bipolar Network. A re-evaluation of the role of antidepressants in the treatment of bipolardepression: data from the Stanley Foundation Bipolar Network.Bipolar. Disord. 5 (6), 396–406.

Singh, V., Muzina, V., Calabrese, J.R., 2005. Anticonvulsants inbipolar disorder. Psychiatr. Clin. North Am. 28 (2), 301–323.

Strejilevich, S., García Bonetto, G., Chan, M., Galeno, R., y col, 1999.Problemas actuales respecto del diagnóstico y tratamiento deltrastorno bipolar en nuestro medio: experiencia y opinión de losusuarios. Pren Méd Argent, vol. 86, pp. 823–830.

Visser, H.M., vanderMast, R.C., 2005. Bipolar disorder, antidepres-sants and induction of hypomania or mania. A systematic review.World J. Biol. Psychiatry 6 (4), 231–241.

Zornberg, G.L., Pope Jr., H.G., 1993. Treatment of depression inbipolar disorder: new directions for research. J. Clin. Psychophar-macol. 13, 397–408.

Gerardo García BonettoMarcelo Garbini

Eduard Vieta