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Research on Bipolar I and II

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I am not trying to reinvent the wheel here. For extensive information on bipolar disorder and treatments, the websites on our LINKS page simply are the finest available on the internet. What I offer here, unless otherwise noted, are abstracts from Pub Med, a clearinghouse of medical research sponsored by the NIMH. These have to do with either very recent research on bipolar disorder, or some unusually interesting insights. Since these are studies written for medical professionals, they can be highly technical -- the "bottom line" is to be found in the last part of the abstract, the "CONCLUSIONS". For anyone who wants to develop a deep understanding of anything related to bipolar disorder, Pub Med is the place to go -- with that in mind I present this selection of abstracts. -ps-


Mitochondrial dysfunction found in bipolar disorder

Arch Gen Psychiatry 2004; 61: 300-308

The expression of nuclear genes that code for mitochondrial proteins appears to be significantly reduced in patients with bipolar disorder, reveal study findings that provide not only clues to the mechanism of the disorder but also potential treatment targets.

"Recent spectroscopic studies have provided evidence for bipolar disorder as a disease of mitochondrial energy metabolism," observe Christine Konradi (McLean Hospital, Belmont, Massachusetts, USA) and colleagues.

Recognizing that mitochondrial dysfunction in bipolar disorder could be due to an abnormal expression of nuclear genes coding for mitochondrial proteins, they determined the expression of 12,558 nuclear genes in the hippocampus of nine patients with bipolar disorder, eight patients with schizophrenia, and 10 mentally healthy individuals.

Using gene arrays to study messenger RNA expression, the team found that the levels for 18 of the genes coding for mitochondrial proteins were significantly decreased in patients with bipolar disorder, but not in those with schizophrenia, or in the healthy controls.

Indeed, bipolar disorder patients were characterized by a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the adenosine triphosphate-dependent process of proteosome degradation, the team reports in the Archives of General Psychiatry.

"This molecular evidence strengthens the hypothesis that decreased pH and high-energy phosphate levels in bipolar disorder are the result of mitochondrial dysfunction," the researchers note.

They suggest that the number of mitochondria per neuron may be reduced or there is selective neuron loss. Alternatively, mechanisms that control transcription could be involved in widespread changes of gene expression.

"It appears the our finding of a decreased expression of genes involved in mitochondrial function and proteasome degradation provides potential targets for the development of novel drug compounds in the treatment of bipolar disorder" Konradi et al conclude.


Psychoeducation shows bipolar treatment promise

J Clin Psychiatry 2003; 64: 1101-1105

Psychoeducation may be an effective add-on treatment for preventing relapses in patients with bipolar I disorder who are adherent to drug therapy, researchers from Barcelona Stanley Research Center in Spain report.

Recognizing that recurrence can occur in some bipolar patients, despite strictly following their prescribed treatment regimen, Francesc Colom and colleagues hypothesized that, by enhancing early recognition of prodromal symptoms, psychoeducative programs could minimize the risk of relapse in such treatment compliant patients.

To investigate, the team carried out a single-blind randomized trial, in which 25 fully compliant bipolar I patients received psychoeducation, comprising 20 sessions of 90 minutes. This was aimed at improving illness awareness, treatment adherence, early detection of prodromal symptoms and relapse, and lifestyle regularity. A further 25 fully compliant patients who did not receive psychoeducation were also studied.

The results, published in the Journal of Clinical Psychiatry, showed that, during 20 weeks of treatment, 14 (56%) patients in the control group experienced a recurrence of mania, hypomania, mixed episode, or depression, compared with just 4 (16%) of those receiving psychoeducation.

This reduced risk of relapse among psychoeducated patients was maintained during a 2-year follow-up phase, during which only naturalistic treatment was continued, with relapse occurring in 23 (92%) controls versus just 15 (60%) of those in the psychoeducation group.

"The action of psychoeducation seems to go beyond compliance enhancement and may support a tripod model composed by lifestyle regularity and health habits, early detection of prodromal signs followed by prompt drug intervention, and, finally, treatment compliance."

Unitary approach to unipolar and bipolar disorders suggested

Am J Psychiatry 2004; 161: 1264–1269

A team of researchers has challenged the distinction between bipolar and unipolar depression, after finding that manic and hypomanic episodes also occur in patients with recurrent unipolar depression.

They argue that "all recurrent depressions are bipolar to a greater or lesser degree," and suggest that a mood spectrum approach may be useful for making a more accurate diagnostic evaluation in patients with mood disorders.

The researchers, led by Giovanni Cassano from the University of Pisa in Italy, assessed the occurrence of manic and hypomanic episodes in a group of 117 patients with remitted recurrent unipolar depression and 106 with bipolar I disorder. All the patients completed the Structural Clinical Interview for Mood Spectrum, which consists of items organized into manic/hypomanic and depressive components.

The average number of mood spectrum items experienced by the patients with recurrent unipolar depression and those with bipolar I disorder were 64.8 and 83.7, respectively.

Patients with unipolar depression experienced a substantial number of manic/hypomanic episodes over their lifetime. Moreover, the more manic/hypomanic items endorsed on the Structural Clinical Interview among patients with unipolar depression, the greater the likelihood of reporting suicidal ideation and delusions. Overall, however, paranoid ideation, auditory hallucinations, and suicide attempts were significantly more frequent in bipolar than unipolar patients.

Further analysis indicated a linear relationship between the number of lifetime manic/hypomanic items and the number of depressive items in both unipolar and bipolar patients.

Reporting in the American Journal of Psychiatry, the researchers write: "Our data suggest that unipolar disorder and bipolar disorder are not two discrete and dichotomous phenomena but that mood fluctuations – up and down – are common to both conditions."

They recommend the use of the Structural Clinical Interview for Mood Spectrum to evaluate these mood fluctuations in order to make more accurate diagnoses.


Bipolar Disord. 2003 Oct;5(5):310-9.


An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).

Post RM, Leverich GS, Altshuler LL, Frye MA, Suppes TM, Keck PE Jr, McElroy SL, Kupka R, Nolen WA, Grunze H, Walden J.

Stanley Foundation Bipolar Network and Biological Psychiatry Branch, NIMH, NIH, DHHS, Bethesda, MD 20892-1272, USA.

AIM AND METHODS: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. RESULTS: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. CONCLUSIONS: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.


World J Biol Psychiatry. 2004 Apr;5(2):107-13.

Validating Kraepelin's two types of depressive mixed states: "depression with flight of ideas" and "excited depression".

Akiskal HS, Benazzi F.

International Mood Center, University of Californai at San Diego, and VA Psychiatry Service CA 92161, USA.

Despite a venerable classic tradition going back to at least Kraepelin, depressive mixed states (DMX) are not represented in official diagnostic manuals in psychiatry. We have operationalised this condition as a major depressive episode (MDE) with three or more intra-episode hypomanic signs and symptoms (DMX3). Of 320 consecutive bipolar II outpatients, presenting for MDE treatment and interviewed using the Structured Clinical Interview for DSM-IV, modified to permit the systematic evaluation of hypomanic features during the index MDE, 200 met our criteria for DMX3 (62.5%). When compared with the remaining non-DMX bipolar II, they had significantly earlier age at onset, higher percentage of females, atypical features and bipolar family history. Multivariate logistic regression ofintra-MDE hypomanic signs and symptoms found evidence supporting an "excited depression" subtype (defined by the core feature of psychomotor agitation, and further characterised by talkativeness, irritable mood and distractability) and a "depression with flight of ideas" subtype (defined by the core feature of racing/crowded thoughts, and further characterised by risky pleasurable impulses including, among others, those with intense sexual arousal). We thereby documented the existence of two distinct DMX subtypes which testify to the clinical acumen of Kraepelin (and his pupil Weygandt) who in 1899 described these two subforms of depressive mixed states in more severely ill hospitalised patients.


Int J Neuropsychopharmacol. 2003 Jun;6(2):127-37.


Long-term symptomatic status of bipolar I vs. bipolar II disorders.

Judd LL, Schettler PJ, Akiskal HS, Maser J, Coryell W, Solomon D, Endicott J, Keller M.

National Institute of Mental Health Collaborative Program on the Psychobiology of Depression Clinical Studies, San Diego, La Jolla, CA, USA.

Weekly affective symptom severity and polarity were compared in 135 bipolar I (BP I) and 71 bipolar II (BP II) patients during up to 20 yr of prospective symptomatic follow-up. The course of BP I and BP II was chronic; patients were symptomatic approximately half of all follow-up weeks (BP I 46.6% and BP II 55.8% of weeks). Most bipolar disorder research has concentrated on episodes of MDD and mania and yet minor and subsyndromal symptoms are three times more common during the long-term course. Weeks with depressive symptoms predominated over manichypomanic symptoms in both disorders (31) in BP I and BP II at 371 in a largely depressive course (depressive symptoms=59.1% of weeks vs. hypomanic=1.9% of weeks). BP I patients had more weeks of cyclingmixed polarity, hypomanic and subsyndromal hypomanic symptoms. Weekly symptom severity and polarity fluctuated frequently within the same bipolar patient, in which the longitudinal symptomatic expression of BP I and BP II is dimensional in nature involving all levels of affective symptom severity of mania and depression. Although BP I is more severe, BP II with its intensely chronic depressive features is not simply the lesser of the bipolar disorders; it is also a serious illness, more so than previously thought (for instance, as described in DSM-IV and ICP-10). It is likely that this conventional view is the reason why BP II patients were prescribed pharmacological treatments significantly less often when acutely symptomatic and during intervals between episodes. Taken together with previous research by us on the long-term structure of unipolar depression, we submit that the thrust of our work during the past decade supports classic notions of a broader affective disorder spectrum, bringing bipolarity and recurrent unipolarity closer together. However the genetic variation underlying such a putative spectrum remains to be clarified.


Biol Psychiatry. 2004 Jul 1;56(1):54-60.


Pramipexole for bipolar II depression: a placebo-controlled proof of concept study.

Zarate CA Jr, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK.

Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institute of Health, Department of Human and Health Services, Bethesda, Maryland, USA.

BACKGROUND: The original serotonergic and noradrenergic hypotheses do not fully account for the neurobiology of depression or mechanism of action of effective antidepressants. Research implicates a potential role of the dopaminergic system in the pathophysiology of bipolar disorder. The current study was undertaken as a proof of the concept that dopamine agonists will be effective in patients with bipolar II depression. METHODS: In a double-blind, placebo-controlled study, 21 patients with DSM-IV bipolar II disorder, depressive phase on therapeutic levels of lithium or valproate were randomly assigned to treatment with pramipexole (n = 10) or placebo (n = 11) for 6 weeks. Primary efficacy was assessed by the Montgomery-Asberg Depression Rating Scale. RESULTS: All subjects except for one in each group completed the study. The analysis of variance for total Montgomery-Asberg Depression Rating Scale scores showed a significant treatment effect. A therapeutic response (>50% decrease in Montgomery-Asberg Depression Rating Scale from baseline) occurred in 60% of patients taking pramipexole and 9% taking placebo (p =.02). One subject on pramipexole and two on placebo developed hypomanic symptoms. CONCLUSIONS: The dopamine agonist pramipexole was found to have significant antidepressant effects in patients with bipolar II depression.


Forget the Neurotransmitters

From McMan's Bipolar Website (see link)

Until very recently, it was thought that the brain could not grow new cells. From a mood disorders point of view, this was particularly distressing, as brain scans and post mortem studies have found reduction in the volume of the prefrontal cortex of depressed and bipolar patients, as well as cell atrophy and loss. In one classic study, Wayne Drevets MD, Chief of Neuroimaging of Mood and Anxiety Disorders at the NIMH, found that the subgenual prefrontal cortex of the brain was 38 percent smaller in bipolar patients and 48 percent smaller for those with chronic unipolar depression In experiments by Robert Sapolsky PhD of Stanford, animals subjected to stress resulted in dead or atrophied neurons in the hippocampus, as well as endangered neurons that were more likely to die when subjected to another stressful event.

One of these casualties is brain derived neurotophic factor (BDNF). BDNF is a neuropeptide that is crucial to the survival and growth of neurons.

Stress elevates cortisol, which in turn ups the excitatory neurotransmitter glutamate, which increases calcium influx into the neuron and activates certain calcium-dependent “death” enzymes. Cortisol may also reduce the neuron’s capacity to take energy-sustaining glucose into the cell so it doesn’t have the strength to deal with a subsequent crisis. Another casualty may be the glia, the “other” brain cell, once thought of as mere mind-glue but now recognized as an active partner of the neuron. One of its functions is thought to be clearing glutamate from the synapse.

Basically, the cells can’t handle the load, Husseini Manji MD, Chief of the Laboratory of Molecular Pathophysiology at the NIMH, explained in a grand rounds lecture delivered at UCLA in Feb 2003 and webcast the same day. Their atrophy and death tends to isolate neurons, affecting their ability to connect to and communicate with other neurons.

Then, in the late nineties, came the startling discovery that under the right conditions, animal brains can grow new cells and shrunken brain cells could grow to normal sizes and make new connections, a process called neurogenesis that takes place mainly in the hippocampus. In 2000, Fred Gage PhD of the Salk Institute discovered neurogenesis also takes place in humans - assuming stress and depression do not sabotage the brain's best efforts.

In 2001 came the finding that antidepressants can cause new cells to grow in the hippocampus. The next year came the discovery that exercise also causes brain cells to grow. Ron Duman PhD and his team at Yale first found that repeated antidepressant treatment "up-regulates" a process known as the cAMP-CREB cascade. cAMP is a signaling molecule inside the cell that is upstream of the protein CREB, which controls the expression for certain genes, among them BDNF. Significantly, CREB and BDNF play critical roles in neuroplasticity, that is, of the brain's capacity to constantly remap itself by learning and forming memories.

The cAMP-CREB cascade also figures in neurogenesis. Dr Duman and his team exposed lab rats to repeated footshocks to induce behavioral helplessness, resulting in a long-lasting down-regulation of neurogenesis. But when the animals were treated with different classes of antidepressants, the behavior was reversed.

Approximately 9,000 new cells a day grow in the hippocampus of an adult rodent. Of these, about 75 to 80 percent become neurons, and half survive after four weeks. It is estimated that in humans the rate of new cell growth is only 10 to 20 percent of rodents, but this may still be a number that is sufficient to influence the function of the hippocampus.

Meanwhile, a study led by Dr Manji found that lithium "significantly increases total gray matter volume in the human brain of people with manic-depressive illness."

Using a gene chip micro-array (a process that allows researchers to record the interactions among thousands of genes simultaneously), Dr Manji and his colleagues started experimenting with lithium and Depakote on brain cell tissue, and found to their surprise these two completely different medications indirectly affected some of the same cell pathways associated with cell survival and death. One protective protein that utilizes these pathways is Bcl-2, which in one experiment was doubled by lithium and Depakote administration. Subsequent experiments on rats found lithium mitigated the effects of lab-induced stroke and led to the growth of new neurons in the hippocampus. When Dr Manji asked Dr Drevets to revisit his study, it was found that those patients on lithium or Depakote did not show brain atrophy. More recently, a study on human patients with bipolar found lithium increased overall brain grey matter.

But producing new brain cells is only part of the picture, and probably not the main part of the picture. What may be even more important is the ability to protect and rescue damaged brain cells and helping them to re-establish connections, according to Dr Manji. To appreciate lithium’s possibilities we need to realize that both depression and bipolar disorder are more than mere mood disorders. The impairments to function and cognition may last far beyond the course of an actual episode, and although not "classic" neurodegenerative diseases such as Parkinson’s and Alzheimer’s, they are clearly illnesses associated with brain cell loss and shrinkage.

Tellingly, Bcl-2 protects against free radicals that can damage brain cells, as well as Parkinson’s and possibly the ravages of mood disorders, Dr Manji informed a session at the National Alliance for the Mentally Ill annual conference held in Cincinnati in July 2002. Dr Manji also drew attention to the related work of Ron Duman PhD and his team at Yale, who found antidepressants turned on the expression of BDNF. Significantly, Dr Duman and his team have recently found that an infusion of BDNF may produce an antidepressant effect in lab rats.

Dr Manji explained how for the last three decades, neurotransmitters have been the focus of mental health research. But recently, he went on to say, we have been learning that mental illness is much more complicated than that. Nerve cells communicate with each other through neurotransmitters, but do not actually go inside the nerve cell. Rather, they are merely the keys that unlock what is going on inside the neuron, "where all the action is."

You can mess all you want with serotonin and dopamine, etc, Dr Manji told his audience at UCLA,;but if you don't have the appropriate [cell] circuitry in place it's not going to have any effect.

According to Dr Manji, there are some 10 different potential targets within the nerve cell that we did not even suspect 10 years ago. Eight of these targets are being actively investigated.

A potential target inside the nerve cell includes protein kinase C (PKC), a signaling pathway that is implicated in nerve cellular excitability. Dr Manji's team discovered that lithium and Depakote have very similar effects on the PKC system, taking days or weeks to act. A PKC inhibitor, however, may be more direct. The drug Novladex (tamoxifen), used to treat breast cancer, inhibits PKC and has been found to significantly reduce mania scores in one small study. Larger placebo-controlled studies are now underway at the NIMH and at Harvard. If these studies work, he said, we can develop a better PKC inhibitor.

And the ALS drug Rilutek (riluzole), a glutamate inhibitor, hasa remarkable antidepressant effect.

Forget the neurotransmitters.  Clearly "beneath the cell membrane" is the future.


Bipolar Disord. 2004 Feb;6(1):62-6.


A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders.

Joffe RT, MacQueen GM, Marriott M, Trevor Young L.

Department of Psychiatry, UMDNJ-New Jersey Medical School, Newark, NJ 07103, USA.

BACKGROUND: There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years. METHOD: Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined. RESULTS: Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups. CONCLUSIONS: Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.


CNS Spectr. 2004 Mar;9(3):227-31.

Presence of irritability during depressive episodes in bipolar disorder.

Deckersbach T, Perlis RH, Frankle WG, Gray SM, Grandin L, Dougherty DD, Nierenberg AA, Sachs GS.

Department of Psychiatry, Psychiatric Neuroscience Program and Bipolar Research Program, Harvard Medical School 149-2611, Massachusetts General Hospital Bldg. 149, 13th Street, Charlestown, MA 02129, USA.

BACKGROUND: This study examined the prevalence of irritability in patients with bipolar I disorder during an episode of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) major depression who do not meet criteria for a mixed episode. METHOD: A chart review of 111 patients with bipolar I disorder treated at the Massachusetts General Hospital Bipolar Clinic between 1998 and 2000 identified 34 patients who met criteria for a DSM-IV major depressive episode in the absence of (1) mood elevation and/or (2) irritability associated with any additional above threshold DSM-IV symptoms of mania. Data gathered from the charts utilized prospective ratings made routinely at each clinic visit using the Clinical Monitoring Form (CMF), a structured assessment instrument which includes modified versions of the mood modules of the Structured Clinical Interview for DSM-IV. Data from these 34 patients were reviewed to determine the presence of irritability. RESULTS: The frequency of abnormal irritability in these 34 patients followed a bimodal distribution: 26% of the patients showed abnormal irritability > or =75% of the time, compared with 68% of the patients with abnormal irritability < or =30% of the time. Of the high-irritability patients, psychomotor agitation was rated as definitely present to a significant degree in 44%. Talkativeness and distractibility were rated present but subthreshold in one patient each. All other symptoms of DSM-IV mania were absent. CONCLUSION: Approximately 25% of patients with bipolar I disorder who meet criteria for a DSM-IV major depressive episode also experienced substantial irritability in the absence of associated symptoms of mania. Our results suggest that abnormal irritability is not limited to mania or mixed states.


Compr Psychiatry. 2003 Jan-Feb;44(1):21-7.


Bipolar II depressive mixed state: finding a useful definition.

Benazzi F.

Department of Psychiatry, National Health Service, Forli, Italy.

Recent studies showed that depressive mixed state (DMX) (major depressive episode [MDE] with few hypomanic symptoms) was common among depressed outpatients. The aim of the present study was to find a clinicallly useful definition of DMX. A useful definition could be one increasing the probability of making the correct diagnosis of bipolar II. Different definitions of DMX were tested by comparing the sensitivity, specificity, and predictive power for the diagnosis of bipolar II. Three hundred thirty-six consecutive bipolar II (n = 206) and unipolar (n = 130) MDE outpatients were interviewed with the DSM-IV Structured Clinical Interview-Clinician Version (SCID-CV). Different DMX definitions were tested, based on factor analysis, multivariate regression, discriminant analysis, and logistic regression analysis results. The sensitivity, specificity, correctly classified, and receiver operating characteristic (ROC) area for bipolar II diagnosis were compared. Two factors (factor 1, including irritability, psychomotor agitation, and more talkativeness, and factor 2, including racing thoughts, irritability, and distractibility) were significantly associated with bipolar II diagnosis. Of the hypomanic symptoms most common in bipolar II DMX, only irritability and racing thoughts were significantly associated with bipolar II diagnosis on discriminant analysis. DMX with three or more concurrent hypomanic symptoms (DMX3) was strongly associated with bipolar II diagnosis. Comparisons of sensitivity, specificity, correctly classified, and ROC area of the different DMX definitions (factor 1, factor 2, DMX3, irritability during MDE, racing thoughts during MDE) for the diagnosis of bipolar II, showed that factor 1 had the best combination of sensitivity and specificity, high correctly classified and ROC, but DMX3 has the highest specificity, and slightly lower correctly classified and ROC than factor 1. A DMX definition having the highest specificity (DMX3) for bipolar II diagnosis may be more useful to clinicians, leading to few false positives. Bipolar II diagnosis has important treatment and clinical implications, but misdiagnosis is common because diagnosis is often based on history of hypomania (dependent on memory and clinical skills). A cross-sectional marker like DMX3 may increase the probability of making the correct diagnosis of bipolar II, and therefore may be a useful definition of DMX. Copyright 2003, Elsevier Science (USA). All rights reserved.


Affect Disord. 2003 Jan;73(1-2):113-22.


Family history validation of the bipolar nature of depressive mixed states.

Akiskal HS, Benazzi F.

VA Medical Center, University of California at San Diego, VA Psychiatry Service (116-A), 3350 La Jolla Village Drive, San Diego, CA 92161, USA.

BACKGROUND: Recent data indicate that depressive mixed states (DMX), major depressive episode (MDE) plus few concurrent hypomanic symptoms are common in clinical practice but omitted in DSM-IV. Our aims were to find the sensitivity and specificity of DMX for the diagnosis of bipolar II disorder, and validate it against familial bipolarity. METHODS: 377 consecutive private outpatients presenting with psychoactive drug-free MDE were interviewed with the Structured Clinical Interview for DSM-IV (Clinician Version). History of past hypomanic episodes and presence of hypomanic symptoms during the index MDE were systematically recorded. Of these, 226 were bipolar II and 151 unipolar. DMX3 was defined as an MDE plus three or more intra-episodic hypomanic symptoms. RESULTS: DMX3 was present in 58.4% of bipolar II, and 23.1% of unipolar patients. It was significantly associated with variables distinguishing bipolar from strictly defined unipolar disorders (younger age at onset, more MDE recurrence, more atypical features, more bipolar II family history). Unipolar DMX3 (MDE with documented hypomania solely intra-episodically) was not significantly different from bipolar II MDE on age at onset, atypical features, and bipolar II family history. CONCLUSIONS: Results support the inclusion of DMX3 (bipolar II and 'unipolar') into the bipolar spectrum. Adding the 23% of the UP-DMX3 to the roster of less-than-manic outpatient depressives will boost the rate of bipolarity in this outpatient depressive population to a respectable 70%, the highest rate yet reported for the bipolar spectrum below the threshold of mania.


Compr Psychiatry. 2001 Mar-Apr;42(2):139-43.


Major depressive episodes with hypomanic symptoms are common among depressed outpatients.

Benazzi F.

Department of Psychiatry, National Health Service (Azienda Unita Santaria Locale), Forli, Italy.

Depressive mixed states (major depressive episodes [MDE] with some hypomanic symptoms) are not classified in DSM-IV. The aim of the present study was to determine the prevalence of depressive mixed states in depressed outpatients, and to compare bipolar II with unipolar depressive mixed states. Seventy consecutive bipolar II and unipolar depressed outpatients were interviewed using the DSM-IV Structured Clinical Interview (SCID). At least one hypomanic symptom was present in 90% of patients, and three or more in 28.5%. Symptoms of depressive mixed states included irritable mood, distractibility, racing thoughts, and increased talking. Bipolar II subjects had more concurrent hypomanic symptoms (three or more in 48.7% v 3.2%, P = 0.000). Depressive mixed states with three or more hypomanic symptoms correctly classified 70.0% of bipolar II subjects. These findings have important treatment implications, as antidepressants may worsen the symptoms of depressive mixed states, and mood stabilizers can be useful. Copyright 2001 by W.B. Saunders Company


Eur Arch Psychiatry Clin Neurosci. 2004 Apr;254(2):69-75.


Is depressive mixed state a transition between depression and hypomania?

Benazzi F.

E. Hecker Outpatient Psychiatry Center, Ravenna, Italy,

BACKGROUND: Depressive mixed states (DMX), described systematically by Kraepelin, have recently been found common among depressed outpatients, with possible important impact on treatment. Study aim was to find if DMX in bipolar II disorder was often a transition period between depression and hypomania, as suggested by Kraepelin. METHODS: 194 consecutive bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV. Hypomanic symptoms during the index MDE were systematically assessed. DMX was defined as a MDE plus > 2 hypomanic symptoms appearing during the MDE (not before it), following Akiskal and Benazzi (2003). History of depression-hypomania cycles and vice versa (without symptom-free intervals) was assessed. If DMX were a transition period, cycles should have been more common in bipolar II with DMX than in bipolar II without DMX. To test if there were differences between DMX with history of cycles and DMX without history of cycles, the two subgroups were compared on many clinical, family history, and temperamental variables. To test if there were differences between bipolar II with DMX and bipolar II without DMX, comparisons between the two subgroups were done on variables often reported to be typically found in bipolar disorders and to be diagnostic validators (young onset, many recurrences, atypical features of depression, bipolar family history, temperamental mood lability, gender). RESULTS: DMX was present in 70.1%, and history of cycles in 79.8%. In bipolar II without index DMX (n = 58) history of cycles was present in 86.2%; in bipolar with index DMX (n = 136) history of cycles was present in 77.2% (p = 0.175). DMX with cycles was not significantly different from DMX without cycles on all study variables (apart from agitation). Bipolar II with index DMX, versus bipolar II MDE without index DMX, had significantly more depressions with atypical features, temperamental mood lability, and more females, while age of onset, recurrences, and bipolar family history were not significantly different. LIMITATIONS: Single interviewer, cross-sectional assessment. CONCLUSIONS: Findings do not support Kraepelin's view of DMX as a transition period between depression and hypomania, and a distinction between DMX with and without cycles. Findings only partly support DMX as a distinct subtype of bipolar II, which seems to require temperamental mood lability for its onset during a bipolar II MDE.


1: J Affect Disord. 2001 Dec;67(1-3):115-22.


Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes.

Benazzi F, Akiskal HS.

Department of Psychiatry, National Health Service, Forli, Italy.

BACKGROUND: Depressive mixed state (DMX), defined by hypomanic features during a major depressive episode (MDE) is under-researched. Accordingly, study aims were to find DMX prevalence in unipolar major depressive disorder (MDD) and bipolar II depressive phase, to delineate the most common hypomanic signs and symptoms during DMX, and to assess their sensitivity and specificity for the diagnosis of DMX and bipolar II. METHODS: 161 unipolar and bipolar II MDE psychotropic drug- and substance-free consecutive outpatients were interviewed during an MDE with the Structured Clinical Interview for DSM-IV. DMX was defined at two threshold levels as an MDE with two or more (DMX2), and with three or more (DMX3) simultaneous intra-episode hypomanic signs and symptoms. RESULTS: DMX2 was present in 73.1% of bipolar II, and in 42.1% of unipolar MDD (P<0.000); DMX3 was present in 46.3% of bipolar II, and in 7.8% of unipolar MDD (P<0.000). The most common hypomanic manifestations during MDE were irritability, distractibility, and racing thoughts. Irritability had the best combination of sensitivity and specificity for the diagnosis of DMX2 and DMX3. Various combinations of irritability, distractibility, and racing thoughts correctly classified the highest number of DMX2 and DMX3, and had the strongest predictive power. DMX2 had high sensitivity and low specificity for bipolar II, whereas DMX3 had low sensitivity (46.3%) and high specificity (92.1%). LIMITATIONS: Single interviewer, cross-sectional assessment, and interviewing clinician not blind to patients' unipolar vs. bipolar status. CONCLUSIONS: When conservatively defined (>or = 3 intra-episode hypomanic signs and symptoms during MDE), DMX is prevalent in the natural history of bipolar II but uncommon in unipolar MDD. These findings have treatment implications, because of growing concerns that antidepressants may worsen DMX, which in turn may respond better to mood stabilizers. These data also have methodological implications for diagnostic practice: rather than solely depending on the vagaries of the patient's memory for past hypomanic episodes, the search for hypomanic features--ostensibly elation would not be one of those--during an index depressive episode could enhance the detection of bipolar II in otherwise pseudo-unipolar patients. Strict adherence to current clinical diagnostic interview instruments (e.g. the SCID) would make such detection difficult, if not impossible.


Ann Clin Psychiatry. 2002 Jun;14(2):97-104.

Agitated depression: unipolar? Bipolar? Or both?

Benazzi F, Helmi S, Bland L.

Outpatient Psychiatry Center, University of California, San Diego, USA.

The classification of agitated depression (major depressive episode (MDE) plus psychomotor agitation) in mood disorders is unclear. DSM-IV is neutral on this point. As antidepressants may increase agitation, a better understanding of agitated depression is important for clinical practice. Study aim was to find if agitated depression was closer to bipolar or to unipolar disorders, by studying its association with variables typically related to bipolar disorders (early onset, many recurrences, more atypical features, more bipolar family history), and by studying its association with bipolar II disorder. Consecutive 151 unipolar and 226 bipolar II psychoactive drug-free MDE outpatients were interviewed with the Structured Clinical Interview for DSM-IV, when presenting for MDE treatment. Agitated MDE patients were compared with nonagitated MDE patients. Statistics were t test for means, two-sample test of proportion, and logistic regression (STATA 7). Agitated MDE was present in 85 patients (22.5%). It had significantly more bipolar II disorder patients (80.0% vs. 54.1%, p = 0.0000), more females, lower age at onset, longer duration of illness, more MDE recurrences, more atypical features, more MDE symptoms, and more family history of bipolar disorders, than nonagitated MDE. To control for the possible confounding effect of bipolar II disorder, logistic regression was used. All the significant differences became nonsignificant. Results might suggest that agitated MDE might be closer to the bipolar spectrum than to unipolar disorder, because it was associated with variables typically distinguishing bipolar from unipolar disorders, and with bipolar II disorder. Further studies on this topic are needed.


Eur Psychiatry. 2004 Apr;19(2):85-90.


Toward a validation of a new definition of agitated depression as a bipolar mixed state (mixed depression).

Benazzi F, Koukopoulos A, Akiskal HS.

Centro Lucio Bini, outpatient private practice, Rome, Italy.

PURPOSE: As psychotic agitated depression is now a well-described form of mixed state during the course of bipolar I disorder, we sought to investigate the diagnostic validity of a new definition for agitated (mixed) depression in bipolar II (BP-II) and major depressive disorder (MDD). MATERIALS AND METHODS: Three hundred and thirty six consecutive outpatients presenting with major depressive episodes (MDE) but without history of mania were evaluated with the Structured Clinical Interview for DSM-IV when presenting for the treatment of MDE. On the basis of history of hypomania they were assigned to BP-II (n = 206) vs. MDD (n = 130). All patients were also examined for hypomania during the current MDE. Mixed depression was operationally defined by the coexistence of a MDE and at least two of the following excitatory signs and symptoms as described by Koukopoulos and Koukopoulos (Koukopoulos A, Koukopoulos A. Agitated depression as a mixed state and the problem of melancholia. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:547-64): inner psychic tension (irritability), psychomotor agitation, and racing/crowded thoughts. The validity of mixed depression was investigated by documenting its association with BP-II disorder and with external variables distinguishing it from unipolar MDD (i.e., younger age at onset, greater recurrence, and family history of bipolar disorders). We analyzed the data with multivariate regression (STATA 7). RESULTS: MDE plus psychic tension (irritability) and agitation accounted for 15.4%, and MDE plus agitation and crowded thoughts for 15.1%. The highest rate of mixed depression (38.6%) was achieved with a definition combining MDE with psychic tension (irritability) and crowded thoughts: 23.0% of these belonged to MDD and 76.9% to BP-II. Moreover, any of these permutations of signs and symptoms defining mixed depression was significantly and strongly associated with external validators for bipolarity. The mixed irritable-agitated syndrome depression with racing-crowded thoughts was further characterized by distractibility (74-82%) and increased talkativeness (25-42%); of expansive behaviors from the criteria B list for hypomania, only risk taking occurred with some frequency (15-17%). CONCLUSIONS: These findings support the inclusion of outpatient-agitated depressions within the bipolar spectrum. Agitated depression is validated herein as a dysphorically excited form of melancholia, which should tip clinicians to think of such a patient belonging to or arising from a bipolar substrate. Our data support the Kraepelinian position on this matter, but regrettably this is contrary to current ICD-10 and DSM-IV conventions. Cross-sectional symptomatologic hints to bipolarity in this mixed/agitated depressive syndrome are virtually absent in that such patients do not appear to display the typical euphoric/expansive characteristics of hypomania-even though history of such behavior may be elicited by skillful interviewing for BP-II. We submit that the application of this diagnostic entity in outpatient practice would be of considerable clinical value, given the frequency with which these patients are encountered in such practice and the extent to which their misdiagnosis as unipolar MDD could lead to antidepressant monotherapy, thereby aggravating it in the absence of more appropriate treatment with mood stabilizers and/or atypical antipsychotics.


J Clin Psychiatry. 2004;65 Suppl 10:11-5.


Evaluation and management of breakthrough depressive episodes.

Keck PE.

Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio.

Clinicians are faced with a diagnostic challenge when a bipolar patient reports breakthrough depressive symptomatology. Breakthrough depressive symptoms during treatment for a bipolar depressive episode may be a manifestation of recurrent bipolar depression or the emergence of a mixed episode. Treatment of recurrent bipolar depression and mixed episodes differs considerably, and antidepressant therapy during a mixed episode can worsen the episode and initiate or exacerbate rapid cycling. Therefore, accurate diagnosis and appropriate treatment are imperative to achieving a positive outcome. Research indicates that optimizing the current mood stabilizer therapy or adding another mood stabilizer may be the best treatment options for patients with a history of rapid cycling-in patients without a history of rapid cycling, adding an antidepressant to a mood stabilizer may be less risky and therefore a reasonable choice. Combination therapy with a mood stabilizer and an atypical antipsychotic may also be effective in managing bipolar depressive episodes.


Bipolar Disord. 2004 Feb;6(1):75-81.


Short-term fluoxetine monotherapy for bipolar type II or bipolar NOS major depression - low manic switch rate.

Amsterdam JD, Shults J, Brunswick DJ, Hundert M.

Depression Research Unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

OBJECTIVES: Current guidelines for the initial treatment of bipolar type II (BP II) major depressive episode (MDE) recommend using either a mood stabilizer alone or a combination of a mood stabilizer plus a selective serotonin re-uptake inhibitor (SSRI). This recommendation is the result of concern over antidepressant-induced manic switch episodes. However, recent evidence suggests that the manic switch rate may be low in BP II MDE during SSRI therapy. METHODS: As part of a randomized, double-blind, placebo-controlled relapse-prevention study of fluoxetine monotherapy in BP II MDE, 37 patients received open-label fluoxetine 20 mg every day for up to 8 weeks. Outcome measures included the Hamilton Depression Rating (HAM-D 17) rating and the Young Mania Rating (YMR) scale. RESULTS: Eleven of 23 patients (48%) who completed 8 weeks of fluoxetine treatment showed a HAM-D 17 reduction of > or =50%, while 14 (38%) of all treated patients had > or =50% reduction in baseline HAM-D 17 score. Using a conservative YMR score of > or =8 to identify hypomanic symptoms, the frequency of patients with YMR score > or =8 during fluoxetine did not differ from that seen during the screen and baseline period. Only three patients (7.3%) had symptoms suggestive of hypomania, and only one patient stopped treatment because of a rapid mood swing into depression. LIMITATIONS: Fluoxetine was given at a fixed dose of 20 mg everyday. Fluoxetine was prescribed in an open-label manner, and the sample size was limited. CONCLUSIONS: These observations support the findings of a low manic switch rate during SSRI monotherapy of BP II MDE, and suggest that fluoxetine monotherapy may be a safe and effective initial treatment of BP II MDE.


J Affect Disord. 2003 Jan;73(1-2):99-104.


TEMPS-a scale in 'mixed' and 'pure' manic episodes: new data and methodological considerations on the relevance of joint anxious-depressive temperament traits.

Brieger P, Roettig S, Ehrt U, Wenzel A, Bloink R, Marneros A.

University Hospital for Psychiatry and Psychotherapy, Martin-Luther-University Halle-Wittenberg, 06097, Halle/Saale, Germany.

BACKGROUND: Temperament is an important factor in affective illness. There is some indication that mixed episodes result from an admixture of inverse temperamental factors (e.g. depressive and/or anxious) to a manic syndrome. To test this hypothesis, which has been first formulated by Akiskal [Clin. Neuropharmacol. 15 (Suppl. 1A) (1992) 632-633], we compared the temperament of non-acute bipolar affective patients with and without the history of a previous mixed episode. METHODS: Patients who had been hospitalized for a bipolar disorder were re-assessed at least 6 months after their last in-patient treatment. Those who met the criteria for a partially remitted or full affective or psychotic episode at re-assessment were excluded from the study. Data concerning illness history, current psychopathology (SCID-I interview), depression (BDI), mania (Self-Report Manic Inventory) and temperament (TEMPS-A scale) were obtained. Patients with and without a history of previous mixed episodes were compared. RESULTS: Of 49 eligible former patients, 22 subjects with and 23 subjects without a former mixed episode in bipolar affective disorder fulfilled the inclusion criteria. Subjects suffering from bipolar affective disorder exhibited significantly more depressive and anxious and less hyperthymic temperament, if they had experienced a mixed episode previously. Concerning cyclothymic and irritable temperament, bipolar affective patients with a former mixed episode presented non-significantly higher scores. Patients with a former mixed episode presented with higher depression scores than patients without such a history. No group differences were found concerning current mania scores. LIMITATIONS: (1). This is a preliminary report from an ongoing study. (2). Temperament had not been assessed premorbidly. (3). Although group comparisons revealed significant differences, these did not seem great enough to fully explain the emergence of a mixed episode. CONCLUSION: Our findings support the study's hypothesis that mixed episodes occur more often in subjects with an inverse temperament (e.g. depressive and anxious), although it cannot be ruled out that subsyndromal features of the bipolar illness had an effect on temperament assessment.


Int J Neuropsychopharmacol. 2003 Sep;6(3):285-91.


Recent placebo-controlled acute trials in bipolar depression: focus on methodology.

Muzina DJ, Calabrese JR.

Cleveland Clinic Foundation, Cleveland, Ohio, USA.

The completion of three recent large-scale, double-blind controlled acute trials in bipolar I depression has improved our understanding of the management of major depressive episodes associated with bipolar disorder. In contrast to the cross-over designs used in the early studies of lithium in bipolar depression, the designs utilized in these recent studies have employed random assignment to parallel arms including the use of placebo as a monotherapy in one study. The analyses of recent studies have all been conducted on intent-to-treat data, and included two types, change from baseline analyses and responder analyses. Lamotrigine monotherapy was shown to be superior to placebo with both types of analyses on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions (CGI) scales, but not the 17-item Hamilton Depression Rating Scale (HAMD) (n=195). The percentage of patients responding to placebo as a monotherapy were 29, 26 and 37%, respectively; there were no differences in switch rates (5% vs. 5%). Paroxetine augmentation was no better than placebo augmentation overall with both types analyses on the CGI and HAMD (n=117); the MADRS was not used. In patients with lithium levels </=0.8 mequiv./l, the change from baseline analysis showed paroxetine to be superior to placebo, but responder analyses were negative; switch rates with paroxetine, imipramine, and placebo were 0, 8 and 2%. Moclobemide monotherapy was similar in efficacy to imipramine (n=156), but had a lower rate of switching (4% vs. 11%).


Am J Psychiatry. 1999 Jul;156(7):1019-23.


Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.

Calabrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J, Keck PE Jr, Rhodes L, Bolden-Watson C, Zhou J, Ascher JA.

Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA.

OBJECTIVE: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy. METHOD: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states. RESULTS: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization. CONCLUSIONS: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.


Ann Pharmacother. 2001 Jan;35(1):45-7.


Treatment of bipolar depression with twice-weekly fluoxetine: management of antidepressant-induced mania.

Megna JL, Devitt PJ.

Department of Psychiatry, SUNY Upstate Medical University, 750 E. Adams St., Syracuse, NY 13210, USA.

OBJECTIVE: To report a case of treatment of bipolar depression and management of antidepressant-induced mania with a low-dose fluoxetine regimen. CASE SUMMARY: A 59-year-old white woman was admitted involuntarily to a New York State psychiatric center with a diagnosis of bipolar (type I) disorder, mixed, with psychotic features. Initial treatment with lithium, olanzapine, and clonazepam produced a remission of manic and psychotic symptoms. However, the patient remained clinically depressed. Addition of oral fluoxetine 10 mg every morning to her medication regimen was followed 22 days later by the development of a manic state. Reduction of the fluoxetine dosage to 10 mg twice weekly was associated with the attainment of euthymia in 18 days. Thirteen days after the fluoxetine dosage reduction, the patient's fluoxetine blood concentration was 20 micrograms/L and the norfluoxetine concentration was reported as 53 micrograms/L. DISCUSSION: To our knowledge, this is the first published case that describes the association between a low-dose fluoxetine regimen and the evolution of a bipolar affective state from depression to euthymia via manic switching. The temporal synchrony of this switching with initial implementation of fluoxetine 10 mg every morning, followed by a dose reduction to 10 mg twice weekly, suggests that bipolar depressed patients are extremely sensitive to low doses of antidepressants and to incremental changes in these doses. However, it also suggests that they can respond clinically to such treatment. Furthermore, our laboratory data indicate that antidepressant blood concentrations may play a contributory role in maintaining the balance between euthymia and mania in these patients. CONCLUSIONS: Manic switching is always a concern when treating a bipolar depressed patient. Utilization of a low-dose antidepressant drug regimen may be a clinically prudent approach in such an individual.


Arch Gen Psychiatry. 2003 Mar;60(3):261-9.


A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder.

Judd LL, Akiskal HS, Schettler PJ, Coryell W, Endicott J, Maser JD, Solomon DA, Leon AC, Keller MB.

Department of Psychiatry, University of California, San Diego, La Jolla 92093-0603, USA.

BACKGROUND: This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II). METHODS: Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. RESULTS: Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (> or =7 days) hypomanias were not significantly different on any measure. CONCLUSIONS: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process.


Strict criteria for mixed states in bipolar II not needed

Psychiatry Res 2004; 127: 247&#8211;257

Study findings suggest that a strict definition of depressive mixed states in bipolar II disorder, similar to the DSM-IV bipolar I mixed state criteria, is not warranted.

Franco Benazzi, from the National Health Service in Forli, Italy, found that "continuity and not discontinuity" characterized the current depressive mixed state definitions.

The researcher sought to test whether the definition of depressive mixed states in bipolar II disorder should require the satisfaction of full criteria for hypomania, or if only a few hypomanic symptoms should be necessary.

He used the Structured Clinical Interview for DSM-IV to assess 260 patients with bipolar II major depressive episode (MDE) for the presence of hypomanic symptoms.

These symptoms were then graded, and the following three definitions of depressed mixed state were compared: MDE plus full criteria for hypomania; MDE plus three or more hypomanic symptoms (DMX3); and MDE plus one or two hypomanic symptoms (DMX1-2).

The frequency of MDE plus full hypomania was 12.3%, that of DMX3 was 46.9%, and that of DMX1-2 was 38.8%.

The results showed that most variables reported to be signs of bimodality, and thus indicative of distinct disorders, such as young age of onset, many recurrences, atypical features of depression, and bipolar family history, did not differ significantly among the three groups.

"The findings do not support a categorical definition of bipolar II depressive mixed state&#8230; but are consistent with a dimensional definition of bipolar II depressive mixed state," Benazzi reports in the journal Psychiatry Research.

He adds that the low frequency of MDE plus full hypomania seen in this study suggests that this definition may not be warranted. Such a strict definition could prevent the identification of many bipolar II patients with a major depressive episode who have a few concurrent hypomanic symptoms.

"This might have effects on the treatment of depression, since clinical observations have found that antidepressants used without mood stabilisers may worsen depression mixed with manic or hypomanic symptoms," Benazzi notes.

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