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Saturday, June 14, 2003
"The Complexity of Co-morbidity in Bipolar
Disorder"
Chair: Giovanni Cassano, M.D.
Video | Audio
(Length: 2 min.)
Psychiatric Comorbidity in Bipolar Disorder
Video | Audio
(Length: 14 min.)
Leonardo Tondo, M.D.
Bibliography
L. Tondo1, C. Ghiani2
1Harvard Medical School, Boston, MA, USA; 2University
of Cagliari, Cagliari, Italy
Comorbidity is a term coined by Feinstein in 1970 (1) and
indicates an additional clinical entity to the one under study. In psychiatry,
the concept is not fully accepted, (2-5) is not cited in the DSM-IV, and not
used by NIMH, which prefers the word co-occurrence (6). More than a semantic
dispute, the controversial issues concern whether the co-presence of symptoms or
syndromes are sufficient for the definition of comorbidity or they could just be
secondary, or even a simple feature of another disorder. For instance, the
presence of anxiety or depressive symptoms can be the consequence, or an aspect
of a more severe disorder. Nevertheless, comorbidity has become a rather popular
expression used to define co-occurrence in the same patient with two disorders
usually from the Axes I and II of the DSM-IV but belonging to two different
diagnostic categories, e.g., Mood Disorders, Anxiety disorders,
Substance-related Disorders, or Personality Disorders. Comorbidity can be
evaluated as the contemporary presence of symptoms belonging to different
psychiatric disorders, or to the presence of these disorders at different times
during the course of the disorder, with the early one usually being less severe
than the second. By extension, the term comorbidity may also be applied to
family studies in which the disorders are present in different members of the
families (7). In bipolar disorders the most common co-occurring illnesses are
substance abuse disorders. It is estimated that 40-60 percent of patients with
bipolar disorder have substance-related problems (8, 9). This type of
comorbidity may result from the self-medication of mood disorder symptoms; mood
symptoms induced by substance abuse or vice versa; and risk factors that may
influence the occurrence of both disorders (10). The co-occurrence of any
anxiety disorder and bipolar disorder may vary from 21%, as reported in a review
of 11 studies, (11) to 42% (9). It is likely that effective and prolonged
treatment of an anxiety disorder may induce a bipolar disorder but the extent of
this phenomenon has not been fully studied. Bipolar disorder may also co-occur
with eating disorders to a lesser extent (about 5%; 9), or with Attention
Deficit and Hyperactivity Disorder (12). The studies on the comorbidity of
psychiatric disorders are relevant because the comorbid symdromes tend to have a
worse prognosis, to respond to a less extent to the usual psychotropic
treatments, and to show a poorer compliance to treatments. Better understanding
of the relationship between substance abuse and bipolar disorder will help
improve both treatment and preventive interventions.
References:
1. Feinstein AR. The pre-therapeutic classification of comorbidity in chronic
disease. J Chron Dis 1970;23:455-468.
2. Winokur G. The concept of secondary depression and its
relationship to comorbidity. Psychiatr Clin North Am 1990;13(4):567-583.
3. Wittchen HU. Critical issues in the evaluation of
comorbidity of psychiatric disorders. Brit J Psychiatry 1996;168(30 Suppl):9s-16s.
4. Van Praag HM. Comorbidity (Psycho) Analysed. Brit J
Psychiatry 1996;168(30 Suppl):129s-34s.
5. Zimmerman M & Mattia JI. Psychiatric diagnosis in clinical
practice: is comorbidity being missed? Compr Psychiatry 1999;40(3):182-191.
6. Bipolar Disorder Research at the National Institute of
Mental Health.
http://www.nimh.nih.gov/publicat/bipolarresfact.cfm
7. MacKinnon DF, McMahon FJ, Simpson SG, McInnis MG, DePaulo
JR. Panic disorder with familial bipolar disorder. Biol Psychiatry
1997;42(2):90-95.
8. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL,
Goodwin FK. Comorbidity of mental disorders with alcohol and other drug abuse:
Results from the Epidemiologic Catchment Area (ECA) study. JAMA
1990;264(19):2511-2518.
9. McElroy SL, Altshuler LL, Suppes T, Keck PE Jr, Frye MA,
Denicoff KD, Nolen WA, Kupka RW, Leverich GS, Rochussen JR, Rush AJ, Post RM.
Axis I psychiatric comorbidity and its relationship to historical illness
variables in 288 patients with bipolar disorder. Am J Psychiatry
2001;158(3):420-4269.
10. Winokur G, Coryell W, Akiskal HS, Maser JD, Keller MB,
Endicott J, Mueller T. Alcoholism in manic-depressive (bipolar) illness:
Familial illness, course of illness, and the primary-secondary distinction. Am J
Psychiatry 1995;152: 365-372.
11. Tondo L, Lai M, Salvatore P. I disturbi d’Ansia e la
comorbidità con i disturbi bipolari dell’umore. In: Altamura CA (ed.): I
Disturbi d’Ansia e la Comorbidità con i Disturbi dell’Umore: Clinica e
Trattamento. In press.
12. Sachs GS, Baldassano CF, Truman CJ, Guille C. Comorbidity
of attention deficit disorder with early- and late-onset bipolar disorder. Am J
Psychiatry 2000;157:466-468.
Comorbid Bipolar Disorder and Panic Disorder:
A Genetically Distinct Subtype of Bipolar Disorder?
Video | Audio
(Length: 12 min.)
Alessandro Rotondo, M.D.
Bibliography
A. Rotondo, L. Dell’Osso, M. Carlini, C. Gonnelli, S. Bouanani,
L. Pardini, C.M. Mazzanti, G.B. Cassano
University of Pisa, Pisa, Italy
Genetic-epidemiologic data and even some linkage data suggest a shared
genetic vulnerability between bipolar disorder (BD)and panic disorder (PD). We
have hypothesized that, by defining a genetic subtype of BD, comorbidity with PD
may influence the strength of the association between BD and candidate genes.
Therefore, we have carried out a case-control association study of BD patients
with (BDPD) or without (BDNPD) lifetime PD. As disturbance in CNS monoamine
neurotransmission is of relevance in BD, we have analyzed polymorphic markers at
Catechol-O-methyltransferase (COMT), tryptophan hydroxylase (TPH) and serotonin
transporter (5-HTT) genes which are involved in monoamine neurotransmission.
Unrelated subjects of Italian descent meeting DSM-IV criteria for life-time BD
(131) with (57) or without (74) comorbid PD and 147 healthy controls were
included in the study. DNA was extracted from blood leukocytes. COMT
Val>Met, 5-HTTLPR and TPH IVS7+779C>A polymorphisms were analyzed as previously
reported. Statistical comparisons were carried out using the chi-square
test. A logistic regression modeling strategy was used to determine the strength
of the relationship between gene polymorphisms and BD with or without PD after
adjusting for the effect of potentially confounding variables. As compared
to controls, a significant increase in the frequency of COMT Met/Met and
5-HTTLPR SS genotypes and respective alleles was detected in BDNPD, but not in
BDPD. TPH IVS7+218A alleles and genotypes approached statistical significance.
The odds ratio of BDNPD being associated with COMT Met/Met (but not with
5-HTTLPR SS or TPH IVS7+218AA) relative to BDPD reached statistical
significance. No other potentially confounding variables (gender, age at onset
of BD, diagnoses comorbid with BD other than PD, suicidality, and presence of
psychotic symptoms) were significant factors in the logistic regression model.
Our findings support the hypothesis that comorbid PD is a specific marker for a
genetic subtype of BD.
Somatic Comorbidity: New Insights into the Link
between the Thyroid System and Bipolar Disorder
Video | Audio
(Length: 12 min.)
Bruno Müller-Oerlinghausen, Dr.med.
Bibliography
B. Müller-Oerlinghausen, M. Bauer
Freie Universitaat Berlin, Berlin, Germany
Somatic comorbidity, i.e. the simultaneous occurrence of somatic disorders or
dysfunctions such as migraine (1, 2) or overweight and diabetes (3-5) is
observed in patients with affective disorders in general and also in bipolar
disorders. It could possibly explain part of their excess cardiovascular
mortality (6-7) and might also be related to endocrinological dysfunctions.
Of all the endocrine systems thought to be linked to the pathophysiology of
bipolar disorder, the hypothalamic-pituitary-thyroid (HPT) system is the prime
candidate. Indices of disturbed peripheral thyroid metabolism are present in
many patients with bipolar disorder and thyroid hormone supplementation is
widely accepted as an effective treatment enhancement. However, there is an
ongoing debate as to whether patients with bipolar disorder are predisposed to
thyroid axis abnormalities and whether administration of thyroid hormone is
beneficial for the course of the illness. The goal of this paper is to review
existing knowledge and recent research data 1) on the relationship between the
thyroid system and bipolar disorder, and 2) on the therapeutic effects of
thyroid hormone in bipolar disorder. Although most patients with bipolar
disorder do not have overt biochemical evidence of hypothyroidism, they do share
numerous clinical stigmata with the manifest endocrine disorder. The detected
endocrine abnormalities in the HPT system in primary affective illness, e.g., an
abnormal TSH response to TRH stimulation, are more subtle and findings are
contradictory in some instances. Abnormalities in thyroid function are of
particular importance in the clinical course of patients with the rapid cycling
variant of bipolar disorder. They have a much higher incidence (about 25%) of
grade II hypothyroidism (defined as increased serum basal TSH with a normal
serum T4 level) than depressed patients in general (2%–5%) or those taking
lithium carbonate (10%). There is growing evidence that thyroid measures
in the low normal range or below the normal range (thyroid hypofunction) may be
especially relevant to the pathophysiology of bipolar disorder and may result in
a less than optimal outcome (8). A study by Cole et al. (9) provided evidence
that patients with bipolar disorder are particularly sensitive to variations in
thyroid function within the normal range. Lower free thyroxine index (FTI)
values and higher TSH values within the normal range were significantly
associated with a poorer treatment response in bipolar patients during the acute
depressed phase. The evaluation of thyroid indices in lithium-maintained
patients with mood disorders has shown an association between decreased serum T3
levels and recurrences (10). A low level of free T4 was also associated with
more affective episodes and greater severity of depression during prophylactic
lithium treatment in patients with bipolar disorder (11). Thus, it appears that
higher free T4 and higher T3 levels are advantageous for long-term lithium
treatment, a finding that would be consistent with the efficacy of treatment
with supraphysiological T4, as this intervention significantly increases the
free T4 and T3 levels. Since Prange's classic triiodothyronine (T3)
acceleration studies in the late 1960s, a series of open and controlled clinical
trials have confirmed the adjunctive therapeutic value of thyroid hormones in
mood disorders. Thyroid hormone supplementation is now widely accepted as an
effective treatment enhancement, especially for patients with refractory
affective disorders (12). There is good evidence that T3 can accelerate the
antidepressant response to tricylic antidepressants, and some studies suggest
that T3 may augment the therapeutic response to tricyclic drugs in refractory
depressed patients, although the latter reports provide inconsistent results. In
a series of open-label studies, it has been shown that adjunctive
supraphysiological doses of levothyroxine (T4) improve the course of illness in
bipolar and unipolar patients, especially in women refractory to standard mood
stabilizers (13-15). Data also suggest that augmentation with supraphysiological
doses of T4 may have immediate therapeutic value in antidepressant-resistant
bipolar and unipolar depressed patients (16). In these studies, a substantial
number of severely ill and refractory resistant patients experienced remission
from affective symptomatology during treatment, and additional research
including a placebo group is under way by an international multicenter study
funded by the Stanley Medical Research Institute. In conclusion, the
evaluation of thyroid status is of vital concern for the treatment plan of
bipolar patients. As we strive to learn more about the association of thyroid
dysfunction with mood, the additional therapy of bipolar disorders with thyroid
hormones will remain a valuable strategy for patients with refractory affective
illness.
References
1. Merikangas KR, Angst J, Isler H (1990)
Migraine and psychopathology. Arch Gen Psychiatry 47:849-853.
2. Breslau N, Merikangas KR, Bowden CL
(1994) Comorbidity of migraine and major affective disorders. Neurology 44 (suppl.
7):S17-S22.
3. Cassidy F, Ahearn E, Carroll BJ (1999)
Elevated frequency of diabetes mellitus in hospitalized manic-depressive
patients. Am J Psychiatry 156:1417-1420.
4. Fagiolini A, Frank E, Houck PR,
Mallinger AG, Swartz HA, Buysse DJ, Ombao H, Kupfer DJ (2002) Prevalence of
obesity and weight change during treatment in patients with bipolar I disorder.
J Clin Psychiatry 63:528-533.
5. McElroy SL, Frye MA, Suppes T, Dhavale
D, Keck PE Jr, Leverich GS, Altshuler L, Denicoff KD, Nolen WA, Kupka R, Grunze
H, Walden J, Post RM (2002) Correlates of overweight and obesity in 644 patients
with bipolar disorder. J Clin Psychiatry 63:207-213.
6. Weeke A, Juel K, Vaeth M (1987)
Cardiovascular death and manic-depressive psychosis. J Affect Disord 13:287-292.
7. Angst F, Stassen HH, Clayton PJ, Angst J
(2002) Mortality of patients with mood disorders: follow-up over 34-38 years. J
Affect Disord 68:167-181.
8. Gyulai L, Bauer M, Bauer MS,
García-España F, Cnaan A, Whybrow PC (2003) Thyroid hypofunction in patients
with rapid cycling bipolar disorder after lithium challenge. Biol Psychiatry, in
press.
9. Cole DP, Thase ME, Mallinger AG, Soares
JC, Luther JF, Kupfer DJ, Frank E (2002) Slower treatment response in bipolar
depression predicted by lower pretreatment thyroid function. Am J Psychiatry
159:116-121.
10. Baumgartner A, von Stuckrad M, Müller-Oerlinghausen B, Gräf KJ, Kürten
I (1995) The hypothalamic-pituitary-thyroid axis in patients maintained on
lithium prophylaxis for years: high triiodothyronine serum concentrations are
correlated to the prophylactic efficacy. J Affect Disord 34:211-218.
11. Frye MA, Denicoff KD, Bryan AL,
Smith-Jackson EE, Ali SO, Luckenbaugh D, Leverich GS, Post RM (1999) Association
between lower serum free T4 and greater mood instability and depression in
lithium-maintained bipolar patients. Am J Psychiatry 156:1909-1914.
12. Bauer M, Whybrow PC (2001) Thyroid
hormone, neural tissue and mood modulation. World J Biol Psychiatr 2:57-67.
13. Bauer MS, Whybrow PC (1990) Rapid cycling bipolar affective disorder.
II. Treatment of refractory rapid cycling with high-dose levothyroxine: a
preliminary study. Arch Gen Psychiatr 47:435-440.
14. Müller-Oerlinghausen B (2002)
Supraphysiological doses of L-thyroxine in the maintenance treatment of
prophylaxis-resistant affective disorders. Neuropsychopharmacology 27:620-628.
15. Bauer M, Priebe S, Berghöfer A, Bschor
T, Kiesslinger K, Whybrow PC (2001) Subjective response to and tolerability of
long-term supraphysiological doses of levothyroxine in refractory mood
disorders. J Affect Disord 64:35-42.
16. Bauer M, Hellweg R, Gräf KJ, Baumgartner A (1998) Treatment of
refractory depression with high-dose thyroxine. Neuropsychopharmacology
18:444-455.
Questions:
The Complexity of Co-morbidity in Bipolar Disorder
Audio
(Length: 11 min.)
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