Mixed Anxiety-Depression

1: J Affect Disord. 2004 Apr;79(1-3):235-9.

Mixed anxiety-depression in a 1 year follow-up study: shift to other diagnoses
or remission?

Barkow K, Heun R, Wittchen HU, Bedirhan Ustun T, Gansicke M, Maier W.

Department of Psychiatry, University of Bonn, Germany.

BACKGROUND: In 1992, the ICD-10 introduced the concept of mixed
anxiety-depression disorder (MAD). However, a study examining the stability of
this ICD-10-diagnosis is lacking. Our objective was to examine the 12 month
outcome of MAD in comparison to the outcome of depression, anxiety, and comorbid
depression and anxiety. METHODS: 85 MAD patients, 496 patients with major
depression, 296 patients with anxiety disorders, and 306 comorbid patients were
reassessed after 12 months. Rates of depression, anxiety, and MAD were compared
using chi(2)-tests. RESULTS: While depressive disorders and anxiety disorders
showed relatively high stability, MAD Patients had no higher rates of MAD at
follow-up than patients with depression, anxiety or both. LIMITATIONS: Detailed
information regarding treatment and disorders during the follow-up interval was
lacking. Prevalence rates of MAD in single centres were too small for
contrasting centres. CONCLUSIONS: MAD cannot be seen as a stable diagnosis: Most
of MAD patients remit; many of them shift to other diagnoses than depression or
anxiety. The ICD-10 criteria have to be specified more exactly.

PMID: 15023500 [PubMed – indexed for MEDLINE]


2: Int J Geriatr Psychiatry. 2003 Nov;18(11):994-1001.

Comment in:
Evid Based Ment Health. 2004 May;7(2):56.

Comorbidity and risk-patterns of depression, generalised anxiety disorder and
mixed anxiety-depression in later life: results from the AMSTEL study.

Schoevers RA, Beekman AT, Deeg DJ, Jonker C, van Tilburg W.

Department of Psychiatry, VU University Medical Centre, Amsterdam, The
Netherlands. robert.schoevers@mentrum.nl

BACKGROUND: Depression and generalised anxiety disorder frequently overlap. The
question remains unresolved whether these are specific disorders, or that they
represent different dimensions of a single disorder. Although both are highly
prevalent disorders in this age group, studies on this issue in the elderly are
scarce. Research is needed that investigates patterns of comorbidity and
possibly different risk profiles for pure depression, pure generalised anxiety
and mixed anxiety-depression in older people. METHODS: GMS-AGECAT diagnoses were
obtained from 4051 community living older persons. Comorbidity was studied along
a severity gradient for men and women separately. Multivariate analysis of risk
factors included demographic variables, environmental vulnerability,
longstanding vulnerability, physical/functional stresses and gender. RESULTS:
The prevalence of pure depression was 12.2%, pure generalised anxiety 2.9%,
mixed anxiety-depression 1.8%. Comorbidity increased with higher severity levels
of both depression and generalised anxiety. Comorbidity was twice as likely in
women than in men. Different risk profiles for diagnostic categories were not
demonstrated for concurrent risk factors. Longstanding vulnerability was
associated significantly stronger with mixed anxiety-depression than with pure
anxiety and pure depression. Mixed anxiety-depression was overrepresented in
women. CONCLUSIONS: Both lines of investigation suggest that, in the elderly, a
dimensional classification is more appropriate than a categorical classification
of depression and generalised anxiety. Mixed anxiety-depression is a more severe
form of psychopathology that is almost specific to women in this age group.
Copyright 2003 John Wiley & Sons, Ltd.

PMID: 14618550 [PubMed – indexed for MEDLINE]


3: J Affect Disord. 2003 Dec;77(3):213-25.

Implicit and explicit memory biases in mixed anxiety-depression.

Tarsia M, Power MJ, Sanavio E.

Department of Psychiatry, University of Edinburgh, Kennedy Tower, Royal
Edinburgh Hospital, Morningside Park, Edinburgh, EH10 5HF, UK.

BACKGROUND: This study investigated and compared implicit and explicit memory
biases in anxiety, depression and mixed anxiety-depression. METHOD: Outpatients
who were either depressed only (n=18), anxious only (n=18) or mixed (anxious and
depressed) (n=18) were compared to normal controls (n=18) on self-report
measures and typical experimental tasks assessing memory biases. The implicit
memory test was a word identification task and the explicit memory test was an
incidental free recall with depression relevant, anxiety relevant, emotional
positive and neutral words. RESULTS: The depressed group showed a positive
implicit memory bias and a mood-congruent bias at free recall. The anxious group
presented an overall higher priming effect in the implicit memory test, whilst
the mixed group exhibited no difference in the quantity of priming effect
compared to normal controls and recalled more anxious relevant words than other
word types. LIMITATIONS: Because of the dimensional perspective adopted in the
present study, the mixed group was composed of both DSM-IV sub-threshold (n=5)
and supra-threshold (n=13) patients. CONCLUSIONS: These results show a specific
pattern for the mixed group and suggest that mixed anxiety-depression represents
a distinct clinical group.

PMID: 14612221 [PubMed – indexed for MEDLINE]


4: Hum Psychopharmacol. 2001 Jan;16(S1):S21-S30.

Comorbidity and mixed anxiety-depressive disorder: clinical curiosity or
pathophysiological need?

Wittchen HU, Schuster P, Lieb R.

Max Planck Institute of Psychiatry, Clinical Psychology and Epidemiology,
Kraepelinstr. 10, 80804 Munich, Germany.

The paper reviews available epidemiological evidence for the existence of and
the implications of comorbidity of anxiety and depressive disorders and mixed
anxiety-depressive (MAD) disorders. Using epidemiolological evidence of
prevalence and incidence and data relating to time-course of illness, risk
factor and outcome, it is concluded: (1) that anxiety-depression comorbidity is
quite frequent in epidemiological and clinical settings throughout the world;
(2) this comorbidity is diagnosis-specific and is associated with increased
vulnerabilities and risks as well as poorer outcome and marked disabilities; and
(3) no such evidence was found for MAD disorders. Contrary to what was
predicted, the prevalence of MAD disorders was quite low even when using the
more recent criteria of the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition. (4) Furthermore, there was quite a heterogeneous pattern
in terms of risk, severity and outcome making it questionable whether this
disorder, as currently defined, is a clinical entity. These findings are
discussed in terms of two perspectives, the ‘lumpers’ with their dimensional
view and the ‘splitters’ with their categorical view. It is concluded that
although comorbidity of threshold anxiety and depressive disorders seems to be
an important phenomenon, no such evidence is provided for MAD disorders.
Copyright 2001 John Wiley & Sons, Ltd.

PMID: 12404532 [PubMed – as supplied by publisher]


5: Pharmacol Biochem Behav. 2002 May;72(1-2):131-41.

Behavioral effects of novel enterosorbent Noolit on mice with mixed
depression/anxiety-like state.

Borodin JI, Kudryavtseva NN, Tenditnik MV, Rachkovskaya LN, Shurlygina AV,
Trufakin VA.

Institute of Clinical and Experimental Lymphology, Siberian Division of the
Russian Academy of Medical Sciences, Novosibirsk, Russia.

The aim of this work was to examine the behavioral effects of a novel
lithium-based enterosorbent, Noolit (665 mg/kg), on male mice with mixed
depression/anxiety-like state evoked by exposure to repeated social defeats in
daily agonistic confrontations. The lithium component allows Noolit to be used
as a psychotropic drug. Two experiments are described, in which the therapeutic
and preventative effects of chronic Noolit treatment were examined. Response to
Noolit was assessed in the plus maze, open field, partition test, and Porsolt’s
test. In both experiments, Noolit produced obvious anxiolytic and antidepressant
effects. Treatment with Noolit fully restored some behavioral parameters in the
plus maze and open field in depressed mice and prevented depression that would
otherwise have developed. It has been suggested that enterosorbent Noolit can be
a potent drug for the treatment of mixed anxiety/depression pathologies and for
prevention of mood disorders.

PMID: 11900780 [PubMed – indexed for MEDLINE]


6: Eur Arch Psychiatry Clin Neurosci. 2001;251 Suppl 2:II53-6.

Prospective studies of cothymia (mixed anxiety-depression): how do they inform
clinical practice?

Tyrer P, Seivewright H, Simmonds S, Johnson T.

Paterson Centre, London, UK.

We suggest that the diagnosis of mixed anxiety depression at syndromal level
(i.e. both anxiety and depressive diagnoses present in the same person and given
equal status) is valuable clinically and should be introduced into the formal
classification of neurotic and mood disorders. Evidence is given from a
systematic review that cothymia has a significantly worse outcome than either an
anxiety or a depressive diagnosis alone (p < 0.0001). Long-term follow-up data
in a 12-year outcome study of neurotic disorder reinforce this finding both with
regard to social functioning and the clinical course of anxiety and depressive
disorders; these were significantly worse (P < 0.001 and P < 0.02 respectively)
in those with cothymia compared with single anxiety disorders. These outcome
differences are much greater than those between anxiety and depressive disorders

PMID: 11824837 [PubMed – indexed for MEDLINE]


7: Int Clin Psychopharmacol. 2000 Aug;15 Suppl 2:S41-5.

Selective serotonin reuptake inhibitors in mixed anxiety-depression.

Berk M.

Department of Psychiatry, University of the Witwatersrand Medical School,
Parktown, South Africa. 039berk@chiron.wits.ac.za

The overlap between the depressive and anxiety disorders is extremely common.
The introduction of the selective serotonin reuptake inhibitors (SSRIs) has,
more than any other development, bridged the gap in terms of efficacy in both
sets of disorders. A substantial body of data exists suggesting that the
available SSRIs have substantial efficacy in anxiety symptoms co-occurring with
depression. The clear utility of the SSRIs in disorders classified apart from
depression is also established. Whilst panic disorder is the best studied,
evidence on the efficacy of the SSRIs in disorders that previously did not
attract much pharmacotherapeutic interest, such as social anxiety disorder and
post-traumatic stress disorder is accumulating.

PMID: 11110018 [PubMed – indexed for MEDLINE]


8: J Affect Disord. 2000 Jul;59(1):67-9.

Sertraline in the treatment of mixed anxiety and depression disorder.

Carrasco JL, Diaz-Marsa M, Saiz-Ruiz J.

Department of Psychiatry, Hospital Fundacion Jimenez Diaz, Universidad Autonoma,
Av. Reyes Catolicos, 2, 28040, Madrid, Spain. jlcarrasco@fjd.es

BACKGROUND: Mixed anxiety and depression disorder (MAD) has been recognized in
ICD-10 as a diagnostic group including those anxious and depressed patients
which do not fit sufficient criteria for any major axis I disorders. MAD is
usually treated as a combination of anxiety and depression, although there are
data indicating that selective serotonin reuptake inhibitors (SSRIs) might be
active on both anxiety and depression. METHOD: 38 patients diagnosed of MAD
according to ICD-10 criteria were treated with flexible doses of sertraline for
8 weeks. Benzodiazepines were not allowed during the trial. Efficacy was
evaluated with the Clinical Global Impression (CGI) improvement scale and with
Hamilton’s depression and anxiety Scales. Personality scales, including the
Cloninger’s TCI and Eysenck’s EPQ, were used to test the predictive value of
personality traits in the response to treatment. RESULTS: Anxiety was reduced by
55% and depression by 60% in Hamilton scales. At week 8, 29 patients were
considered responders (CGI 1 o 2). Two patients discontinued the trial, only one
of them due to adverse events. The mean dose of sertraline was 83.4 mg/day.
CONCLUSION: Sertraline showed an excellent tolerability in patients with mixed
anxiety-depression disorder despite high levels of baseline anxiety. The
response level was high and similar to that reported for patients with major
depression. These results warrant further controlled trials to assess the
efficacy of SSRIs in MAD.

PMID: 10814773 [PubMed – indexed for MEDLINE]


9: Compr Psychiatry. 2000 Mar-Apr;41(2 Suppl 1):55-60.

Mixed anxiety-depression and its implications for models of mood and anxiety

Barlow DH, Campbell LA.

Center for Anxiety and Related Disorders, Boston University, MA 02215-2015, USA.

Recent findings have suggested that there is a distinct group of patients
presenting with subthreshold levels of mixed anxious and depressive symptoms
associated with significant functional impairment. Accumulating evidence of this
type ultimately led to a multisite field trial which investigated the
possibility of developing a new category of mixed anxiety-depression (MAD) for
the DSM-IV. The field trial confirmed both the existence and impairment of a
sizable group of patients with mixed subclinical anxious and depressive
symptoms, and provisional criteria for MAD were proposed. Although the validity
of the tentative MAD category has yet to be established, the unique
characteristics of patients presenting with MAD symptoms have important
implications for models of mood and anxiety disorders. We argue that the
particular pattern of impairment associated with MAD provides additional
evidence that anxiety and depressive disorders have a shared diathesis best
captured by the construct of nonspecific negative affect.

PMID: 10746905 [PubMed – indexed for MEDLINE]


10: J Abnorm Child Psychol. 1999 Jun;27(3):215-23.

Biases in visual attention in children and adolescents with clinical anxiety and
mixed anxiety-depression.

Taghavi MR, Neshat-Doost HT, Moradi AR, Yule W, Dalgleish T.

Shiraz University.

Recent research has indicated that anxious adult and child patients and high
trait-anxious adults selectively shift attention toward threatening stimuli. The
present study extends this research and investigates the content-specificity of
the effects in clinically anxious and mixed anxious-depressed children and
adolescents. Twenty four generally anxious patients, aged 9 to 18, 19 mixed
anxious-depressed patients, and 24 normal controls were comparable with respect
to age, sex, verbal IQ, and vocabulary level. The participants carried out an
attentional deployment task in which probe detection latency data were used to
determine the distribution of visual attention for threat-related and
depression-related material. The results showed that clinically anxious
children, relative to controls, selectively allocated processing resources
toward threat stimuli. However, mixed anxious-depressed children, relative to
controls, did not show any attentional bias towards either threat- or
depression-related stimuli. Preliminary data on age and gender differences are
also presented. The results of this study are discussed in the light of previous

PMID: 10438187 [PubMed – indexed for MEDLINE]


11: Aten Primaria. 1998 Jun 15;22(1):60.

[Prevalence of mixed anxiety-depression syndrome in those attending a care unit
at a health center] [Article in Spanish]

Torras Bernaldez MT, Bernat Lopez MJ, Garcia Curado A, Roig Grau I, Catala Magre

PMID: 9741162 [PubMed – indexed for MEDLINE]


12: Psychopharmacol Bull. 1998;34(2):225-7.

An open-label pilot study of fluvoxamine for mixed anxiety-depression.

Houck C.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at
Birmingham 35205, USA.

The syndrome of mixed anxiety and depression (MAD) has been described and is
familiar to both general psychiatrists and nonpsychiatrists. It was included in
the DSM-IV appendix as a syndrome proposed for further study. Fluvoxamine, a
selective serotonin reuptake inhibitor (SSRI) approved for the treatment of
obsessive-compulsive disorder, was studied for its effectiveness in treating
anxiety and depression simultaneously during an 8-week, open-label trial of
patients with MAD. Thirteen patients were included in the final,
intent-to-treat, analysis. Fluvoxamine showed moderately strong effectiveness in
improving anxiety and depression with a greater effect on the depressive
component. Nausea, insomnia, delayed ejaculation, and nervousness were the most
common side effects reported, with no serious adverse events occurring. Future
double-blind placebo-controlled studies will give more conclusive results.

PMID: 9641005 [PubMed – indexed for MEDLINE]


13: J Clin Psychiatry. 1997;58 Suppl 8:27-34.

Mixed anxiety and depression: from theory to practice.

Boulenger JP, Fournier M, Rosales D, Lavallee YJ.

Centre Universitaire de Sante de l’Estrie, Department of Psychiatry, Sherbrooke,
Quebec, Canada.

The 10th International Classification of Disease (ICD-10) introduced the concept
of mixed anxiety-depression to define patients presenting both anxiety and
depressive symptoms of limited number and/or intensity, not sufficiently severe
to fulfill criteria for a specific diagnosis of depressive or anxiety disorder.
Epidemiologic surveys have shown that these patients may display significant
levels of functional impairment, have unexplained somatic symptoms and a high
use of nonpsychiatric medical care, have long-lasting symptoms, and are at risk
for more severe psychiatric disorders. A DSM-IV field trial concluded that
patients with affective-symptoms not meeting thresholds for DSM-III-R disorders
were at least as common as patients with anxiety or mood disorders, and that
their symptoms were associated with significant distress or impairment. Although
some of these patients present residual symptoms from previous psychiatric
episodes and may request treatment specific to these conditions, it is not known
if those without a psychiatric history could benefit from pharmacologic or
psychological treatments usually used in mild outpatient cases.

PMID: 9236733 [PubMed – indexed for MEDLINE]


14: J Fam Pract. 1996 Dec;43(6 Suppl):S45-53.

Treating comorbid depression and anxiety.

Kuzel RJ.

Dakota Clinic at West Acres, Fargo, ND 58103, USA.

Depression and anxiety disorders are distinct illnesses that often coexist.
Patients suffering from both disorders have more psychological, physical, and
social impairment than do patients suffering from either illness alone. Mixed
anxiety-depression is gaining recognition as a separate diagnosis and has been
included in the International Classification of Diseases, 10th edition, and in
the appendix of the Diagnostic and Statistical Manual of Mental Disorders, 4th
edition. Current treatment recommendations for comorbid depression and anxiety
are based on clinical experience with the treatment of anxiety and depressive
disorders when they occur independently. Tricyclic antidepressants (TCAs),
monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake
inhibitors (SSRIs) have been shown to be effective for simultaneously occurring
anxiety and depression, but the side-effect profiles of the MAOIs and TCAs limit
their use for this condition. Benzodiazepines are useful for the acute treatment
of anxiety symptoms and buspirone for chronic generalized anxiety, but neither
agent is effective for the long-term treatment of depression. The recently
available antidepressants nefazodone and venlafaxine may also be useful for this
patient population. When possible, psychotherapy should be used in conjunction
with pharmacotherapy to improve treatment outcomes.

PMID: 8969712 [PubMed – indexed for MEDLINE]


15: J Clin Psychiatry. 1996;57 Suppl 7:86-91.

Generalized anxiety and mixed anxiety-depression: association with disability
and health care utilization.

Roy-Byrne PP.

Department of Psychiatry and Behavioral Sciences, University of Washington,
Harborview Medical Center, Seattle 98104, USA.

Generalized anxiety and mixed anxiety-depression have received less attention
than the major mood and anxiety disorders ith respect to their possible effects
in increasing disability and health care utilization. A review of recent
studies, however, indicates that these conditions are prevalent in primary care
medical settings and are associated with significant social and occupational
disability. Generalized anxiety disorder is also one of the most common
diagnoses seen in patients presenting with medically unexplained somatic
complaints such as chest pain, irritable bowel symptoms, and hyperventilation
and in patients prone to overutilize health care services in general. It is
poorly recognized by primary care physicians, possibly due to its chronicity,
which may limit the ability of symptoms to “stand out” and be easily detected.
However, it is disproportionately present in “high utilizer” samples found to be
particularly “frustrating” to their physicians and is accompanied by a high rate
of personality disorders, suggesting that maladaptive personality traits and
styles of interaction in such patients may also contribute to underrecognition
of symptoms by primary care physicians. These preliminary associations between
generalized anxiety disorder/mixed anxiety-depression and both disability and
increased health care utilization need to be confirmed with carefully designed
and controlled studies.

PMID: 8690701 [PubMed – indexed for MEDLINE]


16: J Affect Disord. 1995 May 17;34(2):79-84.

Mixed anxiety-depression in a primary-care clinic.

Stein MB, Kirk P, Prabhu V, Grott M, Terepa M.

Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg,

To determine the prevalence and clinical significance of a mixed
anxiety-depressive (MAD) syndrome in primary care, a two-stage sampling design
was applied to 796 consecutive clinic attendees without known psychiatric
illness. Among 78 systematically interviewed subjects, 10.3% (n = 8) had a
depressive disorder alone, 12.8% (n = 10) had an anxiety disorder alone, 19.2%
(n = 15) had a comorbid anxiety and depressive disorder and 12.8% (n = 10) had a
combination of subsyndromal anxiety and depressive features that fulfilled
either ICD-10 or our own operational criteria for MAD. Patients with MAD rated
their disability as being comparable to that of patients with anxiety or
depressive disorders. These findings lend support to the notion that there is a
sizeable subgroup of patients in primary care who appear to be suffering from a
psychiatric syndrome with an admixture of subsyndromal depressive and anxiety
features. Questions about the temporal stability of MAD and preferred approaches
to treatment have yet to be answered.

PMID: 7665808 [PubMed – indexed for MEDLINE]


17: Am J Med. 1995 Mar;98(3):278-84.

Diagnostic dilemmas presented by patients with anxiety and depression.

Goldberg RJ.

Department of Medicine, Brown University, Providence, Rhode Island.

Although anxiety and depression are among the most common symptoms of persons
seen in medical practice, a number of dilemmas still exist in the identification
and management of these disorders. The objectives of this paper are to review
the prevalence and identification of anxiety, depression, and mixed
anxiety-depression in medical practice; to review issues involving the medical
evaluation of these disorders; to clarify the relevance of psychosocial issues
to choice of treatment; and to review issues involving medication treatment

PMID: 7872345 [PubMed – indexed for MEDLINE]


18: J Gen Intern Med. 1994 Sep;9(9):507-12.

Comment in:
J Gen Intern Med. 1994 Sep;9(9):534-5.

Subsyndromal (“mixed”) anxiety–depression in primary care.

Roy-Byrne P, Katon W, Broadhead WE, Lepine JP, Richards J, Brantley PJ, Russo J,
Zinbarg R, Barlow D, Liebowitz M.

University of Washington School of Medicine, Seattle.

OBJECTIVE: To determine in primary care settings the prevalence, clinical
characteristics, and functional status of patients who have anxious and
depressive symptoms who did not meet diagnostic criteria for major mood and
anxiety diagnoses. DESIGN: Patients were screened with the General Health
Questionnaire and interviewed if they exceeded the cutoff score of 5. Also, one
patient whose score was below the cutoff was interviewed for every two patients
whose scores were above the cutoff. SETTING: Five primary care sites in the
United States, France, and Australia. PATIENT: Two hundred sixty-seven patients
presenting to their primary care physicians for general medical care and
follow-up. METHODS: Structured diagnostic interviews were conducted and ratings
of anxiety, depression, and functional impairment were obtained by trained
interviewers. RESULTS: After adjustments for sampling, 5% of the patients had
symptoms of anxiety, depression, and functional impairment, without meeting
formal criteria for a major DSM-III-R mood or anxiety disorder. This was
comparable to the prevalence of diagnosable DSM-III-R mood disorders but only
one-fourth the prevalence of diagnosable anxiety disorders. These patients who
had subsyndromal symptoms had rates of lifetime psychiatric disorders and prior
psychiatric treatment comparable to those of patients meeting criteria for major
mood and anxiety disorders. CONCLUSION: The comparable rates of symptomatic
distress, functional impairment, and prior psychiatric illness and treatment
suggest that patients with subsyndromal anxiety and depressive symptoms warrant
clinical recognition and possibly specific treatment.

PMID: 7996294 [PubMed – indexed for MEDLINE]


19: Am J Psychiatry. 1994 Aug;151(8):1153-62.

The DSM-IV field trial for mixed anxiety-depression.

Zinbarg RE, Barlow DH, Liebowitz M, Street L, Broadhead E, Katon W, Roy-Byrne P,
Lepine JP, Teherani M, Richards J, et al.

Phobia and Anxiety Disorders Clinic, University at Albany, State University of
New York, NY.

OBJECTIVE: This field trial was designed to answer four questions. First, are
patients presenting with anxious or depressed symptoms that are associated with
significant impairment but do not meet DSM-III-R definitional thresholds for
axis I anxiety or mood disorders? Second, is the impairment experienced by these
patients simply the consequence of the severity of their medical conditions?
Third, what percent of these patients present with depressive symptoms only,
anxious symptoms only, and a mixture of both? Fourth, how should the operational
criteria for the syndrome(s) presented by these patients be defined? METHOD: A
total of 666 patients from five primary care medical sites and two outpatient
mental health sites were administered a semistructured psychiatric interview.
RESULTS: Patients presenting with affective symptoms that did not meet
definitional thresholds for DSM-III-R axis I disorders were at least as common
as patients with several of the already established anxiety and mood disorders
in each of the seven sites, and their disorders were associated with significant
distress or impairment. A nonspecific pattern of anxious and depressed symptoms
was the modal presentation among these patients with currently subdefinitional
threshold disorders, and they could be significantly differentiated in terms of
current symptoms from patients presenting with a principal diagnosis of
generalized anxiety disorder, major depressive episode, or panic disorder with
agoraphobia. CONCLUSIONS: The authors recommend that a mixed anxiety-depression
category be included in the DSM-IV appendix for proposed diagnostic categories
that need further study. A criteria set is proposed.

PMID: 8037250 [PubMed – indexed for MEDLINE]


20: Arch Gen Psychiatry. 1993 Oct;50(10):759-66.

Outcome of depression and anxiety in primary care. A three-wave 3 1/2-year study
of psychopathology and disability.

Ormel J, Oldehinkel T, Brilman E, vanden Brink W.

Department of Psychiatry, University of Groningen, The Netherlands.

BACKGROUND: We evaluated the long-term outcome of depression and anxiety and
associated disability among primary-care attenders with common psychiatric
disorders and symptoms (n = 201) using binary and multicategorical,
interview-based outcome measures of psychiatric illness and disability. METHODS:
A two-stage design was used. In the first stage, 1994 consecutive attenders of
25 general practitioners were screened on psychiatric illness with the General
Health Questionnaire and by their physicians. A stratified random sample (n =
292) with differing probabilities was selected for second-stage interview
(Present State Examination and Groningen Disability Schedule). Patients with
psychiatric symptoms (n = 201) were reassessed 1 (n = 182) and 3 1/2 (n = 154)
years later. RESULTS: At 1- and 3 1/2-year follow-ups, many cases no longer met
the criteria of their baseline diagnosis and disability levels had substantially
dropped. However, partial remission, not full recovery, was the rule, and was
associated with residual disability. Depression had better outcomes than anxiety
and mixed anxiety-depression. CONCLUSIONS: We concluded that a multicategorical,
rather than a binary, outcome measure better reflects patient outcomes, since it
highlights partial remission, mild symptoms, and residual disability, and as
such, stresses the need to supplement short-term treatment. A multicategorical
caseness model may be advantageous for research and clinical practice. We
suggest a dynamic-equilibrium model to account for residual symptoms and
disability. This study is a follow-up to two earlier reports on the recognition,
treatment, and 1-year course of common psychiatric illnesses in general

PMID: 8215800 [PubMed – indexed for MEDLINE]


21: Compr Psychiatry. 1993 Sep-Oct;34(5):285-90.

Distinguishing mixed anxiety/depression from anxiety and depressive groups using
the family history method.

Reich J.

Department of Psychiatry, Brown University, Providence, RI.

The relationship between anxiety and depression has long been discussed and
studied. Although it appears that there are pure forms of these disorders,
several investigators have suggested that there is a separate combined
anxiety/depression disorder distinct from either individual disorder. Several
attempts have been made to investigate this distinction using family history
methods. This report compares an anxiety/depression group to a depression-only
group and anxiety-only group in a veteran population (n = 71) using the family
history method. The depression group was clearly differentiated from the
anxiety/depression group on the variables of generalized anxiety disorder and
alcohol abuse. There was also discrimination between the anxiety and
anxiety/depression groups on the DSM-III-R anxious personality disorder cluster.
This is the first report in this area of the literature to use standardized
family history methods that include personality disorder clusters.

PMID: 8306636 [PubMed – indexed for MEDLINE]


22: Encephale. 1993 Aug;19 Spec No 3:493-5.

Mixed anxiety depression. For and against.

Klein DF.

Columbia University, College of Physicians and Surgeons, New York, NY.

The subject of mixed anxiety depression has been the topic of a somewhat
confused discussion. At one point, it was held that anxiety and depression were
both manifestations of an underlying affective disorder, but systematic work by
Martin Roth and others clearly demonstrated that anxiety disorders could be
separated from depressive disorders via a multivariate scale. Interestingly,
spontaneous panic attacks were among the highest loading items on this scale.
Nonetheless, it was plain that many patients were simultaneously anxious and
depressed. Interest then grew in understanding the evolution of these syndromes
over time. In general, anxiety syndromes antecede depressive syndromes, although
there are many exceptions. For instance, some people only develop panic attacks
when in the midst of a depressive episode. To attempt to understand these
complexities, detailed family studies have been attempted with often
contradictory results. We shall present family study data indicating that
patients with comorbid panic disorder and depression have different familial
patterns from those with panic disorder alone. In addition, a practical question
is whether there exist patients, primarily in private settings, who present with
symptoms of anxiety and depression but do not meet full criteria for any of the
currently defined syndromes. Such patients are often referred to as subsyndromal
or subthreshold patients. Epidemiological data indicates that such patients
exist and that their symptomatology is associated with social and functional
impairment. Recently the DSM IV field trial has specifically addressed this
issue by clinical investigations of primary care and psychiatric facilities.
These results will be reported.

PMID: 8299549 [PubMed – indexed for MEDLINE]


23: Encephale. 1993 Jul;19 Spec No 2:397-404.

[Comorbidity of anxiety-depression and its treatment] [Article in French]

Guelfi JD.

Clinique des Maladies Mentales et de l’Encephale (CMME), Service du Pr
Samuel-Lajeunesse, Paris.

The comorbidity of anxiety/depression, or the co-occurrence of anxious and
depressive symptoms is an heterogenous concept. There is comorbidity when a
whole anxious syndrome and a whole depressive syndrome last during a period of
life. The association of minor anxious and depressive disorders in a same
patient during a certain period of time is the definition of mixed anxious and
depressive disorder. The comorbidity of generalized anxiety disorder and
dysthymia is more frequent than each of these two disorders separately
considered. The interpretation of comorbidity needs cautiousness. The results
are very different if one considers only the actual disorders or the occurrence
on the whole period of life. The longitudinal epidemiological studies as the
ones made by Angst and by Wittchen demonstrate that most of the patients with an
anxious disorder become depressive. A third of these patients are cured and one
third to one quarter of them evaluate toward chronicisation. There are many
common features between the chronic depressions, the classical neurotic
depression and the general neurotic syndrome defined by Tyrer. If the presence
of minor mixed symptoms, anxious and depressive, is a clinical reality, to
isolate a “anxiodepressive” syndrome may lead to create a miscellaneous
category, which could cause an excess of drug prescription. The reactivity of
mixed syndromes, anxious and depressive, seems distinct from the one of anxious
disorders and of pure depressive syndromes.

PMID: 7904238 [PubMed – indexed for MEDLINE]


24: J Consult Clin Psychol. 1993 Jun;61(3):412-20.

Efficacy and specific effects data on new treatments: a case study strategy with
mixed anxiety-depression.

Moras K, Telfer LA, Barlow DH.

Department of Psychiatry, University of Pennsylvania Medical School,
Philadelphia 19104-2648.

The case study research strategy presented here can be used to develop new
psychotherapeutic treatments, test theorized mechanisms of action, and obtain
initial outcome data of the type needed to support treatment outcome grant
applications. The strategy is illustrated by 2 case studies of a new
psychotherapeutic intervention for patients with coexisting generalized anxiety
disorder and major depression as described in the Diagnostic and Statistical
Manual of Mental Disorders (3rd ed., rev; American Psychiatric Association,
1987). The treatment is a modification and integration of existing treatments
for panic disorder (Barlow & Craske, 1989) and for major depression (Klerman,
Weissman, Rounsaville, & Chevron, 1984).

PMID: 8326041 [PubMed – indexed for MEDLINE]


25: J Clin Psychiatry. 1993 Jan;54 Suppl:9-15.

Comorbidity and mixed anxiety-depressive disorders: is there epidemiologic

Wittchen HU, Essau CA.

Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.

Recent epidemiologic studies (i.e., studies conducted since 1980) have
consistently demonstrated, on the basis of standardized diagnostic assessments,
that there is a substantial overlap between different types of anxiety and
depressive disorders. The current literature, however, discusses this issue
primarily within the concept of comorbidity and there are some controversies
about the existence of a separate disorder of mixed anxiety-depression (MAD).
MAD can be defined by the presence of mixed symptoms of depression and anxiety
that are below the diagnostic threshold for either one of these diagnoses. Since
MAD has not been included in any of the current official classification systems,
its prevalence, risk factors, course, and outcome have not been studied
specifically in any of the recent epidemiologic studies even though MAD is
thought to be very important, especially in primary care settings. This paper
reviews recent epidemiologic studies and presents data from the Munich Follow-Up
Study, which has found a prevalence of about 1% for MAD as defined by the
ICD-10. Despite the lack of clear diagnostic criteria for MAD, there are some
indications that: (1) this disorder might be frequent in primary care settings,
and (2) patients with MAD frequently demonstrate subjective suffering, show
impairment in personal and occupational functioning, and have high health
service utilization rates. Current empirical evidence is still insufficient for
deciding a suitable classificatory solution for this problem.

PMID: 8425875 [PubMed – indexed for MEDLINE]


26: J Clin Psychiatry. 1993 Jan;54 Suppl:33-8.

Mixed anxiety and depression: clinical implications.

Stahl SM.

Department of Psychiatry, University of California, San Diego.

Although depressive and anxious symptoms frequently coexist, clinical studies
have tended to separate anxiety disorders from depression. A number of
developments are now reversing this trend. One of these developments is the
reworking of the concept of generalized anxiety disorder (GAD) from that of a
residual category (anxiety after all other anxiety disorders are removed) to a
generalized anxiety syndrome that includes symptoms of mild depression that are
less severe than the symptoms of anxiety. GAD is thereby expanded to a broader
concept, namely mixed anxiety/depression (MAD). A second major development,
however, posits a different definition of MAD: a stable core of subsyndromal
symptoms that do not reach the threshold for the diagnosis of GAD or depression,
but which, under stress, will decompensate to an overt anxiety disorder or

PMID: 8425874 [PubMed – indexed for MEDLINE]


27: J Clin Psychiatry. 1993 Jan;54 Suppl:20-3.

The treatment of generalized anxiety disorder in patients with depressive

Rickels K, Schweizer E.

Department of Psychiatry, University of Pennsylvania, Philadelphia 19104-2649.

Concomitant depressive symptoms occur in at least 50% of patients with a primary
diagnosis of generalized anxiety disorder (GAD). The authors review the
treatment implications of the presence of concomitant depressive symptoms. First
considered is the extent to which traditional benzodiazepines, because of their
suggested depressogenic liability, are indicated or contraindicated for such
patients and the possible differential therapeutic advantage of
triazolobenzodiazepines, which have shown preliminary antidepressant effect.
Second, the role of tricyclic antidepressants in the treatment of GAD is
reviewed. A large body of literature, mostly from the 1970s, has found benefit
for the tricyclics in mixed anxiety-depression. Two studies published in the
1980s found that patients suffering from a primary anxiety diagnosis but with
subsyndromic levels of depression benefited from treatment with tricyclic
antidepressants. The authors also review the role of the azapirones, most
notably buspirone, in the treatment of GAD complicated by depressive symptoms.
Evidence for its efficacy in this population comes from both retrospective
analysis of previous GAD treatment studies, as well as a recent prospective
study of depression with concomitant GAD.

PMID: 8093885 [PubMed – indexed for MEDLINE]


28: J Abnorm Psychol. 1991 Aug;100(3):337-45.

Mixed anxiety and depression.

Katon W, Roy-Byrne PP.

Department of Psychiatry and Behavioral Sciences, University of Washington,
Seattle 98195.

We review evidence from community, primary care, and psychiatric samples to
determine whether there are a group of patients who have mixed symptoms of
anxiety and depression that are below diagnostic thresholds for either group of
disorders. A review of the data strongly suggests that such a group of patients
exists and that, despite lacking sufficient symptoms to meet diagnostic
thresholds from the revised 3rd edition of the Diagnostic and Statistical Manual
of Mental Disorders (American Psychiatric Association, 1987), they often have
significant impairment in social and vocational functioning. Because many of
these patients also suffer from medically unexplained somatic symptoms, they may
be more likely to frequently use nonpsychiatric medical care. Longitudinal
studies suggest that persons with mixed anxiety-depression symptoms may
represent a population who are at increased risk for more severe mood and
anxiety disorders.

PMID: 1918612 [PubMed – indexed for MEDLINE]


29: J Abnorm Psychol. 1991 Aug;100(3):316-36.

Tripartite model of anxiety and depression: psychometric evidence and taxonomic

Clark LA, Watson D.

Department of Psychology, Southern Methodist University, Dallas, Texas

We review psychometric and other evidence relevant to mixed anxiety-depression.
Properties of anxiety and depression measures, including the convergent and
discriminant validity of self- and clinical ratings, and interrater reliability,
are examined in patient and normal samples. Results suggest that anxiety and
depression can be reliably and validly assessed; moreover, although these
disorders share a substantial component of general affective distress, they can
be differentiated on the basis of factors specific to each syndrome. We also
review evidence for these specific factors, examining the influence of context
and scale content on ratings, factor analytic studies, and the role of low
positive affect in depression. With these data, we argue for a tripartite
structure consisting of general distress, physiological hyperarousal (specific
anxiety), and anhedonia (specific depression), and we propose a diagnosis of
mixed anxiety-depression.

PMID: 1918611 [PubMed – indexed for MEDLINE]


30: J Clin Psychiatry. 1991 Jun;52 Suppl:48-54.

Coexisting depression and anxiety: special diagnostic and treatment issues.

Lydiard RB.

Institute of Psychiatry, Medical University of South Carolina, Charleston 29425.

Anxiety and depression often coexist in the clinical setting. Using panic
disorder as an example, the author presents an overview of the prevalence,
familial aspects, and long- and short-term outcomes of such comorbid disorders.
Evidence regarding the diagnostic category of mixed anxiety-depression is also
reviewed. On the basis of the limited available data, the author advances
possible treatment strategies for treating patients with comorbid depression and
anxiety disorders. Combined pharmacologic therapies may be indicated to optimize
treatment for some patients. The review underscores the need for treatment
studies in patients with depression and coexisting anxiety.

PMID: 2050649 [PubMed – indexed for MEDLINE]


31: Acta Psychiatr Scand. 1990 Jun;81(6):518-22.

Parental representation in patients with major depression, anxiety disorder and
mixed conditions.

Alnaes R, Torgersen S.

Department of Psychiatry, University of Oslo, Norway.

Differences in parental bonding between patients with pure major depression,
mixed anxiety-depression and pure anxiety disorders were investigated in 272
consecutive outpatients. A low parental care score seemed to be the best
discriminating variable between the mixed group and the 3 other groups. This
study supports previous family and twin studies as well as clinical studies
emphasizing the mixed group as a special disorder group, possibly with a
different etiology. The role of the father in child development seems to be
particularly important.

PMID: 2378242 [PubMed – indexed for MEDLINE]


32: Acta Psychiatr Scand. 1985 Jul;72(1):81-8.

Separate and combined anxiolytic and anti-depressant treatment of mixed
anxiety/depression. A double-blind, placebo controlled comparison. Sussex
Clinical Trials Group.

[No authors listed]

233 patients attending their general practitioners for mixed anxiety/depressive
states were treated on a double-blind random allocation basis with one tablet to
be taken three times daily, containing either 0.5 mg fluphenazine, 10 mg
nortriptyline, a combination of 0.5 mg fluphenazine and 10 mg nortriptyline
(Motival), or placebo. After 7 and 28 days’ treatment, the combination product
was found to be statistically superior to each of its active ingredients alone,
as well as to placebo, with respect to anxiety, depression and non-specific
symptoms. Side effects were not a clinical problem and occurred with similar
frequency in each treatment group. The superiority of Motival over each of its
constituents is in keeping with previous studies showing advantages of the
combination of fluphenazine and nortriptyline over anxiolytic and
anti-depressant drugs on their own.
PMID: 2863922 [PubMed – indexed for MEDLINE]


33: Psychopathology. 1984;17(1):37-48.

Anxiety and depression in affective disorders.

Strian F, Klicpera C.

Anxiety and depression were assessed with self-rating and observer-rating scales
on admission and at discharge in 414 inpatients with endogenous or neurotic
depression, anxiety neurosis or phobic disorders. The results were compared with
findings in a reference group of 2,493 inpatients with a wide range of
psychiatric disorders and a representative sample of the general population
consisting of 1,952 persons. On admission the patients with anxiety neurosis and
all of those with depressive disorders were significantly more anxious than the
psychiatric reference group, whereas the phobic patients were only slightly more
anxious. As was to be expected, the depressive groups showed the greatest
depressivity, whereas the group with anxiety neurosis differed only slightly
from the psychiatric reference group and the patients with phobias were actually
below this reference group. During the treatment period there was a marked
decrease in anxiety among the depressive patients but not in those with anxiety
neurosis. The decrease in depressivity in the neurotic depressive patients was
much less than in those with endogenous depression. Mixed anxiety depression was
found with about the same frequency in both the neurotic and the endogenous
depression groups. In general, anxiety and depressivity decreased over the
treatment period, with persistence greatest in the anxiety neurosis group. On
admission there was a more pronounced connection between anxiety and psychomotor
agitation, on discharge between anxiety and psychomotor retardation.

PMID: 6701261 [PubMed – indexed for MEDLINE]


34: Acta Psychiatr Belg. 1984;84:533-40.

[Differential diagnosis of anxiety states and depressive syndromes] [Article in French]

Verhoeven WM.

Recently the diagnosis and pharmacotherapy of the mixed anxiety-depression
syndrome has gained new interest by the development and introduction of
classification systems and second generation antidepressants respectively. In
this article the terminology, diagnosis and pharmacotherapy of the mixed
anxiety-depression syndrome is mentioned.

PMID: 6528820 [PubMed – indexed for MEDLINE]


35: J Clin Psychiatry. 1979 Apr;40(4):165-70.

A double-blind comparative study of desipramine hydrochloride and diazepam in
the control of mixed anxiety/depression symptomatology.

Kleber RJ.

The comparative therapeutic effects of desipramine hydrochloride and diazepam on
the various symptoms of depression and anxiety were evaluated in a double-blind,
parallel 4 week study of 53 psychoneurotic outpatients who manifested
moderate-to-severe depression and anxiety. The median daily dose for the
desipramine treated group was 150 mg; for the diazepam treated group, 20 mg.
Patients who received desipramine scored significantly better than diazepam
treated patients on 26 of the total of 51 variables derived from The Hamilton
Psychiatric Rating Scale for Depression, The Hamilton Psychiatric Rating Scale
for Anxiety, and 2 clinical global impressions. Patients who received diazepam
scored significantly better on 1 variable, an item pertaining to sleep.

PMID: 370109 [PubMed – indexed for MEDLINE]