1
Neurotoxicity Research (accepted 05.01.06)
IMPORTANCE OF CLINICAL DIAGNOSES FOR COMORBIDITY STUDIES IN
SUBSTANCE USE DISORDERS
Marta Torrens, M.D, Ph.D. and Rocío Martin-Santos, M.D, Ph.D.
Drug Abuse Unit, Institut d’Atenció Psiquiàtrica (IAPS), Hospital del Mar,
Universitat Autònoma Barcelona, Passeig Marítim 25−29, E-08003-Barcelona,
Spain (e-mail: mtorrens@imas.imim.es)
2
ABSTRACT
Many clinical and epidemiologic studies have shown a high frequency of cooccurrence of substance abuse and psychiatric disorders, with important
consequences from health and social perspective. However, the identification of
reliable and valid diagnosis of psychiatric co morbidity in substance abusers is
problematic, mainly because the acute or chronic effects of substance abuse
can mimic symptoms of many other mental disorders, making difficult to
differentiate psychiatric symptoms that represent effects of acute or chronic
substance use or withdrawal, of those that represent an independent disorder.
While DSM-IIII-R and earlier nomenclatures were unclear in differentiating
independent from other psychiatric disorders, DSM-IV and DSM-IV-TR provided
clearer guidelines in diagnosing psychiatric disorders in heavy users of alcohol
and drugs, providing three categories: “primary” psychiatric disorders,
“substance-induced” disorders, and “expected effects” of the substances,
meaning expected intoxication and/or withdrawal symptoms that should not be
diagnosed as symptoms of a psychiatric disorder. The use of the “Psychiatric
Research Interview for Substance and Mental Disorders (PRISM)”, a structured
interview developed to improve the diagnosis of co morbidity in drug abusers
according DSM-IV, supplies new opportunities in the clinical research in this
field.
Key words: dual diagnosis, psychiatric comorbidity, structured interview, PRISM
3
INTRODUCTION
The high frequency of co-occurrence of substance abuse and other psychiatric
disorders documented in different clinical and epidemiologic studies is a matter
of great concern because of its relevant diagnostic and therapeutic implications.
This co-occurrence, also known as ‘psychiatric comorbidity in drug abusers’ or
‘dual diagnosis’ has been associated with poor outcome of subjects affected. In
comparison with patients with a single disorder, dually-diagnosed patients show
a higher psychopathological severity, more emergency admissions (Curran et
al., 2003; Martín-Santos et al., 2006), significantly increased rates of psychiatric
hospitalization (Lambert et al., 2003), and a higher prevalence of suicide
(Oyefeso et al., 1999; Appleby, 2000; Aharonovich et al., 2002). In addition,
comorbid drug abusers show an increased rate of risk behaviors and related
infections, such as HIV and hepatitis C and B virus infection (King et al., 2000;
Carey et al., 2001; Rosenberg et al., 2001) as well as psychosocial
impairments, such as higher unemployment and homelessness rates (Caton et
al., 1994; Vazquez et al., 1997), and a great amount of violent or criminal
behavior (Abram and Teplin, 1991; Cuffel et al., 1994;). Although convincing
evidence supports a strong association between a variety of psychiatric
disorders and substance use disorders, the nature of this relationship is
complex and may vary depending on each particular disorder. The
neurobiological mechanisms and substrates involved in the co-occurrence of
addiction and other psychiatric disorder are currently a priority area of research.
Two main hypothesis explains comorbidity: 1) addiction and other psychiatric
disorders are different symptomatic expressions of similar preexisting
neurobiological abnormalities, and 2) repeated drug administration, through
4
neuroadaptation, leads to biological changes that have common elements with
abnormalities
mediating
certain
psychiatric
disorders.
Recently,
the
neurobiological effects of chronic stress as the bridging construct between
psychiatric and substance use disorders constitutes a promising area of
research (Brady and Sinha, 2005). In spite of the relevance of providing
effective treatment for dual diagnosis, previous studies have reported many
difficulties and poor outcome when treating patients with co-occurrence of
substance abuse and other psychiatric disorders. In fact, current data from
randomized controlled studies, in the treatment of major depression in
substance abuser patients (one of the most frequent of co-occurring disorders
in this population) show a poor efficacy of antidepressant drugs (Nunes and
Levin 2004; Torrens et al., 2005). Accordingly, the study of factors related to the
neurobiological
mechanisms
involved
in
the
dual
diagnosis
and
the
development of effective treatments has major clinical implications (O’Brien et
al., 2004).
But in the core of such research remains an important issue, that is, the
methodological difficulties in diagnosing comorbid psychiatric disorders in a
substance abuser population, suggesting the crucial role of diagnostic accuracy
in the selection of participants both for neurobiological studies and for controlled
clinical trials aimed to assess the efficacy of different therapeutic interventions.
The identification of valid and reliable instruments to establish a definite
diagnosis of comorbid psychiatric disorders in substance abusers has long been
regarded as problematic. In this report, we summarize the methodologic
problems and evolution of diagnostic concepts in psychiatric comorbidity in
substance abuse. The characteristics of the different diagnostic instruments
5
available, particularly the Psychiatric Research lnterview for Substance and
Mental Disorders for DSM-IV (PRISM-IV) (Hasin et al., 2001) are also
commented on.
IDENTIFICATION
OF
PSYCHIATRIC
COMORBIDITY
IN
SUBSTANCE
ABUSERS: DIAGNOSTIC CONCEPTS AND INSTRUMENTS
The clinical identification of psychiatric comorbidity in substance abusers
constitutes a challenge for both medical care and research in dual diagnosis. A
major problem is to establish an accurate diagnosis that has two main
difficulties. Firstly, acute or chronic effects of substance abuse can mimic
symptoms of many other mental disorders making it difficult to differentiate
psychiatric symptoms that represent an independent (primary) disorder from
symptoms of acute or chronic substance use or withdrawal. Secondly,
psychiatric diagnoses are syndromes rather than diseases with known
pathophysiology and associated biological markers. This lack of biological
markers has forced psychiatrists to develop operative diagnostic criteria,
including the Diagnostic and Statistical Manual of Mental Disorders [DSM] and
the International Classification of Diseases Diagnostic Criteria [ICD], and to
design structured clinical diagnostic interviews to improve the validity and
reliability of diagnoses. The use of standard criteria based on directly
observable behavioral symptoms and the incorporation of these into structured
interviews, maximizes the extent to which the same information is elicited and
applied to the same criteria to achieve diagnosis. In this section, a summary of
the evolution of the diagnostic concepts on comorbidity and the characteristics
of the currently available structured diagnostic instruments is presented.
6
Evolution of the diagnostic concepts on comorbidity
Historically, most diagnostic criteria used for diagnosing psychiatric disorders
offered little specific guidance for determining the presence of other cooccurring psychiatric diagnosis from the clinical records of patients affected by
substance use disorders. The approaches to diagnosis of co-morbid psychiatric
disorders among substance abuser patients evolved from the simple one in
Feighner criteria which distinguished between “primary” and “secondary”
disorders according to age at onset of each disorder, being the disorder
diagnosed at the earliest age that named “primary” (Feighner et al., 1972). This
distinction is not useful to differentiate whether the second disorder is
independent from the first or to assess the relationship between both conditions.
Psychiatric disorders tend to have characteristic ages of onset, for example,
conduct disorders begin in childhood, substance use disorders in early to mild
adolescence, and mood disorders in adolescence and adulthood. Therefore,
according to the natural history, antisocial personality disorder would be
considered “primary disorder” and mood disorder “secondary disorder”.
Later, Research Diagnostic Criteria (RDC) (Spitzer et al., 1978), DSM-III
(American Psychiatric Association [APA, 1980) and DSM-III-R (APA, 1987)
used the concept of "organic" vs. “nonorganic” disorders, more theoretically
based, but poorly defined and put into operation. In these classification
systems, subjects in whom organic factors may play a significant role in the
development of the psychiatric disturbance were not considered as having an
independent psychiatric disorder. However, specific criteria for distinguishing
organic from non-organic disorders were not provided, leaving the differentiation
7
process unclear. Because alcohol and drug abuse has shown an increase
among patients with psychiatric disorders, this lack of specificity became
increasingly problematic. DSM-III and DSM-III-R similarly defined “organic”
etiology. A psychiatric syndrome was considered as nonorganic if it could not be
established that an organic factor initiated and maintained the disturbance. As
in RDC, specific criteria for this decision were not provided, leaving room for
discrepant approaches.
Then it is not surprising that the studies using RDC, DSM-III and DSM-IIIR criteria even using structured diagnostic instruments, such as the Schedule
for Affective Disorders and Schizophrenia—Lifetime Version (SADS) (Endicott
and Spitzer, 1978) and the Structured Clinical Interview for DSM-III-R (SCID)
(Spitzer et al., 1992), showed poor reliability (Rounsaville et al., 1991; Bryant et
al., 1992; Williams et al., 1992; Ross et al., 1995) and validity (Kadden et al.,
1995;
Kranzler et al., 1996; 1997) for psychiatric diagnoses in substance
abusers. In addition, a poor agreement seen among groups even when using
the same measures was observed (Weiss et al., 1992).
In response to the increasing recognition of the relevance of comorbid
psychiatric disorders in drug users, both DSM-IV (APA, 1994) and ICD-10
(World Health Organization, 1993) emphasized more the clarification of the
diagnoses of psychiatric disorders in heavy users of alcohol and drugs.
DSM-IV, DSM-IV-TR
The DSM-IV (APA, 1994) placed more emphasis on comorbidity, replacing the
dichotomous terms “organic” vs. “nonorganic” to distinguish three categories:
“primary” psychiatric disorders, “substance-induced” disorders and “expected
8
effects” of the substances, meaning expected intoxication and/or withdrawal
symptoms that should not be diagnosed as symptoms of a psychiatric disorder.
DSM-IV-Text Revision (APA, 2000) provides more specific guidelines for
establishing this differentiation.
A “primary” disorder is diagnosed if symptoms are not due to the direct
physiological effects of a substance. To classify a disorder as “substanceinduced”, a primary classification must be first ruled out. There are four
conditions under which an episode that co-occurs with substance intoxication or
withdrawal can be considered primary: 1) when symptoms are substantially in
excess of what would be expected given the type or the amount of the
substance used or the duration of use; 2) a history of non-substance-related
episodes; 3) the onset of symptoms precedes the onset of the substance use;
and 4) the symptoms persist for a substantial period of time (i.e., at least a
month) after the cessation of intoxication or acute withdrawal. If neither
“primary” nor “substance-induced” criteria are met, then the syndrome is
considered to represent intoxication or withdrawal effects of alcohol or drugs.
A “substance-induced” disorder is diagnosed when DSM-IV symptom
criteria for the disorder are fulfilled; the episode occurs entirely during a period
of heavy substance use or within the first 4 weeks after cessation of use; the
substance used is “relevant” to the disorder (i.e., its effects can cause
symptoms mimicking the disorder being assessed); and the symptoms are
greater than the expected effects of intoxication and/or withdrawal.
The “expected effects” are the predicted physiological effects of
substance abuse and dependence. They are reflected in the substance specific
symptoms of intoxication and withdrawal syndromes for each main category of
9
substances. The expected effects can appear to be identical to the symptoms of
primary mental disorders (e.g., insomnia, hallucinations).
ICD-10
The ICD-10 provides specific criteria to differentiate between primary disorders
and disorders resulting from psychoactive substance use, but only for psychotic
disorders. As in DSM-IV, ICD-10 excludes psychotic episodes attributed to
psychoactive substance use from a primary classification. In ICD-10, psychosis
can be attributed to psychoactive substance use under three conditions: 1) the
onset of symptoms must occur during or within 2 weeks of substance use; 2)
the psychotic symptoms must persist for more than 48 h; and 3) the duration of
the disorder must not exceed 6 months. A psychotic disorder attributed to
psychoactive
use
can
be
specified
as
predominantly
depressive
or
predominantly manic. However, unlike DSM-IV, ICD-10 does not provide a
separate psychoactive substance- related category for any other type of
psychiatric disorder. By definition, ICD-10 “organic mental disorder” excludes
alcohol or other psychoactive substance-related disorders. ICD-10 organic
mood disorder and organic delusional disorder cannot be used to diagnose
episodes co-occurring with heavy psychoactive substance use. Furthermore,
the DSM-IV concept of symptoms that are greater than the expected effects of
intoxication and withdrawal is not included in ICD-10.
Structured diagnostic instruments
Different interviews for psychiatric diagnosis based on DSM-IV or ICD-10
criteria are available for clinical and research studies, including the Structured
10
Clinical Interview for DSM-IV Axis I Disorders (SCID-I) (First et al., 1997), The
Schedule for Clinical Assessment in Neuropsychiatry (SCAN) (Janca et al.,
1994), The Composite International Diagnostic Interview (CIDI) (WHO, 1998),
and the Psychiatric Research lnterview for Substance and Mental Disorders for
DSM-IV (PRISM-IV) (Hasin et al., 2001). Other instruments designed for
epidemiological surveys like “Alcohol Use Disorders and Associated Disabilities
Interview Schedule-DSM-IV version” (AUDADIS) (Grant et al., 2001) are not
included in this review.
SCID-IV
The SCID-IV is a semi-structured interview that allows diagnosis of primary or
substance-induced disorders but provides no more specific guidelines than
stated in the criteria. The differentiation of “primary” and “substance induced”
disorder is made on a syndrome level in the SCID. The interviewer assesses
the substance etiology in a two step process, as shown for example in the
section on depression. In the SCID Depression module, DSM criteria and a list
of “etiological substances” are provided. The subject is asked if she/he has
been drinking or using street drugs before the episode. Based on the subject’s
response, the interviewer decides if there is a possibility of ruling out a
diagnosis of primary depression. If so, the interviewer skips to a series of
questions about the temporal relationship of the mood symptoms and
substance use and if the mood symptoms were greater than the expected
effects of the substance used. Because the SCID relies on the interviewer’s
clinical judgment, the SCID assessment of substance etiology can be
problematic. First, the question about the relevant extent of the subject’s
11
substance use will often yield information that is open to interpretation. Second,
the “primary” vs. “substance-induced” differentiation is established on the level
of syndromes and specific guidelines for differentiating from the expected
effects of intoxication or withdrawal are not provided. Finally, questions to
assess the temporal relationship of the episode and substance use are
unstructured, potentially causing unclear or inaccurate information. At the
present time, reliability data for the SCID-IV in substance abusing samples are
not available. The data of validity will be reported later in this review.
SCAN
The SCAN is a set of instruments for assessing a range of clinical phenomena.
A core instrument of the SCAN is the Present State Examination (PSE-10). The
PSE covers “present state”, the month before the examination, and “lifetime
before”. PSE ratings are coded on score sheets and based on these ratings, a
computer program generates ICD-10 and DSM-IV diagnoses. The PSE is a
semi-structured clinical examination in which the interviewer uses clinical
judgment to ascribe specified definitions to clinical phenomena using the SCAN
Glossary. The Glossary is a list of definitions of clinical symptoms and
experiences. The interviewer questions the subject in detail, matches responses
to a description in the Glossary, and then decides if a symptom is present, and
if so, how severe. After the subject’s report of a symptom, the interviewer
matches it to a Glossary definition, and codes an attributional rating scale for
the item. Alcohol and other psychoactive substances are among the available
attribution choices, like “known primary intracranial process”, non-psychiatric
medication, and toxins. The decision to assign attribution to a psychoactive
12
substance rests on the clinician’s judgment based on information taken from the
interview. The SCAN does not provide specific guidelines for differentiating
between substance-related and independent disorders. As far as we are aware,
data on the SCAN reliability or validity of psychiatric diagnosis in substance
abusers are not available.
CIDI
The CIDI is a fully structured interview designed for survey interviewers who
read the questions as written without interpretation (Robins et al., 1988). For the
primary–substance-induced differentiation, the CIDI relies largely on the
subject’s opinion. The DSM-IV concept of “expected effects” of intoxication or
withdrawal vs. symptoms greater than these effects is not addressed in the
CIDI. The CIDI generates ICD-10 and DSM-IV diagnoses. In the CIDI,
symptoms attributed to alcohol, drugs, or physical illness are eliminated for
consideration when making the psychiatric diagnoses. This symptom-level
evaluation represents a departure from earlier procedures. Generally, the
presence of substance-related factors is evaluated for the entire period of
disorder once it has been established, rather than on a symptom-by-symptom
basis before determining if any episode of the disorder has occurred.
In a preliminary study, we performed a validation study of the Spanish
version of the screening section of the CIDI to detect psychiatric comorbidity
according DSM-IV criteria (Astals et al., 2001). A total of 175 opioid dependent
subjects were assessed with the screening section of CIDI and, in a blind
fashion, by an independent researcher using the PRISM. The results obtained
13
indicate a high sensitivity in most of the psychiatric co-morbid diagnoses, but a
low specificity in many of them, as is shown in Table 1, suggesting the need to
improve the specificity of the instrument to detect psychiatric disorders in
substance abusers.
PRISM-IV
The PRISM was designed to improve the reliability problems in the diagnosis of
comorbid psychiatric disorders in substance-abusing samples. The PRISM was
initially developed and tested for DSM-III-R criteria and used many aspects of
the SCID as a starting point (Hasin et al., 1996). Three important characteristics
of the PRISM that are specific to comorbidity are as follows: 1) adding specific
rating guidelines throughout the interview, including frequency and duration
requirements for symptoms, explicit exclusion criteria, and decision rules for
frequent sources of uncertainty; 2) positioning of the alcohol and drug sections
of the PRISM near the beginning of the interview, before the mental disorder
sections, so that the history of alcohol and drug use is available at the time of
beginning the assessment of mental disorders; and 3) more structured alcohol
and drug histories to provide a context for assessing comorbid psychiatric
disorders. The first version of PRISM, based on DSM-III-R criteria, showed
good to excellent reliability for many diagnoses, including affective disorders,
substance use disorders, eating disorders, some anxiety disorders, and
psychotic symptoms (Hasin et al., 1996). To address the changes in DSM-IV,
the PRISM was updated and revised to provide diagnoses of primary and
substance-induced disorders and to include the expected effects of intoxication
or withdrawal. In addition, the revised version of the PRISM provides a method
14
for operationalizing the term “in excess of” the expected effects of substance in
chronic substance abusers (Hasin et al., 1998). This interview includes the
following disorders: 1) substance use disorders: substance abuse and
dependence for alcohol, cannabis, hallucinogens, licit and illicit opiates, and
stimulants; 2) primary affective disorders, including major depression, manic
episode (and bipolar I disorder), psychotic mood disorder, hypomanic episode
(and bipolar II disorder), dysthymia, and cyclothymic disorder; 3) primary
anxiety disorders, including panic, simple phobia, social phobia, agoraphobia,
obsessive-compulsive disorder, generalized anxiety disorder, and posttraumatic
stress disorder; 4) primary psychotic disorders, including schizophrenia,
schizoaffective disorder, schizophreniform disorder, delusional disorder, and
psychotic disorder not otherwise specified; 5) eating disorders, including
anorexia, bulimia, and binge-eating disorder; 6) personality disorders, including
antisocial and borderline personality
disorders; and 7) substance-induced
disorders, including major depression, mania, dysthymia, psychosis, panic
disorder, and generalized anxiety disorder.
A validity study comparing diagnoses obtained through the PRISM-IV
and SCID-IV in 105 substance abuser patients from substance/dual diagnosis
unit, using the LEAD procedure (Longitudinal, Expert, All Data; Spitzer,1983),
as a “gold standard” has been reported (Torrens et al., 2004). In the absence of
a biological marker as a “gold standard”, the LEAD procedure is conceived as a
standard for validating psychiatric diagnoses (Spitzer, 1983). The LEAD
procedure has been employed as a criterion for the assessment of the
procedural validity of diagnostic instruments. To develop the LEAD diagnoses,
the expert uses all the longitudinal information available for the individual
15
subject, including previous and current clinical evaluations, opinions of other
professionals, laboratory results, and data collected from relatives. The
reliability and validity of the LEAD procedure for diagnosing some psychiatric
comorbidity have been questioned in previous studies (Kranzler et al., 1994;
1997). However, the fact that in these studies the criteria used were DSM-III-R,
with the difficulties mentioned above and, in the absence of a better measure,
LEAD procedure continues being the best method available.
In this study the agreement between the LEAD procedure and the
PRISM in current major depression, past substance-induced depression, and
borderline personality disorder was better than that obtained between the LEAD
procedure and the SCID. Table 2 shows the diagnostic concordance, assessed
by kappa statistics, of current non-substance use DSM-IV diagnoses with
PRISM-IV, SCID-IV, and LEAD.
Recently reliability information in substance abusing samples has been
provided for PRISM-IV (Hasin et al., 2006). In a test-retest reliability study of
DSM-IV diagnoses obtained by PRISM in 285 substance abusing patients from
substance/dual diagnosis and mental health settings, kappas for primary and
substance-induced major depression, psychotic disorders, antisocial and
borderline personality disorders ranged good to excellent, as is shown in Table
3. reliability for most anxiety disorders was lower.
Summarizing, in the last years an effort has been done o improve the
identification of co-occurrence of other psychiatric disorders in substance
abuser subjects in a reliable and valid manner. Currently, most DSM-IV
psychiatric disorders can be assessed in substance-abusing subjects with
acceptable to excellent reliability and validity by using specifically the PRISM.
16
CONCLUSIONS
The co-occurrence of substance abuse and psychiatric disorders is an
important area of research because to the important consequences from a
health and social viewpoint, but also it provides an opportunity to study in depth
the underlying mechanisms in both substance use disorders and non-substance
use disorders, involving genetic mediators and/or neurobiological substrates,
and in the development of specific therapeutics strategies. However, rigorous
phenotypic assessment is essential for all studies on co-morbidity, because
poor or inadequate phenotypic assessment lead to incorrect results. In this
respect, the use of a clinical instrument, such as PRISM, which allows
diagnosing most of comorbid psychiatric disorders in substance abusers in a
reliable and valid manner, offers a useful tool for further comorbidity studies.
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25
Table 1.- Sensitivity and specificity of the diagnoses obtained by means of the screenCIDI in respect to diagnoses obtained with the PRISM in a sample of 175 opioid
dependent patients.
Disorders (DSM-IV)
Sensitivity
Specificity
(%)
(%)
Affective
100
11
Psychosis
50
74
Panic
100
26
Social Phobia
78
66
Specific Phobia
100
32
26
Table 2.- Diagnostic Concordance of Current DSM-IV Diagnoses with PRISM-IV, SCIDIV, and LEAD (n=105) (Modified of Torrens et al, 2004)
Disorder
Current diagnoses
Concordance (kappa and 95% CI)
PRISM-IV vs LEAD
SCID-IV vs LEAD
Kappa (95% CI)
Kappa (95% CI)
Affective
.68 (0.47-0.89)*
.28 (0.07-0.49)
.33 (0.07-0.59)
.29 (0-0.63)
.56 (0.38-0.74)*
.37 (0.18-0.56)
.53 (0.35-0.71)*
.36 (0.18-0.54)
-
-
.85 (0.64-1)*
.33 (0.02-0.60)
.81 (0.61-1)
.76 (0.54-0.98)
.67 (0.49-0.85)
.58 (0.37-0.79)
.66 (0.43-0.89)
.40 (0.07-0.73)
.63 (0.38-0.88)*
.32 (0-0.64)
Major depression
Induced depression
Any Depression
(Major & Induced)
Any affective diagnosis
Psychotic
Induced psychosis
Any psychotic diagnosis
Anxiety
Panic with/without
agoraphobia
Any anxiety diagnosis
Personality
Antisocial
Borderline
* p< 0.05
27
Table 3.- Diagnostic reliability of Current DSM-IV Diagnoses with PRISM-IV (n=285)
(modified of Hasin et al, 2006)
Kappa (SE)
Prevalence
time1/time2
.75 (0.06)
0.12/0.10
.66 (0.09)
0.08/0.05
.69 (0.06)
0.20/0.15
.36 (0.12
0.05/0.04
Disorder
Affective
Major Depression, Primary
Major Depression, Induced
Any Major Depression, Primary or Induced
Any Dysthymia, Primary or Induced
1.00
Mania, Induced
.67 (0.32)
0.004/0.01
.86 (0.08)
0.04/0.04
.86 (0.08)
0.04/0.04)
.75 (0.17)
0.01/0.01
.83 (0.07)
0.06/0.05
.56 (0.16)
0.02/0.02
.24 (2.0)
0.02/0.01
.31 (0.13)
0.03/0.05
.61 (0.10)
0.07/0.06
0.66 (0.18)
0.02/0.01
0.44 (0.12)
0.05/0.04
0.57(0.07)
0.15/0.13
0.69 (0.05)
0.23/0.20
0.67 (0.06)
0.21/0.18
Mania, Primary or Induced
Psychosis
Schizophrenia
Psychotic Primary
Psychotic Induced
Psychotic Primary or Induced
Anxiety
Panic Disorder, Primary
Generalized Anxiety, Primary
Specific Phobia
Social Phobia
Obsessive Compulsive
Post Traumatic Stress
Any Anxiety, Primary or Induced
Personality
Antisocial Personality
Borderline Personality
28