Cognitive functions in patients with panic disorder: a literature review

Mariana Rodrigues Poubel Alves Valeska Martinho Pereira Sérgio Machado Antonio Egidio Nardi Adriana Cardoso de Oliveira e Silva About the authors

Abstract

Objective:

To conduct a review of the literature on the possible neuropsychological deficits present in patients with panic disorder.

Methods:

We performed a systematic review and search of the PubMed, ISI and PsycInfo scientific databases, with no time limits, using the following key words: cognitive, function, panic, and disorder. Of the 971 articles found, 25 were selected and 17 were included in this review. The inclusion criterion was at least one neuropsychological assessment task in patients with panic disorder.

Results:

The number of publications has grown gradually, especially those assessing executive functions, corresponding to the neurobiological model most widely accepted. Of all the functions evaluated, these patients had lower performance in memory tasks and higher performance in affective processing tasks related to the disorder. However, these data require further investigation due to the high rate of comorbidities, the small sample sizes of the included studies and little standardization of instruments used.

Conclusion:

The results showed a greater occurrence of deficits in memory and enhanced affective processing related to panic disorder.

Panic disorder; cognitive function; memory; affective processing; executive functions


Introduction

Panic disorder (PD) is characterized primarily by the presence of recurrent and unexpected panic attacks, followed by at least 1 month of persistent concern about other attacks, the possible consequences of attacks and a significant behavioral change related to the attacks. For a diagnosis of PD, the panic attacks cannot be better accounted for by another mental disorder, by physiological effects resulting from the use of substances or by other medical conditions, such as hypothyroidism.11. American Psychiatric Association. Manual diagnóstico e estatístico de transtornos mentais. 4th ed. Porto Alegre: Artmed; 2002.

Regarding the prevalence of PD, a study found a lifetime rate of 1.6% and an annual rate of 1% in the city of São Paulo. However, this was not a representative sample of the Brazilian population.22. Salum GA, Blaya C, Manfro GG. Panic disorder. Rev Psiquiatr Rio Gd Sul. 2009;31:86-94. Nevertheless, the annual rates are similar to those presented by the National Comorbidity Survey Replication, which estimated the prevalence of PD to be 5% in a lifetime and 1% annually in a representative sample of the U.S. population.22. Salum GA, Blaya C, Manfro GG. Panic disorder. Rev Psiquiatr Rio Gd Sul. 2009;31:86-94.

Neurobiology of panic disorder

The first studies that evaluated the neurobiology of anxiety used animal models because the behaviors of escape, fear and avoidance presented in these disorders are similar to certain responses presented throughout animal phylogeny, such as increase in heart rate and release of glucocorticoids when faced with adverse situations. However, some limitations, such as the inability to verbalize symptoms, resulted in a need for improved research models.33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6. Thus emerged the current models of research, which have focused on the prevention of mental disorders due to their chronic and progressive aspects. Notable research lines include growing interest in neuropsychology and neuroimaging in an attempt to construct a cognitive profile of these populations.22. Salum GA, Blaya C, Manfro GG. Panic disorder. Rev Psiquiatr Rio Gd Sul. 2009;31:86-94.

The neurocircuitry of fear includes two pathways for processing of sensory information. The shorter path consists of the rapid spread of autonomic and behavioral responses in potentially hazardous situations. In this case, the major regions involved are the anterior thalamus and the central and lateral regions of the amygdala. The latter is, in particular, the coordinator of this process because it triggers regions that themselves emit responses. In the longer path, the information passes through several regions, including the cortex, which allows for a more refined analysis of inputs.33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6.

In the case of PD, the hypothesis is that the neurocircuitry would result in dysregulated activation and coordination with increased subcortical activity and consequent neuroendocrine activation, both behavioral and autonomic.33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6. Neuropsychological assessment can ratify or call into question the prevailing neurobiological model, because if cerebral regions are altered in PD, this would be expected to generate cognitive and behavioral responses accordingly.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211.

Neuropsychological assessment

Neuropsychological assessment has several objectives, such as identifying and describing possible changes in cognitive function. An evaluation may be recommended in a variety of cases, such as in patients who sustained an injury (e.g., traumatic brain injury or stroke) or in patients who are experiencing emotional or behavioral changes.

A detailed description of the different cognitive functions contributes to the establishment of more accurate diagnoses and prognoses, especially in cases where no functional changes are detected in neuroimaging studies. Furthermore, this description can assist in follow-up of individual cases when periodic reevaluation is recommended. Finally, this description contributes to a better understanding of the relationship between brain and behavior, demonstrating in practice what is theoretically established.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211.

The importance of establishing a relationship between neuropsychology and mental disorders arises from the need for more reliable and objective data about the abilities and deficits related to these disorders. As our behavioral and cognitive responses correlate with substrates and neural networks, when conducting a neuropsychological evaluation, we obtain a quantitative and qualitative picture of the workings of different cognitive functions and their related neural networks.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211. In the case of PD, few studies have been published; therefore, there is still uncertainty as to which cognitive functions could be affected by the disorder. The cognitive functions expected to be most affected are those related to regions involved in the fear network, i.e., the frontal cortex and limbic regions in particular. This would predominantly involve executive functions and emotional processing.

Understanding these relations in PD could lead to the development of better interventions.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8. These interventions may pertain to the field of neuropsychology, in the development of neuropsychological rehabilitation strategies, or even to the field of psychotherapy, enabling development of psychotherapeutic interventions that could be guided according to the cognitive profile of this group.

Thus, the objective of this study was to conduct a literature review of studies that included neuropsychological evaluations in patients diagnosed with PD, with or without agoraphobia, to investigate possible cognitive changes in this population.

Methods

A literature search of the PubMed, ISI Web of Knowledge and PsycInfo databases was conducted using the following terms: cognitive, function, panic, and disorder. The survey was conducted in August 2012; no time limits were set for any database.

A total of 971 references were found (315 in PubMed, 575 in ISI Web of Science, and 81 in PsycInfo). Of these, 45 articles were in a language other than English and 96 were duplicates, and were therefore excluded. This left 833 references for abstract analysis. Twenty-five articles were selected and recovered, of which only 17 were ultimately included. We excluded articles that only conducted neuroimaging or when the focus of neuropsychological assessment was a psychiatric disorder other than PD. Only articles describing neuropsychological assessment of PD patients, with or without agoraphobia, were included in this review. Studies were required to include at least one neuropsychological assessment task.

Data were stratified by functions evaluated: general intellectual functioning, memory, attention, executive function, psychomotor abilities and processing speed, verbal fluency, and affective processing measured in response to faces and words.

Results

The results of our literature review are summarized in Table 1.

Table 1
Summary of the studies included in the review

General intellectual functioning

Overall cognitive functioning scores map a broad area and specify the patient's overall cognitive functioning. They are used to provide a rapid, initial assessment of the patient rather than a detailed analysis.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211. Only four articles examined general intellectual functioning; three of these used the Wechsler Adult Intelligence Scale (WAIS-R). The other study used Raven's Colored Progressive Matrices. The results were different in each article.

The first study66. Lucas JA, Telch MJ, Bigler ED. Memory functioning in panic disorder: a neuropsychological perspective. J Anxiety Disord. 1991;5:l-20. used four subtests of WAIS-R that assessed the verbal vs. performance IQ measures, as well as the full scale IQ, of patients (n=25) and compared them with a control group (n=25). The results showed lower performance on the picture completion subtest by patients with PD. In another article, patients with PD (n=69) scored approximately 10 points lower in verbal, performance and full scale IQ scores when compared to the control group (n=19).77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31. Another study used four subtests of the WAIS-R and found lower scores in the block design subtest, which measures visuospatial constructional ability. This difference was common to patients with social phobia (n=18) and patients with PD (n=18) when compared to controls (n=16). However, the authors noted that there was no significant difference in the similarities subtest, which shows that this difference was not consistent.88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7. The last study did not find any difference between the control group (n=15) and the other two groups, patients with PD with agoraphobia (n=15) and patients with obsessive-compulsive disorder (n=25).99. Boldrini M, Del Pace L, Placidi GP, Keilp J, Ellis SP, Signori S, et al. Selective cognitive deficits in obsessive compulsive disorder compared to panic disorder with agoraphobia. Acta Psychiatr Scand. 2005;111:150-8.

These differences may be related to the inhomogeneity of the paradigms used for assessment; although three of the studies used the same measurement instrument, there was a difference in the number and type of selected subtests.

Memory

Memory is fundamental to perception because, without it, we do not recognize people or representative objects of our history.2222. Chun MM, Turk-Browne NB. Interactions between attention and memory. Curr Opin Neurobiol. 2007;17:177-84. Most of the articles evaluated different aspects of this function, such as working memory, long-term memory and visual memory.

Of the 10 studies, only three did not find deficits in memory.77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.,1111. Purcell R, Maruff P, Kyrios M, Pantelis C. Neuropsychological deficits in obsessive-compulsive disorder: a comparison with unipolar depression, panic disorder, and normal controls. Arch Gen Psychiatry. 1998;55:415-23. Another two identified impairment in one aspect and preservation of another.66. Lucas JA, Telch MJ, Bigler ED. Memory functioning in panic disorder: a neuropsychological perspective. J Anxiety Disord. 1991;5:l-20.,88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7. In one study, patients with PD (n=18) or social phobia (n=18) had a significantly lower performance in total free recall when compared to the control group (n=16). However, the author notes that this finding may be related to loss of interest, fatigue, some other mediating factor or a state of depression or anxiety, which could have generated a bias in the results.88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7. In another study, patients with PD (n=25) performed worse than controls (n=25) in visual memory tasks but not in verbal memory or concentration.66. Lucas JA, Telch MJ, Bigler ED. Memory functioning in panic disorder: a neuropsychological perspective. J Anxiety Disord. 1991;5:l-20.

The five remaining articles described differences in other areas of memory. In one study, there was impairment of both working memory and explicit memory in patients with PD (n=14) as compared with a control group (n=7). However, the authors emphasize that such deficits may be related to a high level of excitement and anxiety in patients at the time of task execution. Excitement and anxiety could lead to a loss of selective attention, which mediates the process of encoding information and support received.1212. Dratcu L, Bond A. Panic patients in the non-panic state: physiological and cognitive dysfunction. Eur Psychiatry. 1998;13:18-25. Another study found spatial memory impairment in patients with PD with agoraphobia (n=15) and patients with obsessive-compulsive disorder (OCD) (n=25) as compared with a control group (n=15).99. Boldrini M, Del Pace L, Placidi GP, Keilp J, Ellis SP, Signori S, et al. Selective cognitive deficits in obsessive compulsive disorder compared to panic disorder with agoraphobia. Acta Psychiatr Scand. 2005;111:150-8.

Another study found that patients with different anxiety disorders (PD with and without agoraphobia (n=33), social phobia (n=32), obsessive compulsive disorder (n=16), specific phobia (n=24) and generalized anxiety disorder (n=7) tended to remember fewer words in free recall and cued recall as compared with healthy controls (n=175).1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14. These findings were validated by a study that showed poorer short-term memory for numbers and words in patients with PD (n=93) as compared with healthy subjects (n=36).1414. Gordeev SA. Cognitive functions and the state of nonspecific brain systems in panic disorders. Neurosci Behav Physiol. 2008;38:707-14.

Finally, one article compared patients with PD (n=24) and a control group (n=24). The authors found significant deficits in working memory and in the curved means of the results, both in encoding and recall, in different categories. However, PD patients had higher face recognition scores.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8.

Attention

Studies conducted in the 1980s divided attentional processes into two classes: parallel processes that work with unlimited capacity and processes that are more focal and selective and, therefore, work with limited capacity. This distinction also implies that the second type would only be required for more complex tasks.2323. Smith PL, Ratcliff R. An integrated theory of attention and decision making in visual signal detection. Psychol Rev. 2009;116:283-317. Another important characterization of attention is the distinction between automatic and controlled processes. Automatic processes of attention do not require that the subject be focused or willing to perform an action. They are a type of involuntary reaction in the face of innate or previously learned stimuli. Additionally, these processes usually operate from associative connections. The controlled process requires focused attention and, therefore, has a limited capacity. This limitation is a benefit, because it allows better handling of the matter that is under focus.2424. Schneider W, Chein JM. Controlled ? automatic processing: behavior, theory, and biological mechanisms. Cogn Sci. 2003;27:525-59.

Controlled processes were the second most evaluated function, reported in eight articles. Five of these articles found no differences between patients with PD and a control group.77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7.,1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.

11. Purcell R, Maruff P, Kyrios M, Pantelis C. Neuropsychological deficits in obsessive-compulsive disorder: a comparison with unipolar depression, panic disorder, and normal controls. Arch Gen Psychiatry. 1998;55:415-23.
-1212. Dratcu L, Bond A. Panic patients in the non-panic state: physiological and cognitive dysfunction. Eur Psychiatry. 1998;13:18-25. Of the three articles in which differences were found, two reported differences in selective attention.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8.,1414. Gordeev SA. Cognitive functions and the state of nonspecific brain systems in panic disorders. Neurosci Behav Physiol. 2008;38:707-14. In one article, patients with PD (n=24) showed more difficulty in completing a task that required visual attention as compared with a control group (n=24). According to the authors, this result demonstrates the difficulty in selecting relevant stimuli and is related to symptoms of the disorder, in which patients find it difficult to perceive their surroundings because their attention is focused on bodily sensations and concerns.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8. In another study, patients with PD (n=93) were compared with healthy controls (n=36) and showed decreases in selectivity, switching of attention and lower work capacity and stability of attention.1414. Gordeev SA. Cognitive functions and the state of nonspecific brain systems in panic disorders. Neurosci Behav Physiol. 2008;38:707-14.

The third article's results were contradictory to those of the previous two, because the patients evaluated showed no differences in selective attention tasks, although differences were found in divided attention tasks. The authors compared patients with PD with (n=16) and without agoraphobia (n=5), patients with PD and major depressive disorder (MDD) (n=21), and a control group (n=20). In selective attention tasks, the three groups performed similarly, but in divided attention, patients with PD were slightly faster than the patients with MDD and slower than the control group. However, the authors emphasize that these results may be related to use of the dual-task paradigm, which requires a higher attentional load that is not found in selective attention tasks.1515. Lautenbacher S, Spernal J, Krieg JC. Divided and selective attention in panic disorder A comparative study of patients with panic disorder, major depression and healthy controls. Eur Arch Psychiatry Clin Neurosci. 2002;252:210-3.

Executive function

The articles note that Luria was the first author to discuss executive functions. Although he did not use that term, he conceptualized a series of disorders associated with frontal lesions that generated problems of initiative, motivation, development of goals and action plans, and difficulties in self-monitoring. The term ‘executive function’ was first described by Lesak, who defined it as the skills required for effective behavior that is creative and socially acceptable.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211.,2525. Tirapu-Ustárroz J, Muãoz-Céspedes JM, Pelegrín C. Funciones ejecutivas: necesidad de una integración conceptual. Rev Neurol. 2002;34:673-85.

Importantly, this function has different components, which hinders the uniformity of findings. This definition includes decision-making, inhibition of automatic responses, flexibility, and categorization.

Despite the difficulty of homogenizing the definitions of executive functions, one of the authors defines it as the process that links ideas, actions and simple movements to guide the resolution of more complex behaviors.2525. Tirapu-Ustárroz J, Muãoz-Céspedes JM, Pelegrín C. Funciones ejecutivas: necesidad de una integración conceptual. Rev Neurol. 2002;34:673-85.

In total, six studies performed tests that assessed this cognitive function. Of these articles, four found no differences in patients with PD when compared to the control group.88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7.

9. Boldrini M, Del Pace L, Placidi GP, Keilp J, Ellis SP, Signori S, et al. Selective cognitive deficits in obsessive compulsive disorder compared to panic disorder with agoraphobia. Acta Psychiatr Scand. 2005;111:150-8.

10. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.
-1111. Purcell R, Maruff P, Kyrios M, Pantelis C. Neuropsychological deficits in obsessive-compulsive disorder: a comparison with unipolar depression, panic disorder, and normal controls. Arch Gen Psychiatry. 1998;55:415-23. One of these articles found no differences when patients had only the diagnosis of PD (n=22); however, when patients had PD and MDD (n=11), they demonstrated greater latency in decision-making when compared to a control group (n=22).1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.

Of the two articles that found differences in executive functions, one noted that high levels of anxiety in patients with PD could affect cognitive functioning in more complex, generating strategies, such as category formation, which is typically required in executive function. These studies added that such difficulties are related to prefrontal areas and the medial amygdala, part of the neuroanatomical circuit of conditioned fear.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8. The other study used patients with PD with and without agoraphobia (n=33), social phobia (n=32), obsessive-compulsive disorder (n=16), specific phobia (n=24), generalized anxiety disorder (n=7) and a control group (n=175). To measure executive function, the authors used the Trail Making Test, forms A and B. In form A, there was no significant difference between the overall group of anxiety disorder patients, or any of its subgroups, and the control group. However, in the case of form B, the overall anxiety group needed more time to complete the form, as compared with the control group. This included the subgroup of PD patients.1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14.

Psychomotor abilities and processing speed

Visuospatial and psychomotor skills play an important role in daily life, but as they are more automatic than other processes, their importance is perceived clearly only when there is a deficit. For example, when challenged by identification, discrimination, and analysis of a complex stimulus in visual processing, we resort to visuospatial and psychomotor skills.2626. Schoenberg MR, Scott JG. The little black book of neuropsychology: a syndrome-based approach. Springer: New York; 2011.

Six of the included studies evaluated psychomotor abilities or processing speed. Of these, four found no difference between PD patients and the control group.77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.,1212. Dratcu L, Bond A. Panic patients in the non-panic state: physiological and cognitive dysfunction. Eur Psychiatry. 1998;13:18-25.,1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14. One article compared groups of different anxiety disorders, such patients with PD with and without agoraphobia (n=33), social phobia (n=32), obsessive-compulsive disorder (n=16), specific phobia (n=24) and generalized anxiety disorder (n=7) to a control group (n=175); there was no difference between the groups.1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14. Two articles77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,1212. Dratcu L, Bond A. Panic patients in the non-panic state: physiological and cognitive dysfunction. Eur Psychiatry. 1998;13:18-25. compared only patients with PD (n=69; n=14) to a control group (n=19; n=7) and found no differences. Another study1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71. used three subgroups: patients with PD (n=22), patients with MDD (n=11) and a control group (n=22).

Among the articles that found differences, one detected lower visuospatial skills in PD patients. However, it is important to note that these data are only a reflection of differences in processing speed.88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7. The other article found differences in time and distance traveled by patients with PD (n=31) to reach the target of a game played virtually when compared to controls (n=31). However, the authors noted that not all patients had this difficulty, and were able to subdivide the group of PD patients. While one group had such difficulties, the other group's result matched the results of the control group. To understand this difference, the authors noted that the group with difficulties was older and had a longer history of PD. Thus, they proposed that age and the course of the disorder could lead to a greater propensity for changes in cognition and a worsening of behavioral strategies.1616. Gorini A, Schruers K, Riva G, Griez E. Nonhomogeneous results in place learning among panic disorder patients with agoraphobia. Psychiatry Res. 2010;179:297-305.

Verbal fluency

Only two articles77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14. assessed this cognitive function, finding no significant differences. While one study compared patients with PD (n=69) to a control group (n=19),77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31. the other compared different groups of anxiety disorders (patients with PD with and without agoraphobia [n=33], social phobia [n=32], obsessive-compulsive disorder [n=16], specific phobia [n=24] and generalized anxiety disorder [n=7]) to a control group (n=175).1313. Airaksinen E, Larsson M, Forsell Y. Neuropsychological functions in anxiety disorders in population-based samples: evidence of episodic memory dysfunction. J Psychiatr Res. 2005;39:207-14.

Affective processing of faces and words

Six articles were found that evaluated affective processing. Of these, three evaluated face recognition.1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.,1717. Lundh LG, Thulin U, Czyzykow S, Ost LG. Recognition bias for safe faces in panic disorder with agoraphobia. Behav Res Ther. 1998;36:323-37.,1818. Reinecke A, Cooper M, Favaron E, Massey-Chase R, Harmer C. Attentional bias in untreated panic disorder. Psychiatry Res. 2011;185:387-93. In one study, patients with PD (n=30) showed no bias for critical faces, but they did show bias for safe faces, a finding that is consistent with the trend of avoiding dangerous situations and seeking the presence of safe people, when compared to a control group (n=30).1717. Lundh LG, Thulin U, Czyzykow S, Ost LG. Recognition bias for safe faces in panic disorder with agoraphobia. Behav Res Ther. 1998;36:323-37. This finding is confirmed by other studies. Patients with PD with or without agoraphobia (n=23) show greater vigilance toward fearful faces when compared to a control group (n=22).1818. Reinecke A, Cooper M, Favaron E, Massey-Chase R, Harmer C. Attentional bias in untreated panic disorder. Psychiatry Res. 2011;185:387-93. Another study used happy or sad faces with three comparative groups: patients with PD (n=16), PD patients with MDD (n=21) and a control group (n=20). The results showed that the control group made more errors in blocks of sad faces, while the clinical patients made more errors in blocks of happy faces. This suggests that while the controls paid more attention to blocks of happy faces, the patients paid more attention to blocks of sad faces. However, the group with PD showed no differences between sad or happy face blocks. This finding indicates that negative attentional bias could be related to the presence of depressive symptoms.1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71.

Another article showed a difference in the time taken to recognize panic-related words in patients with PD with or without agoraphobia (n=60) when compared to a control group (n=60).1919. Neidhardt E, Florin I. Do patients with panic disorder show a memory bias? Psychother Psychosom. 1998;67:71-4.

The other two articles used neutral words and words related to the disorder; in both studies, PD patients showed an attentional bias for information related to the disorder.2020. Pauli P, Dengler W, Wiedemann G, Montoya P, Flor H, Birbaumer N, et al. Behavioral and neurophysiological evidence for altered processing of anxiety-related words in panic disorder. J Abnorm Psychol. 1997;106:213-20.,2121. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry. 2005;62:922-33. One of the studies compared patients with PD (n=15) to a control group (n=15),2020. Pauli P, Dengler W, Wiedemann G, Montoya P, Flor H, Birbaumer N, et al. Behavioral and neurophysiological evidence for altered processing of anxiety-related words in panic disorder. J Abnorm Psychol. 1997;106:213-20. and the other study compared patients with OCD (n=18), patients with PD (n=15), patients with hypochondriasis (n=14) and a control group (n=19).2121. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry. 2005;62:922-33.

Discussion

Although many studies have evaluated cognitive functions in psychiatric patients,44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211. research into such functions in patients with PD is limited, as observed in this review. Other mental disorders seem to receive more attention in this area.2727. Bédard MJ, Joyal CC, Godbout L, Chantal S. Executive functions and the obsessive-compulsive disorder: on the importance of subclinical symptoms and other concomitant factors. Arch Clin Neuropsychol. 2009;24:585-98.,2828. Olley A, Malhi G, Sachdev P. Memory and executive functioning in obsessive-compulsive disorder: a selective review. J Affect Disord. 2007;104:15-23. Still, a few studies have included neuropsychological testing. Many studies use only a few tests rather than a complete neuropsychological battery, which is necessary for a more comprehensive evaluation.

Studies about the neurobiology of anxiety disorders, particularly in the case of PD, are the foundation for establishing a neuropsychological profile of these patients. Advanced neuroimaging studies and their possible relationship to the effects of psychotherapeutic treatment22. Salum GA, Blaya C, Manfro GG. Panic disorder. Rev Psiquiatr Rio Gd Sul. 2009;31:86-94.,33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6. is also important, as neuroimaging studies provide a detailed picture of possible neuroanatomical substrates involved in PD and sites of specific activity, and can thus help increase treatment effectiveness.33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6. Neuropsychological assessment, in turn, seeks to contribute to a more accurate diagnosis and prognosis and to improve our understanding of possible changes to cognitive functioning resulting from the disorder.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211. Thus, both modalities seek to develop of a clinical profile of these patients.

Neuropsychological assessment aims to map possible cognitive dysfunction from the results of tests, social and individual history and neuroimaging studies. Therefore, a neuropsychological diagnosis is generated from quantitative and qualitative aspects. The quantitative aspects refer to the values obtained in tests and compared to a normative population. The qualitative aspects relate to clinical history, which takes into account not only educational attainment and sociocultural level, but also the timing and history of the presenting complaint, possible impacts of symptoms in activities of daily living, interactions with friends, and professional life, history of family risk factors, medication use and even perceptions about how alert and cooperative the patient is during the evaluation.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211.

The theoretical foundations of neuropsychological assessment come from the interface of different sciences, such as medicine, physiology and psychology. In mental disorders, neuropsychological assessment can contribute to a clarification of the possible cognitive limitations related to a disorder and suggest better medical and psychotherapeutic interventions.44. Ustárroz JT. [The neuro-psychological assessment]. Interv Psicosoc. 2007;16:189-211.

An interest in the potential for cognitive impairment in obsessive-compulsive disorder, especially in memory and executive function,2727. Bédard MJ, Joyal CC, Godbout L, Chantal S. Executive functions and the obsessive-compulsive disorder: on the importance of subclinical symptoms and other concomitant factors. Arch Clin Neuropsychol. 2009;24:585-98.,2828. Olley A, Malhi G, Sachdev P. Memory and executive functioning in obsessive-compulsive disorder: a selective review. J Affect Disord. 2007;104:15-23. is observed in the literature. Initially, the hypothesis was that such patients could have a deficit in remembering their actions, which might account for their compulsions. However, investigations suggest that this memory deficit is secondary; some even question its existence. A new hypothesis suggests that patients exhibit organizational difficulty in processing information or in performing executive functions.2727. Bédard MJ, Joyal CC, Godbout L, Chantal S. Executive functions and the obsessive-compulsive disorder: on the importance of subclinical symptoms and other concomitant factors. Arch Clin Neuropsychol. 2009;24:585-98.,2828. Olley A, Malhi G, Sachdev P. Memory and executive functioning in obsessive-compulsive disorder: a selective review. J Affect Disord. 2007;104:15-23.

As do studies of patients with PD, studies of obsessive-compulsive disorder suggest that larger sample sizes and attempts at better control for comorbidities are necessary in future research. It is unclear whether the findings of these studies represent the specific profile of a disorder or whether they reflect patient anxiety and mood in general. It is important to analyze patient intellectual ability prior to testing to avoid such issues.2727. Bédard MJ, Joyal CC, Godbout L, Chantal S. Executive functions and the obsessive-compulsive disorder: on the importance of subclinical symptoms and other concomitant factors. Arch Clin Neuropsychol. 2009;24:585-98.,2828. Olley A, Malhi G, Sachdev P. Memory and executive functioning in obsessive-compulsive disorder: a selective review. J Affect Disord. 2007;104:15-23.

Findings regarding PD are still inconsistent and divergent; this might be explained by methodological issues. Such issues might include the difficulty of locating a large number of patients without comorbidities in most studies, the challenges of determining the severity of the disorder at the time of evaluation and a lack of methodological standardization. Comorbidities that may be present in patients with PD generate doubt as to whether any deficits found occur only in this specific disorder.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8.

6. Lucas JA, Telch MJ, Bigler ED. Memory functioning in panic disorder: a neuropsychological perspective. J Anxiety Disord. 1991;5:l-20.
-77. Gladsjo JA, Rapaport MH, McKinney R, Lucas JA, Rabin A, Oliver T, et al. A neuropsychological study of panic disorder: negative findings. J Affect Disord. 1998;49:123-31.,1010. Kaplan JS, Erickson K, Luckenbaugh DA, Weiland-Fiedler P, Geraci M, Sahakian BJ, et al. Differential performance on tasks of affective processing and decision-making in patients with panic disorder and panic disorder with comorbid major depressive disorder. J Affect Disord. 2006;95:165-71. Furthermore, the anxiety of the patient while performing tasks can bias results.

A survey of these results raised some questions. Would memory deficits be found only if they were a reflection of the patients' anxiety? Have these patients turned their attention to anxiety to the extent that it prevents them from concentrating on a given task? These questions make even more sense when an increased attentional bias is present, i.e., if the task involves emotional processing, such as in exposure to faces or words that are reminiscent of the disorder.55. Castillo EP, Coy PEC, Shejet FO, Duran ET, Cabrera DM. Evaluación de funciones cognitivas: atención y memoria en pacientes con trastorno de pánico. Salud Ment. 2010;33:481-8.,1212. Dratcu L, Bond A. Panic patients in the non-panic state: physiological and cognitive dysfunction. Eur Psychiatry. 1998;13:18-25.,1717. Lundh LG, Thulin U, Czyzykow S, Ost LG. Recognition bias for safe faces in panic disorder with agoraphobia. Behav Res Ther. 1998;36:323-37.

18. Reinecke A, Cooper M, Favaron E, Massey-Chase R, Harmer C. Attentional bias in untreated panic disorder. Psychiatry Res. 2011;185:387-93.

19. Neidhardt E, Florin I. Do patients with panic disorder show a memory bias? Psychother Psychosom. 1998;67:71-4.

20. Pauli P, Dengler W, Wiedemann G, Montoya P, Flor H, Birbaumer N, et al. Behavioral and neurophysiological evidence for altered processing of anxiety-related words in panic disorder. J Abnorm Psychol. 1997;106:213-20.
-2121. van den Heuvel OA, Veltman DJ, Groenewegen HJ, Witter MP, Merkelbach J, Cath DC, et al. Disorder-specific neuroanatomical correlates of attentional bias in obsessive-compulsive disorder, panic disorder, and hypochondriasis. Arch Gen Psychiatry. 2005;62:922-33.

Another question concerns the possible relationship between a decrease in processing speed and a change in executive functions. This question stems from one study, which hypothesized that differences in this area in one group of patients could be a result of the group itself being more prone to difficulty in behavioral strategies. These strategies relate directly to problem solving, planning, decision making, and impulse control, among other characteristics of executive functions.88. Asmundson GJ, Stein MB, Larsen DK, Walker JR. Neurocognitive function in panic disorder and social phobia patients. Anxiety. 1994-1995;1:201-7. Although most of the articles did not find changes in executive functions, it is necessary to expand upon these studies because change would be expected and would confirm all existing biological models of PD.33. Mezzasalma MA, Valença AM, Lopes FL, Nascimento I, Zin WA, Nardi AE. [Neuroanatomy of panic disorder]. Rev Bras Psiquiatr. 2004;26:202-6.

Notably, four of the six studies that evaluated executive functions were written after 2004; this fact seems to demonstrate a recent and growing concern with the influence of executive functions in PD. This is because executive functions are known to be strongly related to the frontal region, and the neurobiological model of panic takes into account a subcortical hyperactivation and consequent cortical hypoactivation, especially in the frontal regions. Thus, changes in these two areas seem to be related.

In this review, only memory and affective processing showed more consistent differences in patients with PD, compared with control groups or groups of patients with other mental disorders. In the case of memory, scores were lower in these patients, but in the case of affective processing, their performance was higher when information related to the disorder was presented. These findings, especially with regard to affective processing, are consistent with the clinical features of PD, as patients with the disorder are biased to show special attention to all information, images or contexts that relate to PD or to the imminence of a new attack. This reinforces the importance of psychoeducation and exposure, so as to desensitize patients and progressively enable the management of these feelings and distorted thoughts.

Nevertheless, further studies, with larger sample sizes and greater methodological standardization, are required. Furthermore, future studies should be aware of the different degrees of severity of the disorder in patients recruited and their symptomatology. It is noteworthy that studies on PD, the theoretical foundations of neuropsychology and standardized tests are recent. Therefore, the relationship between these factors is still poorly characterized. The interface between the fields of neuropsychology/neuroscience and psychiatric disorders aims to better understand these relationships and provide better primary interventions for patients.

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Publication Dates

  • Publication in this collection
    April-June 2013

History

  • Received
    10 Sept 2012
  • Accepted
    28 Nov 2012
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