2007 overview: Are treatments combining pharmacotherapy and cognitive-behavioural therapy for anxiety disorders more efficient than either treatment alone?

Predicting response to treatment

Being able to accurately predict a patient’s response to a prospective treatment would be a large step forward in the treatment of anxiety disorders. Currently we rely upon diagnostic systems which are probabilistic and address syndromal entities - not necessarily reflecting underlying brain pathology.

In January this year we reviewed a paper by Chambless et al. (ref. 1) which highlights the current limitations of our classification systems. It found that the diagnosis of avoidant personality disorder to be essentially a reflection of severity of social anxiety disorder, questioning again the utility of this as an axis 2 diagnosis.

A possible way to achieve better prediction of treatment outcomes could be by the use of psychometric rating scales which evaluate patient characteristics on domains not traditionally used in classification of psychiatric disorders.

Dusseldorp et al. (ref. 2) set about trying to answer this question by determining if patients beliefs about how much control they have over their panic disorder (their locus of control, or LOC) influences their response to antidepressants or cognitive behavioural therapy (CBT).

Interestingly, those with a moderate LOC performed best, but those with low (expected) or high (unexpected) LOCs performed no better than placebo. In addition, self-preference for CBT did not improve outcome above those randomly assigned to CBT.

This questions the theory that CBT works by increasing a patient's own sense of being able to control ones symptoms and is a promising avenue for future research. However, predicting response to treatments based on prior theoretical considerations is rarely confirmed in clinical studies.

The trial by Ulenhuth et al. (ref. 3), for example, revealed that the Anxious Thought and Tendencies Questionnaire (AT+T) was not predictive of response to benzodiazepine treatment in panic disorder.

Biological Mechanisms of Anxiety

Perhaps in the long term the most fruitful avenue to improve classification and treatment will be to identify the biological correlates of anxiety symptoms. Challenge testing, in vivo functional imaging and specific receptor ligands are all successfully used paradigms to determine differences in pathological states.

Alkin et al. (ref. 4) determined that basilar artery flow increases in panic disorder patients in response to carbon dioxide challenge. This is important as the basilar artery perfuses areas thought to be important in panic disorder, such as the locus coeruleus and brainstem autonomic and respiratory centres.

Carbon dioxide-sensitive serotonergic neurones in the rostral ventral medulla may provide an explanation for the connection between hyperventilation-induced respiratory alkalosis and sympathetic activation (ref. 5); in turn serotonergic modulation of the sympathetic nervous system is also described (ref. 6).

Thus there is preclinical data linking panic, the autonomic nervous system and serotonin. Esler et al. found a fourfold increased turnover of serotonin in panic disorder patients compared to controls. Moreover, this was attenuated by treatment with a selective serotonin reuptake inhibitor (SSRI) (ref. 7). This is an area which our group is also actively researching, examining the link between serotonin, the autonomic nervous system and anxiety (ref. 8, ref. 9, ref. 10).

Imaging studies, although expensive, are invaluable tools for in vivo research into anxiety disorders. A fractional anisotropy imaging study by Han et al. (ref. 12) found increased cingulate connectivity adding further weight to fundamental brain changes in panic disorder (changes in number of GABA-A and 5HT-1A receptors have been known for some time (ref. 13, ref. 14).

The serendipitous occurrence (for the researchers, not the patient) of a spontaneous panic attack in an fMRI scanner revealed increased activity in the right amygdala (ref. 15). This is important as most scanning studies of panic attacks have been provoked by challenge testing, which may be biologically different from spontaneous attacks.

In October we also reviewed a paper showing decreased dopamine transporters in the basal ganglia of patients suffering obsessive compulsive disorder (OCD) (ref. 16). This gives support to the use of drugs with dopaminergic actions in OCD, most commonly neuroleptics are used to augment SSRIs in nonresponsive patients.

Treatment of anxiety disorders

Revolutionary new treatments for anxiety disorders did not appear in 2007, instead a steady increase in information about established treatments occurred. The mainstay of anxiety treatment, SSRIs, had their long term efficacy in panic disorder examined by Dannon et al. (ref. 17 ), confirming what most of us suspected; that their efficacy is sustained.

SSRIs were also found to improve quality of life in panic disorder (ref. 18), which is again unsurprising considering their efficacy in a disabling condition. More importantly a study has shown a significant increase in relapse of panic disorder following treatment cessation after three years of remission on antidepressants (with a median survival of a fifth of those continuing antidepressants) (ref. 19 ).

This study was relatively small and did not account for severity of panic disorder at baseline, or randomly select discontinuation, but gives some insight into the chronicity of panic disorder. It also highlights that, contrary to the experience in depression, the duration of remission may not be a good predictor of possible relapse with discontinuation. Therefore an interesting question is posed; what does predict sustained remission in panic disorder? As mentioned above it may only be by developing tools to measure the underlying pathology of the disorder that we will also gain the tools to reliably predict remission or cure.

Paroxetine was also found to have benefit in comorbid social anxiety disorder and alcohol misuse (and dependency) (ref. 20). This is a useful study as social anxiety disorder and alcohol problems frequently coexist; therefore it adds clinically useful evidence to the knowledge base. Sertraline did not differ from placebo in a randomised controlled trial into military combat induced post traumatic stress disorder (PTSD) (ref. 21). Sertraline has proven efficacy in civilian PTSD, therefore this finding may require further explanation. What are the differences between combat and civilian PTSD?

On a final note, evidence was reviewed that venlafaxine may be efficacious in paediatric generalised anxiety disorder (GAD) (ref. 22). This paper was a combination of two large multi-centre trials. Essentially one trial was positive and the second negative (but a positive trend), making venlafaxine fall short of the Food and Drug Agencies (FDA) requirements for licensing (two positive well designed randomised controlled trials).

An interesting finding of this paper was that there was little evidence of emerging suicidality amongst this group. This may have been influenced to some extent by the selection criteria (those most at risk of suicide excluded). Nonetheless, this is still important considering the recent concern of emerging suicidality with antidepressants (ref. 23), especially in children (ref. 24 ).

There has been much anxiety over whether modern antidepressants cause increased suicidality, which appears to have eroded clinical confidence in these effective medications. Indeed Gibbons et al. (ref. 25 ) showed a decrease in prescribing of SSRIs following the FDA’s warning of possible emergent suicidality with SSRIs in 2003. More worryingly, this paper also showed that during this time suicide rates increased.

The data linking SSRIs to increased suicide comes from randomised controlled trials (ref. 26), which were not designed to investigate this as a primary outcome. Epidemiological studies have not confirmed this link. Indeed they tend to show reduced suicide with higher SSRI prescriptions (ref. 27). Overall the balance of evidence is against SSRIs inducing suicidal ideas or actions in large numbers of patients. Reports such as these are a sobering reminder that these are powerful medications and that close supervision of patients taking them should be the norm.

References

1. Chambless DL, Fydrich T, Rodebaugh TL. Generalized social phobia and avoidant personality disorder: meaningful distinction or useless duplication? Depression and Anxiety 2008;25 (1); 8-19

2. Dusseldorp E, Spinhoven P, Bakker A, van DR, van Balkom AJ. Which panic disorder patients benefit from which treatment: cognitive therapy or antidepressants? Psychotherapy and Psychosomatics 2007; 76 (3); 154-161

3. Uhlenhuth EH, Starcevic V, Qualls C, Antal EJ, Matuzas W, Javaid JI, et al. Cognitive style, alprazolam plasma levels, and treatment response in panic disorder. Depression and Anxiety 2007. [Epub ahead of print]

4. Alkin T, Tural U, Onur E, Oztürk V, Monkul ES, Kutluk K. Basilar artery blood flow velocity changes in patients with panic disorder following 35% carbon dioxide challenge. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2007; 31 (1); 115-122. [Epub 2006 Sep 20]

5. Richerson GB, Wang W, Tiwari J, Bradley SR. Chemosensitivity of serotonergic neurons in the rostral ventral medulla. Respiration Physiology 2001; 129 (1-2); 175-189

6. Bago M, Dean C. Sympathoinhibition from ventrolateral periaqueductal gray mediated by 5-HT(1A) receptors in the RVLM. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2001; 280 (4); 976-984

7. Esler M, Lambert E, Alvarenga M, Socratous F, Richards J, Barton D, et al. Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor. Stress 2007; 10 (3); 295-304

8. Davies SJ, Hood SD, Argyropoulos SV, Morris K, Bell C, Witchel HJ, et al. Depleting serotonin enhances both cardiovascular and psychological stress reactivity in recovered patients with anxiety disorders. Journal of Clinicla Psychopharmacology 2006; 26 (4); 414-418

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14. Nash J, Sargent P, Rabiner E, Hood SD, Argyropoulos SV, Grasby P, et al. Altered 5HT1A binding in panic disorder demonstrated by PET scanning. Journal of Psychopharmacology 2003; 17 (3); 30

15. Pfleiderer B, Zinkirciran S, Arolt V, Heindel W, Deckert J, Domschke K. fMRI amygdala activation during a spontaneous panic attack in a patient with panic disorder. World Journal of Biologicla Psychiatry 2007; 8 (4); 269-272

16. Kim CH, Koo MS, Cheon KA, Ryu YH, Lee JD, Lee HS. Dopamine transporter density of basal ganglia assessed with [123I]IPT SPET in obsessive-compulsive disorder. European journal of nuclear medicine and molecular imaging 2003; 30 (12); 1637-1643. [Epub 2003 Sep 25]

17. Dannon PN, Iancu I, Lowengrub K, Gonopolsky Y, Musin E, Grunhaus L, et al. A naturalistic long-term comparison study of selective serotonin reuptake inhibitors in the treatment of panic disorder. Clinical Neuropharmacology 2007; 30 (6); 326-334

18. Bandelow B, Stein DJ, Dolberg OT, Andersen HF, Baldwin DS. Improvement of quality of life in panic disorder with escitalopram, citalopram, or placebo. Pharmacopsychiatry 2007; 40 (4); 152-156

19. Choy Y, Peselow ED, Case BG, Pressman MA, Luff JA, Laje G, et al. Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study. Comprehensive Psychiatry 2007; 48 (5); 419-425. [Epub 2007 Jul 5]

20. Book SW, Thomas SE, Randall PK, Randall CL. Paroxetine reduces social anxiety in individuals with a co-occurring alcohol use disorder. Journal of Anxiety Disorders 2008; 22 (2); 310-318. [Epub 2007 Mar 12]

21. Friedman MJ, Marmar CR, Baker DG, Sikes CR, Farfel GM. Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting. Journal of Clinical Psychiatry 2007; 68 (5); 711-720

22. Rynn MA, Riddle MA, Yeung PP, Kunz NR. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. American Journal of Psychiatry 2007; 164 (2); 290-300

23. Nutt DJ. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. Journal of Psychopharmacology 2003; 17 (4); 355-364

24. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Archivers of General Psychiatry 2006; 63 (3); 332-339

25. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Erkens JA, et al. Early evidence on the effects of regulators' suicidality warnings on SSRI prescriptions and suicide in children and adolescents. American Journal of Psychiatry 2007; 164 (9); 1356-1363

26. Mann JJ, Emslie G, Baldessarini RJ, Beardslee W, Fawcett JA, Goodwin FK, et al. ACNP Task Force report on SSRIs and suicidal behavior in youth. Neuropsychopharmacology 2006; 31 (3); 473-492

27. Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK, Mann JJ. Relationship between antidepressants and suicide attempts: an analysis of the Veterans Health Administration data sets. American Journal of Psychiatry 2007; 164 (7); 1044-1049