Background

Treatment-Refractory Depression (TRD)

Major Depression is a common psychiatric disorder, with a 12-month prevalence of 6.6 to 9.3% (Kessler, Berglund, Demler, et al, 2003; Kringlen, Torgersen & Cramer, 2001; Lindeman, Hamalainen, Isometsa, et al, 2000) and a lifetime prevalence of 13.2 to 17.8% (Hasin, Goodwin, Stinson, et al, 2005; Kessler, Berglund, Demler, et al, 2005; Kringlen, Torgersen & Cramer, 2001). By 1990, depression was the fourth-ranked cause of disability worldwide (Murray & Lopez, 1997), and the World Health Organisation estimates that it will emerge as the second largest cause by 2020 (Lopez & Murray, 1998). Indeed, the functional disability associated with depression is comparable to medical illnesses such as hypertension, diabetes, and arthritis, and “the degree of persistence in functional limitations was greater than might be expected for an episodic disorder” (Hays, Wells, Sherbourne, et al, 1995). Health-related quality of life, measured with the  Medical Outcomes Study SF-36 (Ware & Sherbourne, 1992), a measure of health status, is lower in those with depression, compared to subthreshold cases and controls (Creed, Morgan, Fiddler, et al, 2002). Employment-related impairments are greater than those associated with rheumatoid arthritis, and persist despite clinical recovery (Adler, McLaughlin, Rogers, et al, 2006). Individuals with major depression may be expected to lose over 27 days of work per worker per year, and up to 225 million workdays may be lost per year in the USA (Kessler, Akiskal, Ames, et al, 2006).

The Economic Burden of Major Depression

UK estimates of the economic costs of depression confirm the huge societal burden of the illness. During 2000, the total cost was estimated at over £9 billion, with direct treatment costs of £370 million (Thomas & Morris, 2003). Hospitalisation consumes 50-75% of the treatment costs, and drug treatments comprise 2-11% (Berto, D'Ilario, Ruffo, et al, 2000). The number of working days lost in the UK due to depression in 2000 was 109.7 million (Thomas & Morris, 2003).

In the USA, the treatment costs for depression have been estimated as approaching $43.7 billion in 1990 (Greenberg, Stiglin, Finkelstein, et al, 1993). By 2000, the cost of depression to the US economy was $83.1 billion (Greenberg, Kessler, Birnbaum, et al, 2003). Over ten years the economic burden had increased by only 7% (the inflation-adjusted figure for 1990 was $77.4 billion), despite the treatment rate of depression increasing to over 50%.

Treatment-refractory depression (TRD) places an additional financial burden upon the economy. Greenberg et al (2004) compared the costs for healthcare of those individuals with major depression but not TRD, with those who were likely to have TRD. Costs were twice as high in the TRD group, with TRD-likely patients using twice the amount of health services. Treating chronic depression is six-times more expensive than non-chronic depression, and patients with chronic depression are twice as likely to be hospitalised (Crown, Finkelstein, Berndt, et al, 2002). Some have even suggested that the costs of treating depression and anxiety are underestimates (Mykletun, Overland, Dahl, et al, 2006).

The Natural Course of Major Depression

For the majority of patients, recurrence after the first episode is highly probable. Solomon et al (2000) followed-up 318 patients (mean age = 39; age range 17-76; M:F sex ratio = 41:59) with unipolar major depression over 10 years. 208 patients were followed-up for the entire 10 years, whilst 263 were followed-up for at least 5 years. The mean number of episodes of major depression per year of follow-up was 0.21 (SD=0.24). For each successive episode, the risk of recurrence was increased by 16%; whilst for each successive six-month period of recovery, the probability of recurrence reduced. The probability of recurrence at 5 years was 60%, and in the group that had had at least one further episode, 74% went on to experience a second reoccurrence.

Kennedy et al (2003) followed up 65 patients in the UK with recurrent depressive disorder.  Over a period of 8-11 years, recurrence had occurred in two-thirds of subjects. Although 92% of subjects had achieved recovery from the index episode, 67% of recovered patients had a recurrence of depression during the follow-up period: 54% of subjects had an episode lasting longer than one year; and 17% suffered from an episode of at least 2 years duration. Predictors of earlier recurrence included previous episodes of depression, severity of index episode, and female gender. The most consistent predictor of poor outcome was severity of initial episode.

In a ten-year follow-up study of depressed patients Thornicroft & Sartorius (1993) found that one fifth (22%) had an episode lasting longer than 12 months, with 24% of patients experiencing severe social impairment for over half of the follow-up period. Over one third (35%) were admitted to hospital at least once and one fifth of patients (21%) did not experience full remission.

Van Londen et al (1998), in a 3-5 year follow-up of a Dutch cohort (n=56) receiving standardised pharmacotherapy (and psychotherapy as needed), found a relapse rate of 41% within 5 years. Patients with residual symptoms tended to relapse earlier (within the first 4 months) compared to those without residual symptoms, who relapsed after 12 months. Most patients relapsed within the first 15 months after remission, despite active pharmacological treatment.
Over longer-term follow-up, recurrence is the norm. In a 25-year follow-up of a small Australian cohort of depressed patients (n=49), Brodaty et al (2001) found that only 12% of patients had remained continuously well. Although 27% of subjects had improved symptomatically according to outcome categories defined by Kiloh et al (1988), at 25 years 55% were unchanged and 18% had worsened. 4% of subjects remained depressed and suicidal.

Failure to treat depression to remission is a significant risk factor for further episodes, with the prevalence of residual symptoms carrying a three-times greater risk of relapse (76% versus 25%) (Paykel, Ramana, Cooper, et al, 1995). Similar findings have been described by Judd et al (1998). In a cohort which included 82 patients with sub-syndromal depressive symptoms (SSD) and 152 asymptomatic patients, those with SSD relapsed to their next major depressive episode (MDE) three times faster than those with full recovery, and to any depressive episode five times faster. SSD was more strongly associated with early relapse than a history of recurrent MDEs. In a prospective, naturalistic follow-up study of 70 asymptomatic patients and 26 patients with SSD following their first episode of major depression, Judd et al (2000) found that the presence of SSD predicted a more severe and more chronic pattern of illness.

Obsessive-Compulsive Disorder (OCD)

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with a lifetime prevalence of 2.2 – 3.1% (Bebbington, 1998). It is frequently comorbid with anxiety disorders and depression (Overbeek, Schruers, Vermetten, et al, 2002; Welkowitz, Struening, Pittman, et al, 2000) and often results in significant impairment of function and quality of life (Lochner, Mogotsi, du Toit, et al, 2003). OCD is thought to be related to disorders of basal ganglia function such as Tourette’s syndrome (Pauls, Towbin, Leckman, et al, 1986), and many believe that OCD shares pathophysiological links with other disorders such as trichotillomania and body dysmorphic disorder (Stein & Hollander, 1995).

The Course of OCD

OCD is commonly a chronic disorder. Symptoms can be very persistent, and spontaneous or therapy-initiated full remission is relatively infrequent. In a long-term follow-up of 122 patients with OCD, Skoog & Skoog (1999) were able to report the outcomes of individuals after 40-years. Perhaps uniquely in follow-up studies of this length, the assessments were performed by the same individuals who had initially assessed and treated the subjects at baseline. At 40-year follow-up, 83% of subjects had improved, with 20% having recovered completed. Ongoing subclinical symptoms were found in 28%. As far as the study was able, the authors concluded that 48% of patients had been symptomatic for over 30 years. Poorer outcome was associated with early age of onset, low social functioning, and a chronic course of illness.

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