Low hedonic tone and attention-deficit hyperactivity disorder: risk factors for treatment resistance in depressed adults.

BACKGROUND: The burdens imposed by treatment-resistant depression (TRD) necessitate the identification of predictive factors that may improve patient treatment and outcomes. Because depression and attention-deficit hyperactivity disorder (ADHD) are frequently comorbid and share a complex relationship, we hypothesized that ADHD may be a predictive factor for the diagnosis of TRD. This exploratory study aimed to determine the percentage of undetected ADHD in those with TRD and evaluate factors associated with treatment resistance and undetected ADHD in depressed patients. SUBJECTS AND METHODS: Adults referred (n=160) for psychiatric consultation completed a structured interview (MINI Plus, Mini International Neuropsychiatric Interview Plus) to assess the presence of psychiatric disorders. RESULTS: TRD was significantly associated with the number of diagnoses (P<0.001), past (P<0.001) and present medications (P<0.001), chronic anhedonia (P=0.013), and suicide ideation (P=0.008). Undetected ADHD was present in 34% of TRD patients. The number of referral diagnoses (P<0.001), failed medications (P=0.002), and past selective serotonin reuptake inhibitor failures (P=0.035) were predictive of undetected ADHD in TRD. CONCLUSION: Undetected ADHD may be more prevalent among TRD patients than previously thought. In addition, TRD patients are more likely to present with psychiatric comorbidity than non-TRD patients. Screening patients with depression for the presence of ADHD and chronic anhedonia/low hedonic tone may help identify patients with TRD and undetected ADHD and improve treatment outcomes.

Adjunctive Vitamin D in the treatment of non-remitted depression: Lessons from a failed clinical trial.

BACKGROUND: Many patients with depression fail to achieve remission after several consecutive treatments. Vitamin D deficiency is prevalent and new research suggests that it may have an impact on mood, primarily through an effect on neurotransmitters. Numerous observational studies suggest a relationship between low levels of vitamin D and increased incidence and severity of mood disorders. A small number of pilot studies have been undertaken but lack rigorous methodology required to draw conclusions about a clinical role for this nutrient in treatment resistant depression. METHODS: This study was designed as a randomized, double-blind, placebo controlled intervention study administering a weekly (bolus) dose of 28 000IU of Vitamin D3 or placebo to 125 patients with non-remitted depression adjunct to current antidepressant medication. Patients were followed weekly for eight weeks plus a one month follow up. Outcomes measured included depression severity, serum vitamin D levels and safety. Due to slow recruitment during the first season, amendments were made. These included extending the age range to 18-75 and removing the requirement for failing to respond to one pharmacologic antidepressant agent. The protocol was amended to reduce the burden on participants by changing the in-office visits to bi-weekly. Three additional tertiary psychiatric clinics were also added as trial sites. RESULTS: Over three recruitment period years (fall/winter), a total of 148 participants completed screening, 24 (16.2%) of whom qualified to participate in the study. Use of too many or no psychiatric medications, comorbid exclusionary psychiatric conditions, current use of a vitamin D supplement, and lack of participant compensation were the predominant reasons for ineligibility or unwillingness to participate. 9 participants were successfully enrolled in the study, 7 (77.8%) of whom completed the trial as per the protocol. After the third season, futility was declared based on inability to enroll participants. The sample size of enrolled participants (7/125, 5.6%) lacks power to conduct a full assessment of findings. DISCUSSION: High accessibility of vitamin D, as well as a growing lack of equipoise in patients and clinicians about the potential ubiquitous benefits of vitamin D for Canadians, not just for mood disorders, resulted in a large proportion of ineligible potential participants. Limited funding provided to studies on natural health products hampered recruitment. The labile and fluctuating nature of non-remitted depression as well as frequent co-morbid conditions creates additional challenges for conducting trials in this population. Future studies assessing vitamin D in depression should consider our experiences in design and conduct of research. Innovations in clinical trial design such as preference trials or accepting patients already using vitamin D but not achieving an optimal target value are potential solutions to some of these challenges.

Intolerance of uncertainty, social anxiety, and generalized anxiety: Differences by diagnosis and symptoms.

Research suggests that Intolerance of Uncertainty (IU) is related to the severity of suffering in Generalized Anxiety Disorder (GAD). However, its role in Social Anxiety Disorder (SAD) has not been extensively studied. This study examines IU in a clinical sample of 248 individuals referred to a tertiary care clinic. Few individuals had a diagnosis of pure SAD or pure GAD, but we examined differences of IU scores by diagnostic category. We further examined the relationships between IU scores, social anxiety scores, and worry through a structural equation model. We found that diagnostic category (SAD versus GAD) accounted for little variability in IU scores, but IU scores were strongly related to symptoms of both GAD and SAD. Results highlight that IU is related to both social anxiety and worry; however aspects of IU associated with being unable to act or avoiding uncertainty are more strongly associated with SAD symptoms, whereas aspects of IU more associated with general stress and perceiving uncertainty as unfair are more strongly associated with GAD symptoms. Our results suggest that IU is an important concept for both social anxiety and generalized anxiety, however the relationship between IU and symptoms of these disorders manifests differently.

Pharmacological approaches to manage persistent symptoms of major depressive disorder: rationale and therapeutic strategies.

Major depressive disorder (MDD) is a highly prevalent chronic psychiatric illness associated with significant morbidity, mortality, loss of productivity, and diminished quality of life. Typically, only a minority of patients responds to treatment and meet criteria for remission as residual symptoms may persist, the result of an inadequate course of treatment and/or the presence of persistent side effects. The foremost goal of treatment should be to restore patients to full functioning and eliminate or relieve all MDD symptoms, while being virtually free of troublesome side effects. The current available pharmacological options to manage persistent depressive symptoms include augmentation or adjunctive combination strategies, both of which target selected psychobiological systems and specific mood and somatic symptoms experienced by the patient. As well, non-pharmacological interventions including psychotherapies may be used in either first-line or adjunctive approaches. However, the evidence to date with respect to available adjunct therapies is limited by few studies and those published have utilized only a small number of subjects and lack enough data to allow for a consensus of expert opinion. This underlines the need for further longer term, large population-based studies and those that include comorbid populations, all of which are seen in real world community psychiatry.

Treating young individuals at clinical high risk for psychosis.

BACKGROUND: Typically, studies investigating those at clinical high risk for psychosis have focused on predictors of conversion and treatments that might prevent conversion to full-blown psychosis. Few studies have followed those who do not go on to develop a psychotic illness. METHODS: Participants were 48 young people who were at risk for developing psychosis based on the Structured Interview for Prodromal Symptoms criteria and participated in a treatment programme where they were offered up to 6 months of psychosocial treatment and psychiatric management. Attenuated psychotic symptoms, negative symptoms, depression, anxiety, social functioning, alcohol and drug use, and meta-cognitive beliefs were assessed at baseline, 6, 12 and 18 months. Personality characteristics were assessed at baseline. Medication use was tracked and psychiatric visits were logged over the 18-month study period. RESULTS: On average, participants attended 12 sessions of psychosocial treatment and had one meeting with the psychiatrist every 6 months. Only 24% were ever prescribed any psychotropic medications, and antipsychotics were not used. Significant improvements were found over time in attenuated positive symptoms, negative symptoms, depression, anxiety, meta-cognitions and social functioning with most improvement occurring in the first 6 months. There was no change in the level of substance use. For personality assessment, participants generally scored high on neuroticism and openness and had low scores on extraversion, agreeableness and conscientiousness. CONCLUSION: With minimal treatment and no antipsychotics, young people who present as being at risk for developing a psychotic disorder demonstrate clinical improvement over time. However, a few continued to have the liability of ongoing attenuated psychotic symptoms.

A randomized controlled trial of cognitive behavioral therapy for individuals at clinical high risk of psychosis.

BACKGROUND: There has been increasing interest in early detection during the prodromal phase of a psychotic disorder. To date a few treatment studies have been published with some promising results for both pharmacological treatments, using second generation antipsychotics, and psychological interventions, mainly cognitive behavioral therapy. The purpose of this study was to determine first if cognitive behavioral therapy (CBT) was more effective in reducing the rates of conversion compared to a supportive therapy and secondly whether those who received CBT had improved symptoms compared to those who received supportive therapy. METHOD: Fifty-one individuals at clinical high risk of developing psychosis were randomized to CBT or a supportive therapy for up to 6 months. The sample was assessed at 6, 12 and 18 months post baseline on attenuated positive symptoms, negative symptoms, depression, anxiety and social functioning. RESULTS: Conversions to psychosis only occurred in the group who received supportive therapy although the difference was not significant. Both groups improved in attenuated positive symptoms, depression and anxiety and neither improved in social functioning and negative symptoms. There were no differences between the two treatment groups. However, the improvement in attenuated positive symptoms was more rapid for the CBT group. CONCLUSIONS: There are limitations of this trial and potential explanations for the lack of differences. However, both the results of this study and the possible explanations have significant implications for early detection and intervention in the pre-psychotic phase and for designing future treatments.

The International Study on General Practitioners and Early Psychosis (IGPS).

BACKGROUND: In much of the world, general practitioners (GPs) are the health professionals most frequently initially contacted when a young person is developing psychosis. However little is known about their expertise in assessing psychosis and its risk. METHODS: To assess the diagnostic patterns and treatment practices related to psychosis of GPs working in a range of health care systems, questionnaires were mailed to 12,516 randomly selected GPs in seven countries: Canada, Australia, New Zealand, England, Norway, Austria and the Czech Republic. Sites were defined as gatekeeping or non-gatekeeping, based on the primary care health system in effect at each site. A gatekeeping system (GK) is one which mandates that patients see a GP before in order to be referred to a specialist. By contrast, in a non-gatekeeping (nGK) system, individuals can seek help directly from specialists without authorization by a GP. RESULTS: Twenty-two percent (n=2784) GPs responded to the mailed questionnaire. They reported low prevalence of early psychosis seen in general practice. Using awareness of functional decline as a prognostic sign as a proxy, gatekeeping (GK) GPs were found to be superior in their knowledge of the signs and symptoms of early psychosis than were non-gatekeeping GPs. GP's with less knowledge as to early psychosis were more likely to refer individuals with suspected psychosis to specialists. GP's reported a preference for access to specialized outpatient services as compared with obtaining continuous medical education relevant to early psychosis. The duration of maintenance treatment recommended by GP's was less than that recommended in international guidelines. GP's also underestimated the risk for relapse after a first episode of psychosis. CONCLUSIONS: As GPs were largely unaware of features of early psychosis, such as functional decline, this should be the target of educational programs for GP's. However, the incidence of psychosis is low and GP's express a preference for access to appropriate referral over continuing medical education. Therefore, the development of specialized services for the assessment and care of patients who are in the early stages of developing schizophrenia may be warranted.

Early detection of psychosis: finding those at clinical high risk.

AIM: In early detection work, recruiting individuals who meet the prodromal criteria is difficult. The aim of this paper was to describe the development of a research clinic for individuals who appear to be at risk of developing a psychosis and the process for educating the community and obtaining referrals. METHODS: The outcome of all referrals to the clinic over a 4-year period was examined. RESULTS: Following an ongoing education campaign that was over inclusive in order to aid recruitment, approximately 27% of all referrals met the criteria for being at clinical high risk of psychosis. CONCLUSIONS: We are seeing only a small proportion of those in the community who eventually go on to develop a psychotic illness. This raises two important issues, namely how to remedy the situation, and second, the impact of this on current research in terms of sampling bias and generalizability of research findings.

Randomized, double-blind trial of olanzapine versus placebo in patients prodromally symptomatic for psychosis.

OBJECTIVE: This study assessed the efficacy of olanzapine in delaying or preventing conversion to psychosis and reducing symptoms in people with prodromal symptoms of schizophrenia. METHOD: This randomized trial occurred at four North American clinics in the Prevention Through Risk Identification, Management, and Education project. Outpatients received olanzapine (5-15 mg/day, N=31) or placebo (N=29) during a 1-year double-blind treatment period and no treatment during a 1-year follow-up period. Efficacy measures included the conversion-to-psychosis rate and Scale of Prodromal Symptoms scores. RESULTS: During the treatment year, 16.1% of olanzapine patients and 37.9% of placebo patients experienced a conversion to psychosis, a nearly significant difference. The hazard of conversion among placebo patients was about 2.5 times that among olanzapine-treated patients, which also approached significance. In the follow-up year, the conversion rate did not differ significantly between groups. During treatment, the mean score for prodromal positive symptoms improved more in the olanzapine group than in the placebo group, and the mixed-model repeated-measures least-squares mean score showed significantly greater improvement between weeks 8 and 28 with olanzapine. The olanzapine patients gained significantly more weight (mean=8.79 kg, SD=9.05, versus mean=0.30 kg, SD=4.24). CONCLUSIONS: A significant treatment difference in the conversion-to-psychosis rate was not demonstrated. However, these results may be influenced by low power. The nearly significant differences suggest that olanzapine might reduce the conversion rate and delay onset of psychosis. Olanzapine was efficacious for positive prodromal symptoms but induced weight gain. Further treatment research in this phase of illness is warranted.

An overview of the genetic risk of developing schizophrenia in relatives of schizophrenic patients.

In this article, we review the recent research evidence of genetic risks in the relatives of patients with schizophrenia, with particular focus on family, twin, adoptive, and gene studies. All current evidence supports a greater role for genetic transmission of vulnerability in the etiology of schizophrenia. Environmental factors appear to play an important role in the timing of expression, the severity and the clinical evolution of the illness.

Treatment response to olanzapine and haloperidol and its association with dopamine D receptor occupancy in first-episode psychosis.

OBJECTIVE: Response to typical antipsychotic medication has been associated with achieving a level of striatal dopamine D2 receptor occupancy in the range of 65% to 70%. We undertook this study to determine whether response to the atypical antipsychotic olanzapine occurs at lower levels of D2 receptor occupancy. METHOD: Eighteen patients who presented with a first episode of psychosis were randomized to receive olanzapine 5 mg daily or haloperidol 2 mg daily in a double-blind design. We acquired positron emission tomography (PET) scans using the D2 ligand [11C]raclopride within the first 15 days of treatment to determine the percentage of D2 receptors occupied by the medication. According to response, dosage was then adjusted to a maximum dosage of 20 mg daily of either drug. PET scans were repeated after 10 to 12 weeks of treatment. RESULTS: At the first PET scan, the 8 olanzapine-treated patients had significantly lower D2 receptor occupancies (mean 63.4%, SD 7.3) than those observed in the 10 patients treated with haloperidol (mean 73.0%, SD 6.1). When patients were rescanned following dosage adjustment, mean D2 receptor occupancies were greater than 70% in both groups. D2 receptor occupancies did not differ significantly between the olanzapine-treated group (mean 72.0%, SD 5.7) and the haloperidol-treated group (mean 78.7%, SD 7.6). CONCLUSIONS: These results suggest that, in patients being treated for a first episode of psychosis, olanzapine has its antipsychotic effect at approximately the same levels of D2 receptor occupancy as are achieved with low dosages of haloperidol.

Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade.

BACKGROUND: It has been suggested that transiently high dopamine-2 (D(2)) receptor occupancy by antipsychotic medication may be sufficient for inducing an antipsychotic response. We treated patients experiencing their first episode of schizophrenia with a single daily dose of quetiapine to achieve a transient daily peak of D(2) receptor blockade, to determine if this would lead to an antipsychotic response. METHOD: Fourteen patients with a DSM-IV diagnosis of schizophrenia or schizophreniform or schizoaffective disorder were treated with quetiapine titrated to a single daily dose (mean +/- SD dose at the time of the positron emission tomography [PET] scan = 427 +/- 69 mg) for 12 weeks. Peak D(2) occupancy approximately 2 hours postdose and trough D(2) occupancy approximately 20 hours postdose were determined using PET and [(11)C]raclopride. Clinical symptoms and side effects were measured at baseline and every 2 weeks during the treatment phase. RESULTS: Quetiapine administration led to a mean peak D(2) occupancy of 62% +/- 10% 2 hours postdose, which declined to 14% +/- 8% approximately 20 hours postdose. Ten (71%) of 14 patients responded to treatment with quetiapine, scoring "much improved" or greater on the Clinical Global Impressions-Improvement scale. Plasma drug levels and peak D(2) occupancy were highly correlated (r = 0.84; p =.003), as were prolactin and plasma drug levels when measured 2.5 hours after drug administration (r = 0.60; p <.05). Mean weight gain for the 10 subjects who completed the 12-week study was 4.2 +/- 4.6 kg (9.3 +/- 10.2 lb). No clinically relevant motor side effects occurred during the trial. CONCLUSION: Patients with a first episode of schizophrenia responded to treatment with a single daily dose of quetiapine despite only transiently high D(2) receptor occupancy. Our findings raise the question of whether continuously high D(2) blockade is necessary for obtaining an antipsychotic response. Future studies aimed at evaluating the relative merits of "transiently high" versus "continuously high" D(2) occupancy are warranted.