The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

A comparison of self- and observer-rated scales for detecting clinical improvement during repetitive transcranial stimulation (rTMS) treatment of depression.

Clinical outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of Major Depressive Disorder (MDD) vary widely, and no single mood rating scale is standard for assessing rTMS outcomes. This study of 708 subjects undergoing clinical rTMS compared the performance of four scales in measuring symptom change during rTMS treatment. Self-report and observer ratings were examined weekly with the Inventory of Depressive Symptomatology 30-item (IDS), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item (POMS), and Hamilton Depression Rating Scale 17-item (HDRS). While all scales were correlated and detected significant improvement, the degree of improvement over time as well as response (33-50%) and remission (20-24%) rates varied significantly. Higher baseline severity was associated with lower likelihood of remission, and greater improvement by sessions 5 and 10 predicted response across all scales. Use of only a single scale to assess outcome conferred 14-36% risk of failing to detect response/remission indicated by another scale. The PHQ was most likely to indicate improvement and least likely to miss response or remission. These findings indicate that assessment of symptom burden during rTMS treatment may be most accurately assessed through use of multiple instruments.

D(1) receptor agonists reverse the subchronic phencyclidine (PCP)-induced novel object recognition (NOR) deficit in female rats.

Development of dopamine (DA) D(1) receptor agonists is a priority to improve cognitive impairment in schizophrenia (CIS). This study examined the dose-response relationship of the selective D(1) agonist, SKF38393 (0.5-40 mg/kg), to reverse the deficit in novel object recognition (NOR), an analog of declarative memory in man, produced by subchronic phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor non-competitive antagonist, and the ability of the D(1) antagonists, SCH23390 (0.05 mg/kg) and SKF83566 (0.15 mg/kg), to impair NOR in normal Long-Evans female rats. We also examined the ability of tandospirone, a serotonin (5-HT)(1A) receptor partial agonist, and LY341495, a mGluR2/3 receptor antagonist, to potentiate or block the effects of SKF38393 on NOR, respectively. SKF38393 reversed the persistent NOR deficit produced by subchronic PCP; the dose-response curve for SKF38393 was an inverted U-shape, with the peak effect at 6 mg/kg. SKF83566 and SCH23390 impaired NOR in normal rats. Co-administration of sub-effective doses of SKF38393 (0.25 mg/kg) and tandospirone (0.2 mg/kg) improved the PCP-induced NOR deficit, while LY341495 (1 mg/kg) blocked the ameliorating effect of SKF38393 (6 mg/kg), respectively. These data provide the first evidence that the reversal of the PCP-induced NOR deficit by D(1) agonism has an inverted U-shaped dose-response curve and that 5-HT(1A) and mGluR2/3 receptor signalling facilitates the efficacy of D(1) agonism to improve these deficits. These data suggest that although D(1) agonists may be useful to improve CIS, these agents, particularly higher doses, may also worsen cognitive function in some patients, because of an inverted U-shaped dose response curve.

Prevention of the phencyclidine-induced impairment in novel object recognition in female rats by co-administration of lurasidone or tandospirone, a 5-HT(1A) partial agonist.

Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.