Bipolar disorder, mood stabilizers and cognitive flexibility: Translationally dissecting illness from drug effects.

Bipolar disorder (BD) effects on cognition are confounded by the putative cognitive impact of its major pharmacological treatments, given the neurotrophic potential of mood stabilizers, particularly lithium. We examined the area of cognitive flexibility (CF), aiming to disentangle BD from medication effects, using translational methodology. CF was assessed by CANTAB-IED (intra- extra-dimensional shift; Study 1, euthymic BD participants) and its animal analog (Study 2, rats). Both studies included groups (1) control, (2) lithium, chronic, current treatment (LI-CHRON-C, A: > 2 years, N = 32; B: 2 months, N = 11); (3) valproate, chronic, current treatment (VPA-CHRON-C, A: > 2 years, N = 30; B: 2 months, N = 12). Study 2 included 2 additional groups; Group 4: LI-CHRON-PAST (2 months, stopped 1 month pretest, N = 13); Group 5: LI-ACUTE (LI on test days only, N = 13). In Study 1, neither total nor stage (discrimination: D; reversal R; intra- extra-dimensional shifts: IED) IED errors differed between groups [Kruskal-Wallis: H(2, N = 94) 0.95 > p > 0.65]. Similarly in Study 2, errors did not differentiate the 5 pharmacological groups. Differences emerged only between LI-ACUTE and Controls in response latencies (D, R, IED ANOVAS: 0.002 > p > 0.0003; contrasts D, R: p = 0.002, 0.0001). In conclusion, LI and VPA BD patients were indistinguishable from Controls in IED errors, as were animals treated with LI-CHRON, current or past, or VPA-CHRON-C vs Controls. LI-ACUTE treatment produced significant latency deficits vs Controls. Within the limitations of translational comparisons, our results suggest that the normal CF noted in euthymic BDs is not attributable to mood stabilizer effects.

Episodic Visual Learning/Memory and Attentional Flexibility in Patients With Major Depressive Disorder After Clinically Effective Electroconvulsive Therapy.

OBJECTIVES: This study is a follow-up of a previous one reporting that the neuropsychological profile of pharmacoresistant patients with major depressive disorder referred for electroconvulsive therapy (ECT, ECT group) contrasted with that of their pharmacorespondent counterparts (NECT group). The NECT group exhibited severe visuospatial memory and minor executive deficits; the ECT group presented the reverse pattern. In that same ECT group, the current follow-up study examined the effects of clinically effective ECT on both cognitive domains 2 months later. METHODS: Fifteen ECT patients were administered Hamilton Depression (HAMD-24), Hamilton Anxiety (HAMA), Mini-Mental State Examination Scales and 5 tests of Cambridge Neuropsychological Test Automated Battery at intake (pre-ECT), end of ECT course (post-ECT), and 2 months thereafter (follow-up). RESULTS: Electroconvulsive therapy was effective in relieving clinical depression. After a post-ECT decline, the patients exhibited significant improvement in both Cambridge Neuropsychological Test Automated Battery, paired associate learning, and Stockings of Cambridge. By contrast, their major pre-ECT deficit in intra/extradimensional set shifting remained virtually unaffected. CONCLUSIONS: Our findings suggest that attentional flexibility deficits may constitute a neuropsychological trait-like feature of pharmacoresistant, ECT-referred major depressive disorder patients. However, this deficit does not seem generalized, given patient improvement in episodic visual learning/memory and some indication of improvement in spatial planning after ECT.

Dopaminergic and serotonergic modulation of persistent behaviour in the reinforced spatial alternation model of obsessive-compulsive disorder.

RATIONALE: We have proposed rewarded T-maze alternation as a model of obsessive-compulsive disorder (OCD): the serotonin agonist m-chlorophenylpiperazine (mCPP) increments persistence therein, while chronic pretreatment with selective serotonin reuptake inhibitor (SSRI fluoxetine) but not benzodiazepine or desipramine abolishes mCPP effects. However, we noted that acute SSRI administration also causes transient persistence increase, counteracted by mCPP pretreatment. OBJECTIVES: This study (a) further explores the cross-tolerance between fluoxetine and mCPP and (b) extends the model by investigating its sensitivity to dopaminergic manipulations (D2, 3 agonism--quinpirole). MATERIALS AND METHODS: In both experiments, baseline and drug testing were carried out under daily T-maze alternation training. Exp. 1: Matched group (n = 8) pairs of rats received one of the following 20-day pretreatments (daily intraperitoneal administration): (1) saline, (2) low-dose fluoxetine (2.5 mg/kg), (3) low-dose mCPP (0.5 mg/kg) or (4) combined fluoxetine + mCPP. One group per pretreatment then received a 4-day challenge with high-dose fluoxetine (10 mg/kg), the other with high-dose mCPP (2.5 mg/kg). Exp. 2: One group (n = 12) of rats received 20-day treatment with saline, another with quinpirole (0.5 mg/kg). RESULTS: Exp. 1: Saline and low-dose mCPP- or fluoxetine-pretreated animals showed significant persistence increases under both challenges, while combined low-dose fluoxetine + mCPP pretreatment afforded full protection from either challenge. Exp. 2: Quinpirole significantly increased directional persistence after 13 administration days. CONCLUSIONS: These results establish the sensitivity of the rewarded alternation OCD model to D2, 3 receptor activation, thereby extending its profile of pharmacological isomorphism with OCD. Furthermore, they suggest a common mechanism of action of an SSRI and a serotonin agonist in the control of directional persistence.

Enhancing effects of chronic lithium on memory in the rat.

BACKGROUND: In spite of recent enrichment of neurochemical and behavioural data establishing a neuroprotective role for lithium, its primary effects on cognitive functioning remain ambiguous. This study examines chronic lithium effects on spatial working memory and long-term retention. METHODS: In three discrete experiments, rats subjected to 30 daily intraperitoneal injections (2mmol/kg) of lithium (lithium groups: serum lithium=0.5+/-0.4mEq/l, 12h post-injection) or saline (controls) were trained in 0-s delay T-maze alternation and then tested in 30-, 45- and 60-s delay alternation (Experiments 1, 2, 3, respectively). Animals from Experiment 1 were further tested in one-trial step-through passive avoidance under mild shock parameters (0.5mA, 1s). Retention was assessed 6h later. Daily lithium or saline injections continued throughout behavioural testing. RESULTS: Lithium animals were indistinguishable from controls during 0-delay alternation baseline (Experiments 1-3, accuracy>88%) but showed significantly higher accuracy than controls at 30- and 45-s delays (93% versus 85% and 92% versus 82%, Experiments 1 and 2, respectively). At 60-s delay (Experiment 3) this beneficial effect of lithium was no longer apparent (lithium and control accuracy=78%). In Experiment 4, the shock used did not support 6-h passive avoidance retention in controls, whereas lithium animals showed significant step-through latency increases. CONCLUSIONS: Chronic lithium enhanced spatial working memory and promoted long-term retention of a weak aversive contingency. The results suggest that lithium may have potential as a cognitive enhancer.

The screening role of an introductory course in cognitive therapy training.

OBJECTIVE: This study examines the role of an introductory course in cognitive therapy and the relative importance of trainees' characteristics in the selection process for an advanced course in cognitive therapy. METHOD: The authors assessed the files of all trainees who completed one academic year introductory course in cognitive therapy over the last seven consecutive years (N = 203). The authors examined variables such as previous training, overall involvement during the course, performance, and ability to relate to others, as well as the trainer's evaluations of their performance. RESULTS: Interaction skills in group situations and performance in written assignments were better predictors for admission into the advanced course. CONCLUSIONS: Trainees' abilities to learn and to successfully relate to others in group situations are critical for entering an advanced cognitive therapy training course. These findings question the policy of full-scale training in cognitive therapy based merely on the candidates' professional background, stressing instead the merits of an introductory course as an appropriate screening procedure.

A survey of the attitudes of Greek medical students toward electroconvulsive therapy.

Data on attitudes toward electroconvulsive therapy have been reported from various countries; no information, however, is available from Greece. In this survey, we report the results of a questionnaire reflecting the general attitude of Greek medical students toward ECT. A total of 161 sixth (final)-year medical students who had no previous exposure to a formal didactic experience on ECT, were asked to complete a questionnaire before attending a scheduled 90-minute lecture on ECT, as part of their regular curriculum. Questions in the questionnaire could be grouped to indicate a positive, a reserved, or a negative attitude toward ECT. Overall, before the lecture, 50.3% held a positive attitude toward ECT, 43.5% were reserved, and 6.2% held a negative attitude. A subgroup of these students (n = 137) were asked again to score the same questionnaire immediately following the lecture to rate the impact of the didactic seminar. The proportion of students with a positive attitude after the lecture was increased to 78.1%, (P < 0.001), while the proportion of students with reserved and negative attitudes were reduced to 20.4% (P < 0.001) and 1.5%, respectively. These encouraging findings reflect, however, only the immediate effects of the lecture and do not guarantee persistence of this change in attitudes over time.