Is Antipsychotic Drug Use During Pregnancy Associated with Increased Malformation Rates and Worsening of Maternal and Infant Outcomes? A Systematic Review.

There is much debate about continuing antipsychotic medication in patients who need it when they become pregnant because benefits must be weighed against potential teratogenic and malformation effects related to antipsychotics themselves. To address this, we conducted a systematic review on the PubMed, PsycINFO and CINHAL databases and the ClinicalTrials.gov register using the following strategy: (toxicity OR teratogenicity OR malformation* OR "birth defect*" OR "congenital abnormality" OR "congenital abnormalities" OR "brain changes" OR "behavioral abnormalities" OR "behavioral abnormalities") AND antipsychotic* AND (pregnancy OR pregnant OR lactation OR delivery OR prenatal OR perinatal OR post-natal OR puerperium) on September 27, 2023. We found 38 studies to be eligible. The oldest was published in 1976, while most articles were recent. Most studies concluded that the antipsychotics, especially the second-generation antipsychotics, were devoid of teratogenic potential, while few studies were inconclusive and recommended replication. Most authoritative articles were from the Boston area, where large databases were implemented to study the malformation potential of psychiatric drugs. Other reliable databases are from Northern European registers. Overall conclusions are that antipsychotics are no more related to malformations than the disorders themselves; most studies recommend that there are no reasons to discontinue antipsychotic medications in pregnancy.

Post-Traumatic Stress Disorder Trajectories the Year after COVID-19 Hospitalization.

Background: Coronavirus disease (COVID-19) hospitalization has been related to Post-Traumatic Stress Disorder (PTSD). Available information is limited by insufficient follow-up and lack of longitudinal studies. Baseline factors (e.g., sex; obesity) have been related to PTSD, but post-hospitalization factors have not been studied. Objective: This study aimed to analyse prevalence, baseline, post-discharge factors and possible clinical courses of PTSD after hospitalization for COVID-19. Method: 109 patients (94.7% of the original sample) completed a programme of three follow-up telephone assessments during the year following hospitalization. Data included clinical and sociodemographic factors as well as psychometric tools assessing PTSD, social support, and perception of threat to life (PTL). Mixture model analysis was performed to study the longitudinal course of PTSD symptoms. Chronic (>6 months) PTSD predictors were also analysed. Results: 1-year PTSD period prevalence was 23.9%, peaking at six months; 11% of the patients suffered chronic PTSD. Pre- and post-hospitalization factors influenced the onset and course of PTSD over time. These included working status, PTL, and lack of social support. Interestingly, obesity, pulmonary diseases and family cluster infection seem specifically related to PTSD following COVID-19. Inversely, clinical interventions, older age and male gender were protective. Conclusions: PTSD following COVID-19 hospitalization is common. The analysed demographic, social, clinical, and psychological factors predict PTSD symptomatology over time and can modify odds of a chronic course. Clinicians could better identify cases at risk of a chronic PTSD course. Finally, treatment as usual appeared related to a better outcome and should be proposed to patients with PTSD.

Amygdala structure and function in paediatric bipolar disorder and high-risk youth: A systematic review of magnetic resonance imaging findings.

OBJECTIVE: Converging evidence from structural and functional magnetic resonance imaging (MRI) studies points to amygdala alteration as crucial in the development of paediatric bipolar disorder (pBP). The high number of recent studies prompted us to comprehensively evaluate findings. We aimed to systematically review structural and functional MRI studies investigating the amygdala in patients with pBP and in youth at high-risk (HR) for developing pBP. METHODS: We searched PubMed from any time to 25 September 2020 using: 'amygdala AND (MRI OR magnetic resonance imaging) AND bipolar AND (pediatr* OR child OR children OR childhood OR adolescent OR adolescents OR adolescence OR young OR familial OR at-risk OR sibling* OR offspring OR high risk)'. In this review, we adhered to the PRISMA statement. RESULTS: Amygdala hyperactivity to emotional stimuli is the most commonly reported finding in youth with pBP and HR compared to healthy peers (HC), whereas findings from structural MRI studies are inconsistent. CONCLUSIONS: Hyperactivation of the amygdala might be an endophenotype of pBP.

Depressive Symptoms among Individuals Hospitalized with COVID-19: Three-Month Follow-Up.

Individuals affected by Coronavirus Disease 2019 (COVID-19) may experience psychiatric symptoms, including depression and suicidal ideation, that could lead to chronic impairment and a reduction in quality of life. Specifically, depressive disorder shows high incidence and may lead to chronic impairment and a reduction in the quality of life. To date, no studies on the presence of suicidality and quantitative analysis of depressive symptoms and their risk factors have yet been published. In this study, we aim to assess the prevalence of depressive symptoms and related risk factors at 3 months after discharge to home care following hospitalization for COVID-19 infection. METHODS: Participants were contacted three months after hospital discharge from one of the five COVID-19 hospitals in Rome, as part of a larger project on health outcomes in COVID-19 inpatients (Long Term Neuropsychiatric Disorder in COVID-19 Project), and the Patient Health Questionnaire-9 (PHQ-9) was administered by telephone interview. RESULTS: Of 115 participants, 14.8% (N = 17) received a PHQ-9-based diagnosis of depression, and n = 7 of them scored 1 or more on the item on suicidality. A linear regression model showed the predictive role of female sex, pulmonary chronic condition and previous mental disorder in the development of depressive disorder; the latter was confirmed also by binary logistic regression. Severity indexes of disease (length of hospitalization and intensive care treatment) were found not to be associated with the development of depressive symptoms. CONCLUSIONS: A small but clinically meaningful number of participants in the current study reported that they experienced symptoms of depression and suicidal ideation 3 months post-discharge from their COVID-19 hospitalization. In particular, given the findings that a history of prior psychiatric disorders was predictive of the development of depression symptoms, clinicians should carefully monitor for the presence of all psychiatric symptoms at follow-up visits.

Post-Traumatic Stress Symptoms in Healthcare Workers Dealing with the COVID-19 Pandemic: A Systematic Review.

Prevention of post-traumatic stress symptoms (PTSS) in healthcare workers (HCWs) facing the current COVID-19 pandemic is a challenge worldwide as HCWs are likely to experience acute and chronic, often unpredictable, occupational stressors leading to PTSS. This review aims to analyze the literature to discover which topics have been focused on and what the latest developments are in managing the occupational risk of PTSS in HCWs during the current pandemic. For the purpose of this review, we searched for publications in MEDLINE/Pubmed using selected keywords. The articles were reviewed and categorized into one or more of the following categories based on their subject matter: risk assessment, risk management, occurrence rates. A total of 16 publications matched our inclusion criteria. The topics discussed were: "Risk Assessment", "Occurrence Rates", and "Risk Management". Young age, low work experience, female gender, heavy workload, working in unsafe settings, and lack of training and social support were found to be predictors of PTSS. This review's findings showed the need for urgent interventions aimed at protecting HCWs from the psychological impact of traumatic events related to the pandemic and leading to PTSS; healthcare policies need to consider preventive and management strategies toward PTSS, and the related psychic sequelae, in HCWs.

Oral Bacteriotherapy Reduces the Occurrence of Chronic Fatigue in COVID-19 Patients.

Long COVID refers to patients with symptoms as fatigue, "brain fog," pain, suggesting the chronic involvement of the central nervous system (CNS) in COVID-19. The supplementation with probiotic (OB) would have a positive effect on metabolic homeostasis, negatively impacting the occurrence of symptoms related to the CNS after hospital discharge. On a total of 58 patients hospitalized for COVID-19, 24 (41.4%) received OB during hospitalization (OB+) while 34 (58.6%) taken only the standard treatment (OB-). Serum metabolomic profiling of patients has been performed at both hospital acceptance (T0) and discharge (T1). Six months after discharge, fatigue perceived by participants was assessed by administrating the Fatigue Assessment Scale. 70.7% of participants reported fatigue while 29.3% were negative for such condition. The OB+ group showed a significantly lower proportion of subjects reporting fatigue than the OB- one (p < 0.01). Furthermore, OB+ subjects were characterized by significantly increased concentrations of serum Arginine, Asparagine, Lactate opposite to lower levels of 3-Hydroxyisobutirate than those not treated with probiotics. Our results strongly suggest that in COVID-19, the administration of probiotics during hospitalization may prevent the development of chronic fatigue by impacting key metabolites involved in the utilization of glucose as well as in energy pathways.

The Koukopoulos mixed depression rating scale (KMDRS) and the assessment of mixed symptoms during the perinatal period.

BACKGROUND: Mixed symptoms in depression may underlie bipolar diathesis rather than unipolarity. Uncovering mixed depression (MxD) is crucial for appropriate management, especially in the perinatal period, as it may affect treatment planning and impact future child development. We used a scale specific for identifying MxD and tested its validity in pregnant and postpartum women with depression. METHODS: Women developing a major depressive episode (MDE) during their perinatal period extending from pregnancy to one year postpartum from November-2012 through June-2019 were assessed with BPRS-18, EPDS, CGI-S, GAF, HAM-A, HAM-D, Koukopoulos' Mixed Depression Rating Scale (KMDRS), TEMPS, and YMRS. They were classified, based on KMDRS criteria, as with mixed (MxD) or without (nonMxD) mixed symptoms. We conducted ROC analysis and performed factor analysis of the KMDRS. RESULTS: Of 45 included, MxD (N = 19) were biased towards diagnosis of bipolar disorder and nonMxD (N = 26) towards major depressive disorder. Other sociodemographic variables did not differ significantly between MxD and nonMxD. MxD scored higher on total YMRS, BPRS, and KMDRS, and on KMDRS-6 Subjective Feelings of Irritability and KMDRS-12 Suicidal Impulsiveness items. The KMDRS correlated in the entire sample, in MxD and nonMxD, with the YMRS and the BPRS, while correlating with the HAM-D in nonMxD only. The KMDRS showed acceptable AUC distribution, with a 68% sensitivity and 58% specificity. Best-fit was three-factor-structure, explaining 54.66% of cumulative variance. LIMITATIONS: Small sample and cross-sectional design. CONCLUSIONS: The KMDRS is fit for investigating MxD along with the YMRS and the BPRS in perinatal women with a MDE.

Stabilization Beyond Mood: Stabilizing Patients With Bipolar Disorder in the Various Phases of Life.

BACKGROUND: There are different ways to define stabilization and currently, the main standpoint regards it as no-depression/no-mania. Furthermore, each person is physiologically different from childhood to adulthood, and in old age, thus the meaning of stabilization should take into account both growth and maturity. We aimed to review systematically studies focusing on mood stabilization in all phases of bipolar disorder (BD) and across all life phases, including pregnancy and the perinatal period, which is still a different phase in women's life cycles. METHODS: We carried out a PubMed search focusing on studies of bipolar disorder treated with drugs and aimed at stabilization with the following search strategy stabiliz*[ti] OR stabilis*[ti] OR stable[ti] OR stability[ti]) AND mood[ti] AND bipolar. In conducting our review, we followed the PRISMA statement. Agreement on inclusion was reached by consensus of all authors through a Delphi rounds procedure. RESULTS: The above search strategy produced 509 records on January 25, 2020. Of them, 58 fitted our inclusion criteria and were discussed. The eligible studies spanned from September 1983 to July 6, 2019. CONCLUSIONS: No clear-cut indications could be drawn due to a number of limitations involving sample inconsistency and different methods of assessing mood stabilization. The evidence collected so far does not allow recommended treatments for Adolescents, pregnant or perinatal women, and aged patients. However, adults, not within these groups, better focused upon. For their manic/mixed phases, second generation antipsychotic drugs may be useful in the short-to-medium run, alone or combined with mood stabilizers (MSs). However, MSs, and especially lithium, continue to be pivotal in chronic treatment. Bipolar depression should rely on MSs, but an antidepressant may be added on and can prove to be helpful. However, there are concerns with the tendency of antidepressants to induce the opposite polarity or mood instability, rendering the need for concurrent MS prescription mandatory.

Early clinical predictors of long-term morbidity in major depressive disorder.

AIMS: To identify early clinical factors predictive of later morbidity in major depressive disorder (MDD). METHODS: We analysed factors associated with long-term depressive morbidity (%-time ill) between a first-lifetime major depressive episode and last follow-up of 116 adults diagnosed with DSM-IV major depressive disorder. Bivariate comparisons were followed by multivariable linear regression modelling. RESULTS: Three factors were independently associated with an average of 25%-time-depressed over 17 years at risk: (a) agitated-mixed, or psychotic features in initial major depressive episodes, (b) anxiety syndromes prior to a first-lifetime major depressive episode, and (c) anxiety symptoms in childhood. CONCLUSION: Early anxiety symptoms and syndromes and agitated-mixed or psychotic initial depressive episodes predicted more long-term depressive morbidity in MDD.

The Koukopoulos Mixed Depression Rating Scale (KMDRS): An International Mood Network (IMN) validation study of a new mixed mood rating scale.

BACKGROUND: It has been proposed that the broad major depressive disorder (MDD) construct is heterogenous. Koukopoulos has provided diagnostic criteria for an important subtype within that construct, "mixed depression" (MxD), which encompasses clinical pictures characterized by marked psychomotor or inner excitation and rage/anger, along with severe depression. This study provides psychometric validation for the first rating scale specifically designed to assess MxD symptoms cross-sectionally, the Koukopoulos Mixed Depression Rating Scale (KMDRS). METHODS: 350 patients from the international mood network (IMN) completed three rating scales: the KMDRS, Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). KMDRS' psychometric properties assessed included Cronbach's alpha, inter-rater reliability, factor analysis, predictive validity, and Receiver Operator Curve analysis. RESULTS: Internal consistency (Cronbach's alpha = 0.76; 95% CI 0.57, 0.94) and interrater reliability (kappa = 0.73) were adequate. Confirmatory factor analysis identified 2 components: anger and psychomotor excitation (80% of total variance). Good predictive validity was seen (C-statistic = 0.82 95% CI 0.68, 0.93). Severity cut-off scores identified were as follows: none (0-4), possible (5-9), mild (10-15), moderate (16-20) and severe (> 21) MxD. LIMITATIONS: Non DSM-based diagnosis of MxD may pose some difficulties in the initial use and interpretation of the scoring of the scale. Moreover, the cross-sectional nature of the evaluation does not verify the long-term stability of the scale. CONCLUSIONS: KMDRS was a reliable and valid instrument to assess MxD symptoms.

Neurobiological Evidence for the Primacy of Mania Hypothesis.

BACKGROUND: Athanasios Koukopoulos proposed the primacy of mania hypothesis (PoM) in a 2006 book chapter and later, in two peer-reviewed papers with Nassir Ghaemi and other collaborators. This hypothesis supports that in bipolar disorder, mania leads to depression, while depression does not lead to mania. OBJECTIVE: To identify evidence in literature that supports or falsifies this hypothesis. METHOD: We searched the medical literature (PubMed, Embase, PsycINFO, and the Cochrane Library) for peer-reviewed papers on the primacy of mania, the default mode function of the brain in normal people and in bipolar disorder patients, and on illusion superiority until 6 June, 2016. Papers resulting from searches were considered for appropriateness to our objective. We adopted the PRISMA method for our review. The search for consistency with PoM was filtered through the neurobiological results of superiority illusion studies. RESULTS: Out of a grand total of 139 records, 59 were included in our analysis. Of these, 36 were of uncertain value as to the primacy of mania hypothesis, 22 favoured it, and 1 was contrary, but the latter pooled patients in their manic and depressive phases, so to invalidate possible conclusions about its consistency with regard to PoM. All considered studies were not focused on PoM or superiority illusion, hence most of their results were, as expected, unrelated to the circuitry involved in superiority illusion. A considerable amount of evidence is consistent with the hypothesis, although indirectly so. LIMITATIONS: Only few studies compared manic with depressive phases, with the majority including patients in euthymia. CONCLUSION: It is possible that humans have a natural tendency for elation/optimism and positive self-consideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.

Free Interval Duration: Clinical Evidence of the Primary Role of Excitement in Bipolar Disorder.

BACKGROUND: Cyclicity is the essential feature of Bipolar disorder, but the effect of different cycle patterns on the clinical features is poorly understood. Moreover, no studies investigated the relationship between mania and depression inside the manic-depressive cycle. OBJECTIVE: The aim of this study is to verify the presence of a relationship between the manic and the depressive phase during the course of bipolar disorder. METHOD: 160 consecutive patients with BD type I were recruited and followed for a mean period of 10 years. During the follow-up period, four types of euthymic phases were collected: free intervals present between a depressive and a manic/hypomanic episode (D-M); free intervals present between a manic/hypomanic and a depressive episode (M-D); free intervals present between two depressive episodes (D-D); free intervals present between two manic/hypomanic episodes (M-M). One-way ANOVA using the groups as independent variable and the duration of the free intervals as dependent variables was used. Furthermore, ANOVA was followed by Fisher's Protected Least Significant Difference post-hoc test to measure between-group differences. RESULTS: M-D-free interval phases were shorter than D-M-free intervals. M-D intervals were the shortest ones, the D-D and D-M did not differ, and the M-M were the longest. CONCLUSION: The strict temporal link between manic and depressive phases supports the idea that the manic-depressive cycle usually begins with a manic episode, and that the subsequent depression is often the consequence of subsiding mania.

Treatment-resistant, five-year long, postpartum-onset Capgras episode resolving after electroconvulsive therapy.

Postpartum psychosis, which rarely presents with Capgras syndrome (delusional misidentification), requires rapid symptom resolution. First-line drugs have important drawbacks, such as delayed onset of clinical response and secretion in breast milk. In this report, we report successful treatment of a treatment-resistant woman presenting with treatment-resistant Capgras syndrome, with onset during postpartum. A 36-year-old woman had presented with Capgras syndrome during postpartum. For more than five years, she believed her son and other family members were substituted by impostors. All adequately administrated treatments were unsuccessful. We suggested electroconvulsive therapy to overcome treatment resistance. After six electroconvulsive therapy sessions, delusions of doubles subsided and other symptoms improved. She was discharged two weeks later with a mood stabilizer and low-dose atypical antipychotic combination and is well at the one-and-a-half-year follow-up. Electroconvulsive therapy followed by a mood stabilizer-antipsychotic drug combination showed rapid, permanent, and effective control of long-standing Capgras syndrome in a young woman.

Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder.

BACKGROUND: Developing safe and effective long-term treatments for bipolar disorder remains a major challenge. Given available treatments, patients with bipolar disorder remain unwell in half of long-term follow-up, mostly in depression. As memantine, an N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist used to treat dementia, has been proposed for testing in bipolar disorder, we carried out a 3 + 3-year, mirror-image, chart-review study of the effects of adding memantine to stably continued, but insufficiently effective, ongoing mood-stabilizing treatments. METHOD: Outpatients diagnosed with DSM-IV-TR bipolar disorder (I or II), followed intensively at the Lucio Bini Mood Disorder Center, Rome, Italy, had responded consistently unsatisfactorily to standard treatments (lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy) for ≥ 3 years (2005-2013). Memantine (20-30 mg/d) was added clinically to otherwise stable regimens for another 3 years. On the basis of chart review, we compared morbidity measures and Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) score before versus during memantine treatment. RESULTS: The 30 bipolar I (n = 17) and II (n = 13) subjects showed consistent morbidity for 3 years before memantine, but improved progressively (r = 0.28, P < .01) over 3 years with memantine (23 ± 4.8 mg/d). Markedly decreased (all P values ≤ .01) were (1) percentage of time ill (total, mania, or depression; averaging -75.0%), (2) CGI-BP severity scores (-67.8%), (3) duration of new episodes (-58.6%), and (4) episodes/year (-55.7%). Subjects with previous rapid or continuous cycling were particularly improved (t = 2.61, P = .016). Adverse effects were mild and rare. CONCLUSIONS: Memantine added substantial long-term benefits by preventing or ameliorating depressive as well as mania-like morbidity in previously consistently poorly responsive patients with bipolar disorder. Further testing in randomized, controlled trials is required.

Features preceding diagnosis of bipolar versus major depressive disorders.

BACKGROUND: Better and earlier predictive differentiation of bipolar (BD) vs. unipolar major depressive disorder (UD) diagnoses should improve long-term clinical planning. METHODS: We reviewed randomly selected clinical records of 334 adults diagnosed with DSM-IV-TR BD-I (n=109), BD-II (n=106), and UD (n=119) and compared features preceding major affective episodes or diagnoses, using bivariate, multivariate, and Bayesian methods. RESULTS: We identified antecedents selectively associated with later BD vs. UD in 52.6% vs. 31.1% of subjects in childhood, starting at age 7.4 years, and 60.0% vs. 32.8% in adolescence, with far more features in BD than UD cases (10.3 vs. 4.64/100 person-years; p<0.001). In multivariate modeling, BD-selective factors were: younger at first clinical event > male sex > family BD-history > cyclothymic or hyperthymic temperament > antecedents/person-year. Nonaffective (anxiety, eating, or substance-use) disorders preceded BD vs. UD in 41.4% vs. 28.6% of subjects (p=0.02). By ROC analysis, differential prediction of BD vs. UD was optimal with any ≥ 3 factors/person. LIMITATIONS: The validity and timing of antecedent events and factors identified retrospectively from clinical records could not be verified independently, but information was recorded systematically and consistently by a single mood-disorder expert prior to diagnosis, and extracted by two independent observers. COMMENT: Early clinical features distinguished later BD from UD, often by years. Such prediction should improve treatment-planning and limit risk of mood-switching.

Low-dose acetazolamide in the treatment of premenstrual dysphoric disorder: a case series.

The treatment of premenstrual dysphoric disorder (PMDD) is far from satisfactory, as there is a high proportion of patients who do not respond to conventional treatment. The antidiuretic sulfonamide, acetazolamide, inhibits carbonic anhydrase and potentiates GABAergic transmission; the latter is putatively involved in PMDD. We therefore tried acetazolamide in a series of women with intractable PMDD. Here, we describe a series of eight women diagnosed with DSM-IV-TR PMDD, five of whom had comorbidity with a mood disorder and one with an anxiety disorder, who were resistant to treatment and responded with symptom disappearance after being added-on 125 mg/day acetazolamide for 7-10 days prior to menses each month. Patients were free from premenstrual symptoms at the 12-month follow-up. We suggest that acetazolamide may be used to improve symptoms of PMDD in cases not responding to other treatments. GABAergic mechanisms may be involved in counteracting PMDD symptoms.

Effectiveness of short-term olanzapine in patients with bipolar I disorder, with or without comorbidity with substance use disorder.

OBJECTIVES: Prognosis of comorbid bipolar disorder (BD) and drug abuse is poor. We assessed the efficacy of olanzapine in manic or mixed BD patients, with (SUD) or without (N-SUD) comorbidity with substance use disorder (SUD) and its effect on drug abuse, days of abuse, and craving. METHODS: Eighty patients with BD-I (40 SUD) were hospitalized for a manic or mixed episode and received add-on olanzapine. Assessments were conducted at admission, discharge, and 4 and 8 weeks after discharge. Primary outcome was the proportion of responders and remitters in each group. We used a logistic regression model to adjust for possible confounders. We assessed craving and drug-abuse days with a visual analog scale and the Timeline Follow-Back. RESULTS: SUD and N-SUD were similar on response and remission, adjusted for sex, age, years ill, age at first episode, first episode depressive, number of hospitalizations, and duration of hospitalization (odds ratio, 1.09; 95% confidence interval, 1.02-2.29). Mood rating scores dropped significantly from baseline to end point in both groups. Timeline follow-back decreased in SUD from 22.5 to 7.3 at 8 weeks postdischarge, whereas craving dropped from 8.3 to 5.1 (P < 0.03). CONCLUSIONS: The effectiveness of short-term olanzapine in BD-I mania or mixed mania did not differ according to SUD comorbidity. Treatment was followed by less substance use/abuse and craving in comorbid bipolar-SUD patients.

The wnt pathway in mood disorders.

OBJECTIVES: To review the evidence of the involvement of the Wnt signalling pathway in mood disorders and in the action of drugs used to treat these disorders. METHODS: We performed a careful PubMed search using as keywords all possible terms relevant to the Wnt pathway and crossing them with each of four areas, i.e., developmental effects, behavioural effects, mood disorders, and drugs used in their treatment. Papers were selected on the basis of their content and their data used for discussion. RESULTS: Neurodevelopmental and behavioural data point to the possibility of involvement of the Wnt pathway in the pathophysiology of mood disorders. Clinical and post-mortem data are not sufficient to corroborate a definite role for Wnt alterations in any mood disorder. Combining genetic and pharmacological data, we may state that glycogen synthase kinase is the key molecule in bipolar disorder, as it is connected with many other signalling pathways that were shown to be involved in mood disorders, while Wnt molecules in the hippocampus appear to be mainly involved in depressive disorders. CONCLUSIONS: Altered Wnt signalling may play a role in the pathophysiology of mood disorders, although not a central one. It is premature to draw conclusions regarding the possible usefulness of Wnt manipulations in the treatment of mood disorders.

The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: findings from a 12-month naturalistic trial.

BACKGROUND: We have recently provided preliminary clinical observations indicating that memantine, as augmenting agent, was associated with a meaningful antimanic and mood-stabilizing effect in treatment-resistant bipolar disorders. To further investigate the therapeutic and prophylactic action of the drug we administered memantine, as augmenting agent, to 40 treatment-resistant bipolar disorder patients, monitored and evaluated for 12 months. METHODS: The sample population encompassed 40 treatment-resistant bipolar disorder patients monitored for 12 months. Memantine, at the dose of 10-30 mg/day, was added to the ongoing treatment, which was left unmodified. The severity of the patients' condition before memantine and the changes after memantine addition were evaluated on the Clinical Global Impression Bipolar (CGI-BP) Overall Bipolar Illness Scale. The severity of patients' condition was scored before memantine and the change was evaluated after memantine addition at 6 and 12 months. LIMITATIONS: The present study has the limitations of an open clinical study and the observed effects require testing in a blinded, randomized, controlled trial which is planned. RESULTS: The average CGI-BP score of the patients was 6.7 (SD=0.58, range: 5-7) before the addition of memantine. After 6 months of memantine treatment, 72.5% of patients were very much or much improved. Among the rapid cyclers 68.4% of patients reached stability, defined by the absence of recurrences. Patients very much or much improved were 72.5% at 12 months; while 12.5% discontinued memantine or were lost to follow-up. CONCLUSIONS: The results confirm our previous observations and strongly suggest that memantine, as augmenting agent, was associated with a clinically substantial antimanic and sustained mood-stabilizing effect, with excellent safety and tolerability profile.