Current Neuropharmacology (v.15, #3)

Meet Our Editorial Board Member by Marco Capogna (333-333).

EDITORIAL: “The Faces of Mania: The Legacy of Athanasios Koukopoulos” by Gabriele Sani, Georgios D. Kotzalidis, Paolo Girardi (334-337).

Neurobiological Evidence for the Primacy of Mania Hypothesis by Georgios D. Kotzalidis, Chiara Rapinesi, Valeria Savoja, Ilaria Cuomo, Alessio Simonetti, Elisa Ambrosi, Isabella Panaccione, Silvia Gubbini, Pietro De Rossi, Lavinia De Chiara, Delfina Janiri, Gabriele Sani, Alexia E. Koukopoulos, Giovanni Manfredi, Flavia Napoletano, Matteo Caloro, Lucia Pancheri, Antonella Puzella, Gemma Callovini, Gloria Angeletti, Antonio Del Casale (339-352).
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 selfconsideration, that are more akin to mania; the depressive state could be a consequence of frustrated or unsustainable mania. This would be consistent with PoM.


Depression and Mania in Bipolar Disorder by Leonardo Tondo, Gustavo H. Vazquez, Ross J. Baldessarini (353-358).
Background: Episode duration, recurrence rates, and time spent in manic and depressive phases of bipolar disorder (BD) is not well defined for subtypes of the disorder.

Methods: We reviewed the course, timing, and duration of episodes of mania and depression among 1130 clinically treated DSM-IV-TR BD patients of various types, and compared duration and rates as well as total proportion of time in depressive versus manic episodes during 16.7 average years at risk.

Results: As expected, episodes of depressions were much longer than manias, but episode-duration did not differ among BD diagnostic types: I, II, with mainly mixed-episodes (BD-Mx), or with psychotic features (BD-P). Recurrence rates (episodes/year) and proportion of time in depression and their ratios to mania were highest in BD-II and BD-Mx subjects, with more manias/year in psychotic and BD-I subjects. In most BD-subtypes, except with psychotic features, there was more time in depressive than manic morbidity, owing mainly to longer depressive than manic episodes. The proportion of time in depression was highest among those who followed a predominant DMI course, whereas total time in mania was greatest in BD with psychotic features and BD-I. and with an MDI course.

Conclusions: Subtypes of BD patients differed little in episode-duration, which was consistently much longer for depression. The findings underscore the limited control of bipolar depression with available treatments.


The Role of Electroconvulsive Therapy (ECT) in Bipolar Disorder: Effectiveness in 522 Patients with Bipolar Depression, Mixed-state, Mania and Catatonic Features by Giulio Perugi, Pierpaolo Medda, Cristina Toni, Michela Giorgi Mariani, Chiara Socci, Mauro Mauri (359-371).
Objective: We evaluated the effectiveness of Electroconvulsive Therapy (ECT) in the treatment of Bipolar Disorder (BD) in a large sample of bipolar patients with drug resistant depression, mania, mixed state and catatonic features.

Method: 522 consecutive patients with DSM-IV-TR BD were evaluated prior to and after the ECT course. Responders and nonresponders were compared in subsamples of depressed and mixed patients. Descriptive analyses were reported for patients with mania and with catatonic features.

Results: Of the original sample only 22 patients were excluded for the occurrence of side effects or consent withdrawal. After the ECT course, 344 (68.8%) patients were considered responders (final CGIi score ?2) and 156 (31.2%) nonresponders. Response rates were respectively 68.1% for BD depression, 72.9% for mixed state, 75% for mania and 80.8% for catatonic features. Length of current episode and global severity of the illness were the only statistically significant predictors of nonresponse.

Conclusion: ECT resulted to be an effective and safe treatment for all the phases of severe and drugresistant BD. Positive response was observed in approximately two-thirds of the cases and in 80% of the catatonic patients. The duration of the current episode was the major predictor of nonresponse. The risk of ECT-induced mania is virtually absent and mood destabilization very unlikely. Our results clearly indicate that current algorithms for the treatment of depressive, mixed, manic and catatonic states should be modified and, at least for the most severe patients, ECT should not be considered as a “last resort”.


Diagnosis and Treatment of Cyclothymia: The “Primacy” of Temperament by Giulio Perugi, Elie Hantouche, Giulia Vannucchi (372-379).
Background: Contrary to DSM-5 definition based on recurrence of low grade hypomanic and depressive symptoms, cyclothymia is better defined in a neurodevelopmental perspective as an exaggeration of cyclothymic temperament. Emotional dysregulation with extreme mood instability and reactivity is the core features of the complex symptomatology.

Method: In the present article, we critically reviewed the literature on the diagnosis and treatment of cyclothymia, focusing on the temperamental and neurodevelopmental perspectives.

Results: Current epidemiological and clinical research showed the high prevalence and the validity of cyclothymia as a distinct form of bipolarity, frequently associated with multiple comorbidities with anxiety, impulse control, substance use, and so called “personality” disorders. Many patients receive correct diagnosis and treatments after many years of illness, when the superposition of complications reduces the possibility of complete remission. A therapeutic model combining the focus on symptomatic presentations with a temperamental perspective seems to represent an effective approach for cyclothymic patients with complex clinical presentations.

Conclusion: Cyclothymic mood instability is an understudied issue despite the evidence of its clinical relevance. Unresolved issues concern its diagnostic delimitation and the possible relationships with emotional dysregulation observed in other neurodevelopmental disorders. We need to confirm the specificity of the disorder and to improve its recognition in early phase of the life, especially in youth. Early recognition means avoiding unnecessary complications and establishing specific treatments and clinical management since the beginning.


Parental Reports of Prodromal Psychopathology in Pediatric Bipolar Disorder by Mariely Hernandez, Ciro Marangoni, Marie C. Grant, Jezelle Estrada, Gianni L. Faedda (380-385).
Objectives: Early psychopathology in children diagnosed with Bipolar Disorder (BD) remains poorly characterized. Parental retrospective reports provide helpful details on the earliest manifestations and their evolution over time. These symptoms occur early in the course of BD, often before a formal diagnosis is made and/or treatment is implemented, and are of great importance to early recognition and prevention.

Methods: Parents of pre-pubertal children and adolescents with DSM-IV diagnoses of BD attending an outpatient mood disorders clinic provided retrospective ratings of 37 symptoms of child psychopathology. Stability and comorbidity of diagnoses were evaluated, and severity of symptoms for each subject was assessed by identifying the earliest occurrence of the reported symptoms causing impairment.

Results: Severe mood instability, temper tantrums, anxiety symptoms, sleep disturbances and aggression were among the most common signs of psychopathology reported in children diagnosed with BD before puberty. Symptoms were already apparent in the first three years in 28%, and formal diagnoses were made before the age of 8 y in the majority of cases.

Conclusions: Retrospective parental reports of early symptoms of psychopathology in pre-pubertal children with BD revealed a very early occurrence of affective precursors (irritability and mood dysregulation) and clinical risk factors like impulsive aggression and anxiety that can precede the syndromal onset of mania by several years. These findings support previous reports suggesting a progression of symptoms from abnormal, non-specific presentations to sub-threshold and finally syndromal BD. The importance of early identification and intervention is discussed.


Pediatric Mania: The Controversy between Euphoria and Irritability by Giulia Serra, Mai Uchida, Claudia Battaglia, Maria Pia Casini, Lavinia De Chiara, Joseph Biederman, Stefano Vicari, Janet Wozniak (386-393).
Pediatric Bipolar Disorder (BD) is a highly morbid pediatric psychiatric disease, consistently associated with family psychiatric history of mood disorders and associated with high levels of morbidity and disability and with a great risk of suicide. While there is a general consensus on the symptomatology of depression in childhood, the phenomenology of pediatric mania is still highly debated and the course and long-term outcome of pediatric BD still need to be clarified. We reviewed the available studies on the phenomenology of pediatric mania with the aim of summarizing the prevalence, demographics, clinical correlates and course of these two types of pediatric mania. Eighteen studies reported the number of subjects presenting with either irritable or elated mood during mania. Irritability has been reported to be the most frequent clinical feature of pediatric mania reaching a sensitivity of 95-100% in several samples. Only half the studies reviewed reported on number of episodes or cycling patterns and the described course was mostly chronic and ultra-rapid whereas the classical episodic presentation was less common.

Few long-term outcome studies have reported a diagnostic stability of mania from childhood to young adult age. Future research should focus on the heterogeneity of irritability aiming at differentiating distinct subtypes of pediatric psychiatric disorders with distinct phenomenology, course, outcome and biomarkers. Longitudinal studies of samples attending to mood presentation, irritable versus elated, and course, chronic versus episodic, may help clarify whether these are meaningful distinctions in the course, treatment and outcome of pediatric onset bipolar disorder.


Free Interval Duration: Clinical Evidence of the Primary Role of Excitement in Bipolar Disorder by Gabriele Sani, Alessio Simonetti, Daniela Reginaldi, Alexia E. Koukopoulos, Antonio Del Casale, Giovanni Manfredi, Georgios D. Kotzalidis, Paolo Girardi (394-401).
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.


Background: Athanasios Koukopoulos provided a radical model for understanding depressive and manic conditions.

Objective: To review, explain, and analyze Koukopoulos' concept of the primacy of mania, with special attention to the role of antidepressants.

Method: A conceptual review of Koukopoulos' writings and lectures on this topic is given.

Results: Koukopoulos held that depressive states are caused by manic states; the former do not occur without the latter. The most common scenario of the inseparability of depressive and manic symptoms occurs in mixed states, which we estimate to represent about one-half of all depressive episodes in all patients (not just bipolar illness). In a review of the empirical evidence for this topic, we conclude that empirical evidence exists to support the primary of mania thesis in almost 80% of depressed patients. Since antidepressants worsen mania, they would be expected to worsen depression as well in this model. We provide evidence that supports this view in most persons with depressive states.

Conclusion: Koukopoulos' model of affective illness is one where manic states are the primary pathology, and depressive conditions are a secondary consequence. Hence treatment of depression with antidepressants would be less effective than treatment with mood stabilizers, since treating an effect is less successful than treating its cause. This approach would reverse current assumptions in psychiatry.


Who's the Leader, Mania or Depression? Predominant Polarity and Alcohol/Polysubstance Use in Bipolar Disorders by Delfina Janiri, Marco Di Nicola, Giovanni Martinotti, Luigi Janiri (409-416).
Background: Predominant polarity characterises patients who mainly manifest recurrences of depression or mania/hypomania. Alcohol use disorder (AUD) and polysubstance use (PSU), which often complicate bipolar disorder (BD) and affect its clinical course, can influence predominant polarity. Nevertheless, previous studies have not clarified if BD patients differ in predominant polarity from BD patients with substance use disorder (SUD) comorbidity.

Objective: The aim of this study was to compare predominant polarity between BD without SUD, BD with AUD and BD with PSU. We also investigated the association between predominant polarity and first episode polarity in each diagnostic group.

Method: We evaluated predominant polarity (?2:1 lifetime depressive vs. manic/hypomanic episodes) in 218 DSM-IV-TR BD patients. Specifically, data were obtained from 86 patients with BD without SUD, 69 patients with BD and AUD, and 63 patients with BD and PSU with alcohol as the primary substance abused.

Results: The three groups significantly differed for predominant polarity. The most common predominant polarity in BD without SUD was manic, while in BD with AUD and in BD with PSU it was depressive. Uncertain predominant polarity was the least common in BD without SUD and BD with PSU, whereas in BD with AUD, manic predominant polarity was least common. Predominant polarity matched onset polarity in all groups.

Conclusion: BD without SUD, BD with AUD, and BD with PSU have different predominant polarities. The correspondence between predominant polarity and polarity at the onset may impact diagnosis and treatment of BD.


Background: Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder.

Methods: We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders.

Results: A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST.

Conclusion: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the “bipolar-like” behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.


Is Mania the Hypertension of the Mood? Discussion of A Hypothesis by Zoltan Rihmer, Xenia Gonda, Peter Dome (424-433).
Beyond both being biphasic/bidirectional disorders (hypo)mania and essential hypertension share a surprising number of similarities and an overlap between their genetics, biological background, underlying personality and temperamental factors, precipitating factors, comorbidity and response to treatment, indicating a possibly partially shared biological background. Based on theoretical knowledge, similarities related to characteristics, manifestation and course, and the results of pharmacological studies related to the effects and side effects of pharmacotherapies used in the treatment of these two distinct disorders, the authors outline a hypothesis discussing the similar origins of these two phenomena and thus mania being the hypertension of mood in memory of Athanasios Koukopoulos, one of the greatest researchers and theoreticists of mania of all time.

Melatonin: Pharmacology, Functions and Therapeutic Benefits by Sylvie Tordjman, Sylvie Chokron, Richard Delorme, Annaelle Charrier, Eric Bellissant, Nemat Jaafari, Claire Fougerou (434-443).
Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock.

Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed.

Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects.

Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.


Opioids Resistance in Chronic Pain Management by Luigi A. Morrone, Damiana Scuteri, Laura Rombola, Hirokazu Mizoguchi, Giacinto Bagetta (444-456).
Chronic pain management represents a serious healthcare problem worldwide. Chronic pain affects approximately 20% of the adult European population and is more frequent in women and older people. Unfortunately, its management in the community remains generally unsatisfactory and rarely under the control of currently available analgesics. Opioids have been used as analgesics for a long history and are among the most used drugs; however, while there is no debate over their short term use for pain management, limited evidence supports their efficacy of long-term treatment for chronic noncancer pain. Therapy with opioids is hampered by inter-individual variability and serious side effects and some opioids often result ineffective in the treatment of chronic pain and their use is controversial. Accordingly, for a better control of chronic pain a deeper knowledge of the molecular mechanisms underlying resistance to opiates is mandatory.