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Drugs can be divided into two major categories, symptomatic and disease modifying. This review explores whether and how psychiatric drugs fall into one or the other of those categories, and the implications of those results for clinical practice and research in psychopharmacology.Narrative review.Most psychiatric drugs have only short-term effects of improving active symptoms. They do not show long-term benefits for the underlying disease, such as improving the course of illness and improving mortality. Evidence is provided for this claim in the treatment literature of antidepressants for depressive illness and antipsychotics for schizophrenia. Developing truly beneficial drugs for disease modification also is limited by the poor clinical and biological validity of Diagnostic and Statistical Manual diagnoses as well as the use of invalid falsely positive maintenance efficacy randomized discontinuation trial designs.Current psychopharmacology is limited mostly to symptomatic effects, not transformative treatments for the diseases underlying those symptoms. A change in approach is needed in psychopharmacology practice and research, focusing on long-term disease modification rather than short-term symptom improvement.

Objectives Polypharmacy is common in maintenance treatment of bipolar illness, but proof of greater efficacy compared to monotherapy is assumed rather than well known. We systematically reviewed the evidence from the literature to provide recommendations for clinical management and future research. Method A systematic review was conducted on the use of polypharmacy in bipolar prophylaxis. Relevant papers published in English through 31 December 2019 were identified searching the electronic databases MEDLINE, Embase, PsycINFO, and the Cochrane Library. Results Twelve studies matched inclusion criteria, including 10 randomized controlled trials (RCTs). The best drug combination in prevention is represented by lithium + valproic acid which showed a significant effect on time to mood relapses (HR = 0.57) compared to valproic acid monotherapy, especially for manic episodes (HR = 0.51). The effect was significant in terms of time to new drug treatment (HR = 0.51) and time to hospitalization (HR = 0.57). A significant reduction in the frequency of mood relapses was also reported for lithium + valproic acid vs. lithium monotherapy (RR=0.12); however, the trial had a small sample size. Lamotrigine + valproic acid reported significant efficacy in prevention of depressive episodes compared to lamotrigine alone. Conclusions The literature to support a generally greater efficacy with polypharmacy in bipolar illness is scant and heterogeneous. Within that limited evidence base, the best drug combination in bipolar prevention is represented by lithium + valproic acid for manic, but not depressive episodes. Clinical practice should focus more on adequate monotherapy before considering polypharmacy.

Background Lithium is an old proven medication, but it is infrequently used in current practice. This review examines evidence for its benefits and risks and provides clinical guidance to its use. Method Narrative review. Results Besides its benefit in bipolar illness, lithium has important underappreciated proven benefits in prevention of unipolar depression and suicide. Emerging data support neurobiological benefits for cognition and possible dementia prevention. Likely benefits also exist in low doses for mood temperaments (cyclothymia and hyperthymia). High doses (over 1.0 mmol/L) should be avoided since they increase side effects, complications associated with long-term use, and risk of toxicity. Conversely, low dosing can be legitimate, especially for suicide and dementia prevention. Nuisance side effects of lithium may affect adherence, and medically serious side-effects can occur. Managing strategies are available for side effects. Conclusion Lithium is the most effective medication in psychiatry, because it has disease-modifying, not just symptomatic, effects. It is effective not only for bipolar illness but also for prevention of suicide, episodes of unipolar depression, mood temperaments, and possibly dementia. Its many benefits need better appreciation, while lowered dosing can reduce risks.

Objective To examine the empirical literature on diagnostic validators in borderline personality and bipolar illness. Method Using principles of evidence-based medicine, the highest levels of evidence were emphasized in interpretation of similarities or differences between bipolar illness and borderline personality on the five standard diagnostic validators in psychiatric nosology: symptoms, course, genetics, treatment response, and neurobiology. Results Bipolar illness and borderline personality were found to be similar in the nosological validator of symptoms of mood lability and impulsivity, but differed notably on all other diagnostic validators, especially the course validator of past sexual abuse and the genetic validator of a bipolar family history. They also differ notably in the symptom validator of parasuicidal self-harm. Treatment response and neurobiological differences were also present and consistent. Conclusion This review of the literature indicates that these two conditions, bipolar illness and borderline personality, are different and can be distinguished. The much stronger biological and genetic evidence for bipolar illness in particular suggests that the two conditions can be reasonably seen as different kinds of clinical entities, namely a biological disease versus a psychosocially caused clinical picture. If this interpretation is correct, similarities between the two conditions, such as mood lability and impulsivity, are superficial, while differences are profound. Further, true comorbidity may be much less common than often presumed.

Objective The differential diagnosis of bipolar illness vs. borderline personality is controversial. Both conditions manifest impulsive behavior, unstable interpersonal relationships, and mood symptoms. This study examines whether and which mood clinical features can differentiate between both conditions. Method A total of 260 patients (mean ± standard deviation age 41 ± 13 years, 68% female) attending to a mood clinic were examined for diagnosis of bipolar illness and borderline personality disorder using SCID-I, SCID-II, and clinical mood criteria extracted from Mood Disorder Questionnaire (MDQ). They were analyzed using diagnoses as dependent variables. Predictors of bipolar and borderline diagnoses were identified by multivariable logistic regressions, and predictive validity of models was assessed using ROC curve analysis. Results Bipolar illness was strongly predicted by elevated mood (OR = 4.02, 95% CI: 1.80–9.15), increased goal-directed activities (OR = 3.90, 95% CI: 1.73–8.96), and episodicity of mood symptoms (OR = 3.48, 95% CI 1.49–8.39). This triad model predicted bipolar illness with 88.7% sensitivity, 81.4% specificity, and obtained an auROC of 0.91 (95% CI: 0.76–0.96) and a positive predictive value of 85.1%. For borderline personality disorder, only female gender was a statistically significant predictor (OR = 3.41, 95% CI: 1.29–13.7), and the predictive model obtained an auROC of 0.67 (95% CI: 0.53–0.74). Conclusion In a mood disorder clinic setting, manic criteria and episodic mood course distinguished bipolar illness from borderline personality disorder.

Phelps J, Ghaemi SN. The mistaken claim of bipolar ‘overdiagnosis’: solving the false positives problem for DSM-5/ICD-11. Objective: For psychiatric diagnoses, solving the problem of false positives is thought to be a matter of tightening diagnostic criteria. But low prevalence illnesses by their nature have high false positive rates. A recent study of bipolar disorder found the predictive value of bipolar diagnoses to be 50% requires diagnostic specificity of >95%. Holding specificity at a level already achieved clinically (86%), increasing prior probability yields predictive values as high as 83%. Conclusion: Systematic assessment of clinical factors that increase the prior probability of illness, before applying DSM/ICD criteria, could raise PPV substantially compared with targeting greater specificity via more stringent diagnostic criteria.

Long-term antidepressant (AD) treatment for depression in bipolar disorder (BPD) patients is highly prevalent, but its benefits and risks remain uncertain, encouraging this meta-analysis of available research.We reviewed randomized controlled trials for BPD involvingor=6 months of treatment with AD +/- mood stabilizer (MS) vs. placebo +/- MS, using meta-analyses to compare reported risks of new depression vs. mania.In seven trials (350 BPD patients) involving 12 contrasts, long-term treatments that included ADs yielded 27% lower risk of new depression vs. MS-only or no treatment [pooled relative risk, RR = 0.73; 95% CI 0.55-0.97; number-needed-to-treat (NNT) = 11], but 72% greater risk for new mania [RR = 1.72; 95% CI 1.23-2.41; number-needed-to-harm (NNH) = 7]. Compared with giving an MS-alone, adding an AD yielded neither major protection from depression (RR = 0.84; 95% CI 0.56-1.27; NNT = 16) nor substantial increase in risk of mania (RR = 1.37; 95% CI 0.81-2.33; NNH = 16).Long-term adjunctive AD treatment was not superior to MS-alone in BPD, further encouraging reliance on MSs as the cornerstone of prophylaxis.

Objective: To assess frequencies of types of publications about bipolar disorder (BD) and evaluate methodological quality of treatment studies. Method: We classified 100 randomly selected articles (1998–2002) from five psychiatric journals with highest impact ratings, by topic areas, and assessed methods employed in treatment studies. Results: Topics ranked: treatment (41%; 37% on pharmacotherapy) > biology (31%) > psychopathology (14%) = miscellaneous (14%). Of treatment studies, only 19% of original articles were randomized, 15% were relatively large (n ≥ 50) but non-randomized, 65% were small non-randomized, case-series or -reports, and 53% relied on baseline-to-endpoint contrasts without a control group. Patient dropout rates were ≥40% in 43% of prospective studies. Only two reports provided confidence intervals; one included a power analysis, and 53% included no references on study design or statistical methods. Conclusion: Even in highly respected journals, the typical methodological quality of recent reports on therapeutics for BD was unexpectedly limited, and psychopathology and psychotherapies were little studied.