Joseph F. Goldberg, MD

Joseph F. Goldberg, MD, shares some key takeaways from “Medical Crossfire: Treatment Approaches to Mixed Features of Bipolar vs Unipolar Depression,” his discussion with Sanjai Rao, MD, of the University of California, San Diego, and Nassir Ghaemi, MD, of Tufts University School of Medicine, at the 

is a clinical professor of psychiatry at Mount Sinai School of Medicine.

Articles

Treatment Approaches to Mixed Features of Bipolar vs Unipolar Depression

From randomized trials, clinicians can take away a number of general principles to help guide the process of constructing a “profile” for optimal candidacy with one treatment relative to another.

Joseph F. Goldberg, MD, provides tips to tailoring treatment of mood disorders using a measured approach.

is clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai, New York. The author reports the following disclosures: Abbvie Pharmaceuticals: Speakers Bureau; American Psychiatric Publishing: Royalties; BioXCel: Consultant; Intra-cellular Therapies: Speakers Bureau; Neurocrine: Consultant; Otsuka: consultant; Sage Pharmaceuticals: Consultant; Sunovion: Consultant, Speakers Bureau. Dr Goldberg spoke at 

in a presentation titled “Tailoring Individualized Pharmacotherapy for Bipolar Disorder: How to Translate Findings from Clinical Trials to a Single Patient.”

Videos

Tips to tailoring treatment of mood disorders using a measured approach. 

Assessing the Literature for Optimal and Individualized Treatment

Slideshows

Baseline factors that can influence treatment outcomes in psychiatric treatment.

10 Factors That Influence Treatment Outcomes

“It is much more important to know what sort of a patient has a disease

than what sort of disease a patient has”

Imagine devising a pharmacotherapy regimen for each and every patient you see with the same kind of individualized precision and artisanal craftsmanship that an expert tailor uses to create a bespoke suit of clothing. Clinicians sometimes merely equate “personalized medicine” with biomarkers (such as pharmacogenetics), dismissing most other aspects of pharmacotherapy decision-making as largely a trial-and-error process. Yet, when one considers the numerous other clinical, demographic and psychosocial factors that impinge on how any given psychiatric disorder presents, it is not hard to reframe Sir William Osler’s aphorism about “what sort of patient has a disease” as a reckoning of clinical diversity (or what geneticists might call phenotypic heterogeneity).

Rather than simply matching a treatment (say, lithium or divalproex) to a disease state per se (say, bipolar mania), modern psychopharmacology can draw in a much more nuanced fashion from randomized trial data to predict the chances for success with one treatment (or combination) relative to another, based on the presence or absence of key clinical characteristics. “Tailored” pharmacotherapy, informed by the clinical trials literature, involves assessing patient-specific characteristics in order to make reasonable predictions about what treatment or drug combinations have clear rationales and likelihoods for successful outcomes for any one given patient, rather than for a broad diagnosis per se.

In the case of bipolar disorder, clinical diversity is more common than rare. Consider its multitude of contributing factors: patients can manifest pure or mixed mood states, with persistent or undulating symptoms, varying levels of severity and residual symptoms, with or without psychosis, often colored by comorbid medical or psychiatric conditions and personality traits. Bipolar I versus II disorders may differ in symptom profiles (as in depression-proneness or suicide risk) and treatment response (as in the case of 

Some affective or psychomotor symptoms may be more prominent than others; and features such as impulsivity, aggression, suicidality, trauma, cognitive dysfunction, and circadian rhythm disturbances often pose their own conspicuous treatment targets. Tailored approaches also take into account the impact of factors called 

 that can either enhance or derail an otherwise efficacious treatment once it is begun—such as drug adverse effects, treatment adherence, drug-drug interactions, new substance misuse, strength of the therapeutic alliance, or loss of patient insight about the need for ongoing treatment. Biostatisticians call baseline factors that can influence outcome 

Profiling patient candidacy for a given treatment

From randomized trials, one can take away a number of general principles to help guide the tailoring process of constructing a “profile” for optimal candidacy with 1 treatment relative to another. For example:

• Divalproex may yield a better response than lithium in mania involving mixed (rather than pure manic) episodes,

• The combination of lithium plus divalproex seems better than divalproex alone in rapid cyclers

 or during relapse prevention following a 

• Comorbid anxiety symptoms have been shown to improve during treatment for bipolar depression with each of the four existing FDA-approved agents for bipolar depression. Co-therapy with gabapentinoids offers a rationale-based further anxiolytic approach. With the exception of paroxetine, the anxiolytic properties of SSRIs in bipolar patients are largely unknown and cannot be assumed.

• Lithium may warrant independent consideration for its apparent anti-impulsivity effects in patients at risk for acting on suicidal thoughts.

• Among second-generation antipsychotics (SGAs), there is tremendous variability in efficacy (or lack thereof) for bipolar depression. Aripiprazole, ziprasidone, and risperidone have only negative randomized trials in bipolar depression. Relative to quetiapine or olanzapine-fluoxetine combination, lurasidone and cariprazine are the more weight- and metabolically neutral SGAs FDA-approved for bipolar depression; all 4 exert large effects in bipolar depression, so how else do they differ? Lurasidone lacks data in mania and failed to show value for relapse prevention, but it has demonstrated cognitive benefits.

 Cariprazine, by contrast, treats both manias and depressions and its high affinity for D3 dopamine receptors makes it an attractive option in the setting of low motivation and reward. Its potential value for relapse prevention is unknown. Both lurasidone and cariprazine pose concerns for dose-related akathisia and EPS, suggesting that low doses often may be more useful and tolerable than high doses.

• Beyond 6 months after a manic episode, continuing an SGA 

 mood stabilizer may add no greater value for relapse prevention than an antimanic mood stabilizer 

How trial designs tweak the pharmacology evidence-base

Understanding how clinical trial designs affect study findings is another key aspect of using evidence-based data when crafting a bespoke treatment regimen. An important example involves recognizing 

 as a moderator that can inflate placebo response and obscure true drug advantages. One of the best illustrations of this was the failure of lamotrigine to outperform placebo in FDA trials of acute bipolar depression—likely not so much because the drug was ineffective (and having nothing at all to do with lamotrigine’s titration schedule), but rather, because the placebo response rate was inordinately high among low baseline severity patients.

 By contrast, in patients with high baseline severity, a much lower placebo response rate allowed clear separation of drug effect from placebo.

So what does this mean for the practitioner, who is otherwise left thinking only that lamotrigine is just “a mood stabilizer” that’s sometimes used off-label to treat bipolar depression? Quite a bit: the evidence base for lamotrigine shows that it does exert efficacy in bipolar depression, but the unexpectedly high placebo response rate in pivotal trials (due at least partly to low baseline severity) clobbered any meaningful difference between it and active drug. Meanwhile, other studies have shown lamotrigine to synergize with lithium or quetiapine, consequently relegating it to an often more ambiguous role in treating acute bipolar depression.

Antidepressants: bespoke or “unspoke”?

What about antidepressants in bipolar depression—an area that remains mired more in controversy and strong opinion than extensive evidence? Most modern antidepressants (those developed after 1999) have never been formally studied versus placebo in bipolar depression, making them 

 experimental options. Much-publicized concerns that antidepressants are mainly “hazardous” for inducing mania or cycle acceleration run counter to prospective studies that report only about a 12% incident rate of antidepressant-induced mania.

Popular admonitions that antidepressants as a class are ineffective for bipolar depression come from scant placebo-controlled trial literature involving mostly older studies of paroxetine. Fluoxetine (either combined with lithium or olanzapine, or even as monotherapy in bipolar II depression) and sertraline (in bipolar II depression; reviewed by Goldberg1) actually both are among the more evidence-based treatment options in bipolar depression. Antidepressant “candidacy” in bipolar depression is favored by the profile of characteristics listed in 

Perhaps the strongest moderator of a successful outcome is a marked acute response, which tends to predict a better enduring effect with minimal risk for mood destabilization; by contrast, a partial or weak acute response bodes poorly. Importantly, less than one-third of patients with bipolar depression display strong antidepressant responses to modern studied antidepressants (ie, sertraline, venlafaxine, or bupropion). And, similar to unipolar depression, chances for responsivity drop precipitously with each successive failure.

Final considerations: pharmacological parsimony

A third or more of individuals with bipolar disorder take 3 or more psychiatric drugs;12 therefore, let each one count purposefully. Elegance comes from targeting multiple treatment domains with the fewest agents or capitalizing on known synergies while avoiding mechanistic redundancies. Divalproex, for instance, may represent the treatment of choice in a mania-prone male patient with migraine headaches, impulsive aggression, and alcohol use disorder. 

Bupropion could be a handy intervention for a patient with bipolar II pure-depression, prone to nonmixed depression-polarity who is also overweight, smokes, and has attentional complaints. (Ar)modafinil or lisdexamfetamine added to an antimanic drug may neatly address bipolar depression, anergia, and attentional complaints, while the latter may additionally help to manage binge eating or overweight. Every component of a treatment regimen should have a definable purpose; agents deemed ineffective after an adequate trial warrant deprescribing; and decisions about sequential pharmacotherapies are in turn best guided by a careful assessment of patients’ moderating features alongside an informed knowledge of the existing clinical trials literature.

is clinical professor of psychiatry, Icahn School of Medicine at Mount Sinai, New York. The author reports the following disclosures: Abbvie Pharmaceuticals: Speakers Bureau; American Psychiatric Publishing: Royalties; BioXCel: Consultant; Intra-cellular Therapies: Speakers Bureau; Neurocrine: Consultant; Otsuka: consultant; Sage Pharmaceuticals: Consultant; Sunovion: Consultant, Speakers Bureau. Dr Goldberg spoke at PsychCongress 2020 in a presentation titled “Tailoring Individualized Pharmacotherapy for Bipolar Disorder: How to Translate Findings from Clinical Trials to a Single Patient.”

Determining patient candidacy for antidepressant use in bipolar disorder

2. Sajatovic M, Forester BP, Tsai J, et al. Efficacy oflurasidonein adults aged 55 years and older with bipolar depression: post hoc analysis of 2 double-blind, placebo-controlled studies. 

3. Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002;63(10):942-947.

4. Swann AC, Bowden CL, Morris D, et al. Depression during mania: treatment response to lithium or divalproex. 

5. Swann AC, Bowden CL, Calabrese JR, et al. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. 

6. Salloum IM, Cornelius JR, Daley DC, et al. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. 

7. Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. 

8. Geddes JR, Goodwin GM, Rendell J, et al.

 Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised, open-label trial

9. Yatham LN, Mackala S, Basivireddy J, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. 

10. Yatham LN, Beaulieu SchafferA, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: a CANMAT randomized double-blind trial. 

11. Geddes JR, Calabrese JR, Goodwin GM. Lamotrigine for treatment of bipolar depression: independent meta-analysis and meta-regression of individual patient data from five randomised trials. 

12. Goldberg JF. Complex combination pharmacotherapy for bipolar disorder: knowing when less is more or more is better. 

The author discusses evidence-based treatment, highlighting clinical trials that support specific uses and patterns of efficacy. 

Bespoke Psychopharmacology for Bipolar Disorder: An Individualized Patient Approach

With well over two dozen traditional antidepressants available in the US, and an ever-growing list of other psychotropic compounds with apparent antidepressant properties, pharmacological options for treating clinical depression today are broad and vast. However, recent findings suggest that the magnitude of efficacy for most antidepressants compared with placebo may be more modest than previously thought.

 Most depressed patients do not respond fully to a first antidepressant trial, and with each consequent trial, there is less chance of symptom remission.

 About one-third of patients receiving long-term treatment report persistent moderate-to-severe depression.

 Hence, there remains more than a little room for improvement.

Since the late 1950s, the traditional view of treating depression has focused on the role of monoamines (serotonin, norepinephrine, and dopamine) as the main targets for medications. Newer treatments are looking beyond effects on monoamines as potential strategies to leverage depressive symptoms.

A major challenge for progress in novel pharmacotherapies has been our lack of a full understanding about the causes of depression. Advances in functional neuroimaging and genetic markers have begun to shed new light on brain regions and pathways associated with aberrant neural functioning in depression, but not in ways that have led to treatments aimed at remedying its pathogenesis. This makes it hard to think of antidepressant medications as “treating” the pathophysiology of depression (as when antibiotics eliminate the cause of an infection); rather, antidepressant relieve symptoms by counteracting or compensating for depression’s consequences (as when diuretics alleviate peripheral edema regardless of its etiology).

Gone are the days of oversimplified theories that depression is caused by a “chemical imbalance.” More likely, depression involves changes in brain architecture and the interplay of complex circuits in which chemicals, or neurotransmitters, are the messengers of information, rather than the causes of faulty functioning. 

 summarizes some of the major conceptual shifts that have occurred in thinking about the probable causes of depression (or at least its neurobiological context), which sets the stage for new ways to consider innovative treatment strategies. Looking beyond the role of monoamines as treatment targets in depression, a number of novel therapeutic strategies have begun to receive growing interest in preclinical and clinical trials. Key points about emerging novel depression pharmacotherapies are summarized in 

Subanesthetically dosed intravenous (IV) ketamine currently represents perhaps the most dramatic and innovative antidepressant pharmacotherapy to emerge in decades.

It is pharmacodynamically unique in its rapid onset (hours rather than days to weeks) and its potential ability to reduce suicidal ideation after a single dose, independent of its antidepressant properties.

 (While both lithium and clozapine have been shown to reduce suicidal behaviors, neither has been shown to reduce ideation, much less in the same day after a single dose.) Meta-analyses suggest that 0.5 mg/kg IV ketamine produces nearly a 10-fold greater likelihood of response than placebo at day 1 and a 4- to 5-fold likelihood of sustained response after one week.

The exact psychotropic mechanism of action of ketamine remains elusive. Initial work focused on blockade of ionotropic N-methyl-D-aspartate (NMDA) receptors as accounting broadly for its antidepressant effects. However, subsequent negative randomized trials with other NMDA receptor antagonists (such as riluzole

) redirected interest toward ketamine’s other, non-NMDA receptor-related mechanisms, such as sigma receptor agonism, mu opioid receptor antagonism, or midbrain monoaminergic inhibition. Other authors have suggested that at low doses, ketamine’s antidepressant effects may derive from an increase in glutamate transmission with increased Î±-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression, leading to increased release of brain-derived neurotrophic factor (BDNF).

 recently observed the necessity of AMPA receptor activation for the antidepressant effects of ketamine. They reported that “directly targeting the NMDA [receptor] may not be required.” As noted by the American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments,

 future advances will depend on a better understanding of the many mechanisms of action relative to the antidepressant properties of ketamine.

Ketamine is currently not approved by the FDA as a treatment for depression. Uncertainty remains as to whether repeated dosing is safe, effective, and necessary to avoid relapse and, if so, when, at what frequency, and for how long. The aforementioned APA Council on Research Consensus Statement on ketamine treatment for depression

 stated that while some clinics already offer 2- to 3-week courses of ketamine delivered 2 to 3 times per week, “there remain no published data that clearly supports this practice, and . . . the relative benefit of each ketamine infusion [should] be considered in light of the potential risks associated with longer term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration.” 

 Thus far, studies of other pharmacotherapies to sustain an initial ketamine response (such as riluzole or lithium) have proven no better than placebo.

Enantiomeric esketamine remains investigational as a possible easier-to-administer intranasal (IN) antidepressant, although IN bioavailability is only about half that of IV ketamine’s 100%. Two randomized multi-site trials of IN esketamine added to antidepressants showed dose-related better efficacy than placebo: Daly and colleagues

 found that 28 mg to 84 mg of IN ketamine twice weekly over two weeks produced significant improvement in depressive symptoms as compared to placebo beginning after 1 week and continuing through week 9 for the majority of responders. A study by Canuso and colleagues

 demonstrated a significant reduction in depressive symptoms within 4 hours of administration (56 mg to 84 mg insufflated over 15 minutes) and a medium to large effect size, sustained after 25 days; suicidal ideation reduced significantly at 4 hours but not beyond that time. Another recent randomized pilot trial of IN racemic ketamine (the mixture of S- and R-ketamine) was prematurely discontinued due to poor tolerability (including cardiovascular and neurological adverse effects) and highly variable absorption across subjects.

Modulation of the endogenous opioid system has long been a target of interest in the treatment of mood disorders, but it is limited by safety risks, tolerance, and addiction potential. Recent work has focused on a proprietary combination of the Î¼-opioid partial agonist/kappa antagonist buprenorphine plus the Î¼-opioid receptor antagonist samidorphan (ALKS 5461). The potent blockade of Î¼-opioid receptors in samidorphan, which prevents buprenorphine access to these receptors, effectively renders buprenorphine a selective kappa opiate receptor (KOR) antagonist, which is its putative antidepressant mechanism. After initial favorable Phase II trials, in 2013 the FDA granted ALKS 5461 fast track status for accelerated regulatory review as an antidepressant adjunct. Subsequent randomized trials in treatment-resistant major depression revealed statistically significant differences from placebo on some, but not all, depressive symptom outcome measures and at some, but not all, doses studied.

 The FDA initially refused to review the new drug application for ALKS 5461 as an adjunctive therapy for depression because of concerns about bioavailability and lack of evidence, but then reversed its position. ALKS 5461 is currently under regulatory review and a decision regarding its possible approval is expected by early 2019.

There has been growing recognition of complex interrelationships between depression and inflammation. Some but not all patients with clinically significant depression appear to have elevated serum markers of systemic inflammation, such as high sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines. While causal relationships between depression and inflammation are poorly understood and questions remain whether depression causes inflammation or vice versa, randomized trial data suggest potential antidepressant value of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the COX-2 inhibitor celecoxib. A pooled meta-analysis of 5447 participants from 10 NSAID trials and 4 cytokine inhibitors (as mono- or add-on therapy for depression) revealed statistically significant advantages over placebo, with small to medium effect sizes, for response (odds ratio = 6.6; 95% confidence interval=2.2-19.4) or remission (odds ratio = 7.9; 95% confidence interval=2.9-21.1)

 It has not been established whether adding celecoxib or other NSAIDs to an antidepressant may be more useful only in the setting of elevated serum markers of inflammation. Elsewhere, preliminary studies reveal that inflammatory depressive subtypes (ie, high baseline hs-CRP) may respond better to a tricyclic than SSRI,

 or the tumor necrosis factor (TNF) antagonist infliximab (admnistered IV at 5 mg/kg over 3 doses).

The antimicrobial minocycline exerts anti-inflammatory and anti-oxidative properties and has been preliminarily studied mostly in small or open/nonrandomized trials. A meta-analysis of 3 randomized controlled trials found an overall significantly greater effect than placebo with a medium to large effect size and good tolerability, although the small number of well-designed studies and samples sizes (total N = 158) limits their generalizability.

Harkening back to the 1970s hypothesis that depression could reflect cholinergic-adrenergic dysregulation, interest has turned to the possible antidepressant effects of the muscarinic cholinergic antagonist scopolamine. Preliminary studies of intravenous scopolamine dosed at 4 µg/kg in both unipolar and bipolar depression have produced remission rates from 45% to 56% (Cohen’s d ranged from 1.2-3.4) typically within several days of administration, with persistence for 10 to 14 days.

 Antimuscarinic adverse effects such as sedation, dry mouth, and blurry vision are common but transient. Neurocognitive measures reaction time during selective attention tasks reveal no significant delays following IV scopolamine infusion.

 Analogous to IV ketamine, questions remain about the optimal number of infusions to minimize relapse as well as the use of nonparenteral formulations.

Brexanolone (SAGE-547), also known as allopregnanolone, is a positive allosteric modulator of GABA-A receptors. It is a progesterone metabolite that exerts neuroprotective, pro-cognitive, and possible antidepressant/anxiolytic properties. Precipitous drops in progesterone and allopregnanolone after childbirth prompted interest in the use of allopregnanolone specifically in postpartum depression. A small (N = 21) initial trial of brexanolone (administered intravenously because of its short half-life and poor oral bioavailability) or placebo for severe postpartum depression yielded a substantial reduction in depressive symptom severity within 60 hours (effect size = 1.2).

 Further data remain pending. SAGE-217 is reformulated brexanolone that has good oral bioavailability, allowing for oral administration, as well as a longer half-life allowing once-a-day dosing. It is currently being studied as an adjunctive agent for treatment resistant depression.

Thiazolidinediones are insulin sensitizers that also demonstrate antidepressant properties in animal studies and appear to possess anti-inflammatory, neuroprotective, antioxidant and anti-excitatory properties. Pioglitazone, a PPAR-Î³ agonist thiazolidinedione, has been studied versus placebo or metformin in major depression, both as monotherapy and in combination with antidepressants or lithium. A meta-analysis of 4 trials revealed significantly higher remission rates than controls (27% versus 10%, respectively; odds ratio of remission in major depression = 5.9 (95% confidence interval=1.6-22.4), p = .009), with an NNT = 6.25 Even though PPAR-Î³ agonists can decrease insulin resistance, weight gain can be an undesired adverse effect that is possibly a result of a combination of fat cell proliferation, fluid retention, and increased appetite. Pioglitazone also carries serious adverse risks for congestive heart failure and bladder cancer.

Another class of antidiabetic drugs known as glucagon-like peptide 1 (GLP-1) agonists mimic the action of insulin (so-called incretins) and are of interest as a potential target for depression. GLP-1 agonists such as liraglutide possess neuroprotective and antiapoptotic properties, and animal studies suggest it has antidepressant and pro-cognitive effects, particularly involving reward and motivation. Human studies have thus far focused more on weight-reducing and possible cognitive benefits of liraglutide more than its potential antidepressant efficacy, but its mechanism represents a promising direction for further study.

This brief overview has focused on emerging novel pharmacotherapies for depression. While the provisional nature of proof-of-concept studies may be encouraging, they are far from definitive. The aforementioned findings are largely preliminary and meant more to prompt larger randomized trials to establish efficacy, safety, and generalizability rather than inspire premature immediate uptake into clinical practice.

Given the focus on neuroprotection and enhanced neuroplasticity as proposed targets of treatment, it would seem remiss not to at least mention the neurobiological impact of depression-specific psychotherapies, mindfulness meditation, and related psychosocial interventions. Psychotherapy is, among other things, a behavioral learning paradigm, presumably rendering alterations in cognitive functions (memory, attention, and decision-making), fear extinction, and emotional processing. Evidence-based psychotherapies for depression have been shown to produce changes in brain network connectivity

 (recapitulating the idea of Hebbian synapses, where “neurons that fire together wire together”) and upregulation of intracellular transcription factors involved in neuronal plasticity.

 Enhanced neuroplasticity may represent a common denominator target for effective biological or psychosocial treatments for depression.

 are diversifying to include broader classes of molecules. A more neuroscience-based nomenclature for psychotropic drugs has already been proposed

 and will no doubt invoke more novel drug mechanisms, supplanting older concepts about depression as a chemical imbalance as perspectives continue to evolve about how antidepressants impact neuronal viability and brain microarchitecture.

Dr Goldberg is Clinical Professor of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY.

Dr Goldberg has been on the speaker bureau for Merck, Neurocrine, and Sunovian, and Takeda-Lundbeck and has been a consultant for Neurocrine and Sunovian.

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https://www.ecnp.eu/research-innovation/nomenclature.aspx