Chris Aiken, MD

There are many reasons why symptoms worsen in younger patients who are prescribed antidepressants. Five possible scenarios are discussed in this podcast.

You get an urgent call from the mother of a 12-year-old patient. Three weeks ago she started fluoxetine for depression, and now she seems even more depressed. She is emotionally reactive: irritable, tearful, or anxious over everyday hassles. She is agitated and her sleep is worse, but there are no clear-cut symptoms of mania. What do you do?

, Associate Professor of Psychiatry and Behavioral Sciences and Director of the 

Stanford Pediatric Mood Disorders Program

, describes how she approaches cases like these. I met her at the American Psychiatric Association meeting in San Francisco, where she released a 

 The book is a thoughtful synthesis of the diverse views on this subject. There are many reasons why younger patients get worse on antidepressants, and we need to keep an open mind to all possibilities including:

1. Age of the child. Children younger than 12 are more likely to worsen on antidepressants. A slow and careful titration is very important in this population.

2. Family history of bipolar disorder. While 1 in 10 children get worse on an antidepressant in the general population, those odds rise to 1 in 2 when the child has a parent or first-degree relative with bipolar disorder.

3. Subthreshold manic symptoms. These include patients who have symptoms of mania that are too few in number or too short in duration to count toward a full diagnosis of 

. While DSM-5 requires 4 days of hypomanic symptoms to meet the criteria for bipolar disorder, hypomania tends to be shorter in children and adolescents.

4. Personal and family history of antidepressant response. If other family members have taken antidepressants, ask them how they responded. Often children who get worse on antidepressants have family members who had a similar response.

5. Dose response. Carefully evaluate how the symptoms changed-getting better or worse-as the dose was raised or increased. Sometimes going slower resolves the problem.

Whether to stop the medication, lower the dose, or switch to a mood stabilizer depends on what is causing the problem. For more tips on this decision, listen to the full interview above.

Dr Aiken is Instructor in Clinical Psychiatry at the 

Wake Forest University School of Medicine

 in Winston-Salem, NC. He is Editor in Chief of 

and Bipolar Disorder Section Co-Editor for

Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from W.W. Norton & Co. for a book he co-authored with James Phelps, MD, 

Clinical Handbook for the Diagnosis and Treatment of Pediatric Mood Disorders

Washington, DC: American Psychiatric Publishing; 2019.

This podcast was originally posted on June 19, 2019, and has since been updated. -Ed

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There are many reasons symptoms worsen in younger patients who are prescribed antidepressants. Five possible scenarios are discussed in this podcast.

When Children Get Worse on Antidepressants: Activation or Bipolar?

Chris Aiken, MD, and Kellie Newsome, PMH-NP, discuss how to dose quetiapine for the treatment of bipolar disorder.

Dr Aikenis the Mood Disorders Section Editor for Psychiatric Times, the Editor in Chief of 

 His written several books on mood disorders, most recently 

with his co-host Kellie Newsome, PMH-NP. Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 



Kellie L. Newsome, PMH-NP, is the cohost of the 

 and is also a practicing Psychiatric Mental Health Nurse Practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

For more on this topic, see 

Top Mood Stabilizers for Bipolar Disorder

Chris Aiken, MD, and Kellie Newsome, PMH-NP, discuss best practices for dosing quetiapine for the treatment of bipolar disorder.

Dosing Tips for Bipolar Disorder: Quetiapine

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Ten sleep specialists assessed widely accepted beliefs and here's what they found.

6 Sleep Myths: Experts Weigh In

, the presenters listed 4 mood stabilizers that stand out in bipolar disorder treatment. In this podcast, Dr Aiken and Ms Newsome will discuss how to dose one of them: lithium.

 Dr Aiken, how do you start a patient on lithium?

 I start patients on lithium very slowly. This is a medication that is meant to work for the long term. It is not that effective for acute episodes, so there's no reason to rush it. Patients are often afraid of lithium; it has kind of a bad reputation out there, which isn't necessary because it's relatively well tolerated. For example, it has a chance of causing sedation around 1 in 28 patients, compared with 1 in 5 or 1 in 10 for most other mood stabilizers. It is also a little friendlier when it comes to weight gain and cognitive side effects than many of the other mood stabilizers. 

If you start lithium too quickly, the patient is liable to stop it because of one big side effect: nausea. That is the one you need to prepare them for. Nausea shouldn't be a reason to stop lithium, because it almost always gets better with time. So if you can just get your patient through that whether it's using 

or ginger tablets or taking it after food or raising the dose real slowly, it'll pay off in the long term.

Generally, I'll start with 300 mg at night and raise it by 300 mg each week until I reach 900 mg, at which point, I'll check the level. If the patient is on a drug that interacts with lithium, such as 

or if they're older or frail or afraid of side effects, I'll start lower cutting all of those doses in half. Of course, if your patient is actively manic or you're trying to keep them out of the hospital, you might go faster with this.

Do you give lithium all at night or twice a day. 

Lithium is often dosed twice a day, but I think that's out of convention rather than science. Its half-life is 24 hours so there's no reason to do that. And in a few long term studies, patients actually had lower rates of renal problems if the lithium was dosed entirely at night rather than twice a day. It seems that the kidneys do better when they get a bolus of lithium at night, rather than spread evenly throughout the day.

So what if you're using a high dose? Wouldn't you need to spread that out? 

 First of all, the dose doesn't really matter in lithium; it's the blood level. So that is a good question though, what if the blood level is high, would we need to spread that out. Nobody knows the answer to that. But what I do is if the blood level is going above 0.8, I will spread it out and give a little bit of the dose in the morning. The reason is that we do have long term studies where if lithium level is kept at 0.8 or below, there is much lower risk of renal problems. So we don't know for sure, but I'm hedging my bets and saying let's try to keep that level, less than 0.8 throughout the day to save the kidneys.

Lithium comes in several forms, instant release, lithobid, and eskalith. Which one do you prefer?

 Generally, I'll use lithobid, but each has its advantage. Lithobid and eskalith are the extended released versions, and they're going to cut most of the side effects in half so they're better tolerated overall. However, if the patient has constipation, that often improves with the instant release, whereas diarrhea and nausea tend to improve with the controlled release. Another reason you might use the instant release is if you're starting real low like 150 mg, that dose only comes as an instant release, and eskoleth. I can't see much reason to prefer eskoleth over lithobid, other than the tablet size, which does matter to patients. Most patients, rather take 2 pills than 3. And since eskoleth comes as a 450 often use 2 of those rather than 3 of the lithobids, once they get to the dose of 900.

Once you get to 900 and you check the level, what levels are you actually looking for? 

This is something we have a lot of research on so there are good numbers to know here. The target level for lithium is 0.6, to 0.8 for depression as well as for the maintenance phase. You want to keep it in that sweet spot. If the patient has active mania, you should go up to 0.8 to 1.2. But you might want to bring it down after they've recovered, again to save the kidneys. Children by the way require the same levels as adults, but if the patient is over 65, they might need levels that are 20% to 30% lower than the ones I just quoted for an interesting reason. In older age, the brain tends to absorb more of the lithium, so they actually get a good therapeutic effect at a slightly lower dose.

is the Mood Disorders Section Editor for Psychiatric Times, the Editor in Chief of 

with his co-host Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

 and is also a practicing Psychiatric Mental Health Nurse Practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

Chris Aiken, MD, and Kellie Newsome, PMH-NP, discuss how to dose lithium for the treatment of bipolar disorder.

Dosing Tips: Lithium for Bipolar Disorder

If you were stranded on a desert island, which mood stabilizers would you want on the formulary? That question and more will be discussed in this podcast with Chris Aiken, MD, and Kellie Newsome, NP.

Which one rises to the top of your list? More in this podcast.

Mood Stabilizers for Bipolar Disorder

Treatment-resistant depression (TRD) is a category that is all-too-easy to fall into. A lack of meaningful response to two full antidepressant trials is all it takes, and 1 in 3 patients with depression end up there. Once they do, the path out is uncertain. We have two FDA-approved therapies for TRD: olanzapine/fluoxetine combination (Symbyax, approved in 2009) and intranasal esketamine (Spravato, approved in 2019).

Beyond that, most research on TRD used a looser definition: failure of just one trial (also known as Stage I TRD in the Thase-Rush Staging Method). That was how transcranial magnetic stimulation (TMS) got approved and how the majority of antidepressant augmentation studies have been conducted.For example, in a 2015 meta-analysis of TRD, three quarters of the studies included patients who had only failed one antidepressant, and half of them focused 

A new meta-analysis set out to address this gap by focusing only on studies of true TRD with at least two failed antidepressants. They arrived at some surprising results which I’ll review here.

Led by Allan Young, the British and Canadian researchers gathered 27 medication trials and 3 psychotherapy trials and analyzed the data 2 different ways. First by comparing the change in depressive symptoms with each treatment (the pre- post- effect size), and then through a network meta-analysis that 

They found a significant benefit with the atypical antipsychotics, specifically 

 aripiprazole (5), brexpiprazole (5), cariprazine(1), olanzapine (combined with fluoxetine) (1), and quetiapine (2). All of those are FDA-approved as antidepressant augmentation except cariprazine, which only worked in 2 out of 3 of its published 

 did not work as well when limited to patients with true TRD. That conclusion was problematic though, as the authors lumped it with lamotrigine. A 2017 meta-analysis, however, 

only marginal benefits for lithium and lamotrigine in true TRD when the two were analyzed separately, but with the small size of the trials I would say that the jury is still out.

The novel finding in this analysis was the large effect of glutamatergic therapies: ketamine (3) and two repurposed antibiotics, minocycline (1) and d-cycloserine (1). When lumped together

 their effect size was large (0.9), compared to the small effect size (0.2) of the atypical antipsychotics. This finding supports the glutamatergic system as a target for difficult to treat depressions, with a few caveats.

First, mechanisms of action are rarely clear, and it is possible that these medications exert their effects through other pathways. 

also has anti-inflammatory and neuroprotective effects,

works through the glutamate or opioid system or some combination of the two.

Second, ketamine’s benefits are rapid but short-lived. After 1 week, its safety and efficacy are 

 Esketamine (Spravato), the S- isomer of ketamine, has controlled 

 but its benefits declined over that time and in some studies were no longer significant by the 4-week mark.

The large effect in the glutamatergic category was not limited to ketamine but was shared by the novel agents minocycline and d-cycloserine as well. Each of these, however, was supported by only one small trial in true TRD.

 Of the two, minocycline is better studied, with 18 randomized controlled trials in depression which─when analyzed together─also yielded a large effect size (0.78).

With each failed treatment, life’s problems multiply. Relationships grow strained, job performance declines, and avoidant behaviors become further ingrained. It should not come as a surprise then that psychotherapy works in TRD, but the magnitude of that effect is unexpected. In Young’s analysis, psychotherapy had a slightly larger effect than pharmacotherapy in TRD. Those therapies were cognitive behavioral therapy (CBT) for 6 weeks, mindfulness based CBT for 8 weeks, and psychoanalytic psychotherapy, delivered weekly over 1.5 years. 

The caveat here is that it is very difficult to compare treatments across different studies with different types of placebos, but the message is clear. Psychotherapy is not just for mild depression, but has proven its worth in moderate-severe depression, chronic depression, and─with these three recent trials─stage II TRD.

Network meta-analyses have many limitations. Chief among them is the assumption that all of these trials share a common placebo effect. The “placebo,” however, is not a sugar pill, but an amalgam of varied factors including hope, the kind attention of the research team, and the natural course of the illness. If these effects were small, this wouldn’t be a big deal, but they are not. They account for around 30% of the improvement in antidepressant trials.

Young’s work digs up some new tools for TRD, but it also reveals how limited the TRD toolbox is. Novel medications had large effects but limited track records, while established therapies had only small effect sizes. Electroconvulsive therapy (ECT) was left out of the analysis, but even this gold standard becomes less likely to work with each failed medication trial, starting with the first one.

 Time is of the essence here. It is much easier to treat depression after 6 months of non-response than 6 years, regardless of which intervention is used.

When you set out on this work, bring the toolbox, but also bring a compass and a map (ie, a 

 like the PHQ). You’ll need that to guide the treatment. Otherwise, you’re left asking the patient where to go. And while collaborative care is essential to this work, symptoms like hopelessness, indecisiveness, and inertia are unlikely to steer a steady course. Left unattended, they may lead to drop-out. It’s our job to attend.

is the Mood Disorders Section Editor for 

 with his co-host Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for 

Comparative efficacy, acceptability, and tolerability of augmentation agents in treatment-resistant depression: systematic review and network meta-analysis.

2. Carter B, Strawbridge R, Husain MI, et al. 

Relative effectiveness of augmentation treatments for treatment-resistant depression: a systematic review and network meta-analysis.

3. Strawbridge R, Carter B, Marwood L, et al. 

Augmentation therapies for treatment-resistant depression: systematic review and meta-analysis.

Efficacy of adjunctive low-dose cariprazine in major depressive disorder: a randomized, double-blind, placebo-controlled trial.

5. Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N. 

Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: A systematic review and network meta-analysis.

Efficacy and tolerability of minocycline for depression: A systematic review and meta-analysis of clinical trials.

7. Perez-Caballero L, Perez V, Berrocoso E. 

What ketamine can teach us about the opioid system in depression?

2020;1-4. doi:10.1080/17460441.2020.1781812

Effects of low-dose and very low-dose ketamine among patients with major depression: A systematic review and meta-analysis.

Adjunctive intranasal esketamine for major depressive disorder: A systematic review of randomized double-blind controlled-placebo studies.

10. Fedgchin M, Trivedi M, Daly EJ, et al. 

Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: Results of a randomized, double-blind, active-controlled study (TRANSFORM-1).

11. Ochs-Ross R, Daly EJ, Zhang Y, et al. 

Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression-TRANSFORM-3.

2020;28(2):121-141. doi:10.1016/j.jagp.2019.10.008

12. Canuso CM, Singh JB, Fedgchin M, et al. 

Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study.

13. Heresco-Levy U, Gelfin G, Bloch B, et al. 

A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression.

14. Husain MI, Chaudhry IB, Husain N, et al. 

Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.

Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2).

16. Dombrovski AY, Mulsant BH, Haskett RF, Prudic J, Begley AE, Sackeim HA. 

Predictors of remission after electroconvulsive therapy in unipolar major depression.

Articles

It is much easier to treat depression after 6 months of non-response than 6 years, regardless of which intervention is used, so time is of the essence. 

New Answers for Treatment-Resistant Depression

 had a problem, and the medications weren’t solving it. “I've taken a lot of Prozac, Paxil, Wellbutrin, Effexor, Ritalin, Focalin. I’ve also studied deeply in the philosophies of the religions, but cheerfulness kept breaking through.”

The “cheerfulness” Cohen complained of was a wry euphemism for something darker. The poet, novelist, and songwriter had “dealt with depression ever since my adolescence. . . Moving into some periods, which were debilitating, when I found it hard to get off the couch, to periods when I was fully operative, but the background noise of anguish still prevailed.”

By his mid-60s Cohen had been through several hospitalizations and tried tricyclics, MAOIs, second generation antidepressants, and anticonvulsants without success. Despite releasing one of the most successful albums of his career, The Future, he found himself “really, really low, on many medications . . . I pulled my car over to the side of the road. I took out all the medication and threw it out the window.”

A few years later the depression lifted, and, by Cohen’s report, it did not return. Depression is overdetermined, to borrow Freud’s phrase, and its resolution is equally mysterious. But a new study sheds light on some of the forces that may have been at play in Cohen’s recovery.

Cohen’s depression had reached “a certain unendurable point” in 1994. He retreated from public life and joined a 

, where he was later ordained as a monk. There he learned to shift his focus away from the “loyalty and the tyranny” of his inner thoughts-the self-focused, ruminative kind that come with depression.

Rumination is a repetitive pattern of thought that plagues many patients with depression. It is also a strong predictor of depressive relapse. Rumination is problem solving gone awry, brooding over unresolvable conflicts and questions that can’t be answered. “Why am I such a loser . . . When will this end . . . What do people really think of me . . . What is the point?” Rumination arises from the brain’s default mode network, which engages in thoughts about the self, the future, and the social world.

 The default mode is activated when we’re bored, uncomfortable, or lonely. For people who are prone to depression, the slightest trigger will turn it on.

Yet there is a brighter side to the dark imaginations of the default mode. When not conjuring foreboding possibilities, it can dream up creative solutions and inspire great art. That might explain why so many creative thinkers have strong ruminative tendencies.

 That dogged style of thought also lends itself to the persistence that is necessary to create great works. As Cohen described it, songwriting was an act of drudgery where “you’re not doing anything else but trying to find the rhyme for ‘orange.’ It doesn’t exist. Some people say it’s ‘door hinge,’ but that’s not right.”

Buddhism did not answer Cohen’s ruminative questions. In his words, it simply “dissolved them.” Psychologists call this metacognitive awareness. It is the ability to see one’s thoughts objectively, with some detachment, and it is a strong predictor of sustained remission from depression.

 It is also a key ingredient in mindfulness, which is derived from the kind of Buddhist practice that Cohen pursued.

Twenty years after Cohen’s recovery, a remarkable study came out of 

, the same Indian city where Cohen broke free from his depression.

 It was a controlled trial of Buddhist meditation for bipolar II depression. By psychotherapy standards, the study was huge, with 622 patients. Half were randomized to cognitive behavioral therapy, and the other half underwent training in meditation. The study lasted 2 years, during which the meditation group was advised to follow a simple 30-minute practice once a week (see 

). That is correct-only 30 minutes per week. The teaching was also low intensity: 5 to 10 two-hour sessions interspersed throughout the 2-year study.

 (CBT) group with a large effect size (0.7). How did this mild intervention outperform cognitive behavioral therapy with such a large effect?

The secret may lie in the 2-year duration. That is how long it took Leonard Cohen’s mood to lift “by imperceptible degrees” while he studied meditation in Mumbai. Other behavior changes, like exercise and social rhythm therapy, also show more robust effects when allowed to build for 6 to 12 months. The challenge is to help patients stay motivated through those imperceptible degrees of progress.

This article was originally posted on March 26, 2020, and has since been updated. -Ed

, and the Director of the Mood Treatment Center. He has written several books on mood disorders, most recently 

 podcast with his co-host Kellie Newsome, PMH-NP. Dr Aiken does not accept honoraria from pharmaceutical companies but receives royalties from PESI for T

The default mode network and social understanding of others: what do brain connectivity studies tell us

. 2014;8:74.
	2. Perkins AM, Arnone D, Smallwood J, Mobbs D. 

Thinking too much: self-generated thought as the engine of neuroticism

. 2015;19:492-498.
	3. Teasdale JD, Moore RG, Hayhurst H, et al. 

Metacognitive awareness and prevention of relapse in depression: empirical evidence

Meditation for treating adults with bipolar disorder II: a multi-city study

A recent study shows that meditative practice is surprisingly effective for bipolar depression. The late poet helps explain why.

What Leonard Cohen Can Teach Us About Depression

These mood stabilizers cover a lot of ground, but it is important to know how to use them.

Dosing Secrets for the Top Mood Stabilizers

I’ve been pouring over textbooks and treatment guidelines, and these four mood stabilizers keep rising to the top.

 None of them are perfect, but each has a unique role in bipolar disorder:

Lithium and quetiapine top the lists for all three phases of the illness: mania, depression, and the maintenance phase. Lurasidone and lamotrigine are either untested (lurasidone) or ineffective (lamotrigine) in mania, but they are essential tools for bipolar depression.

Lithium stands out for its preventative effects in bipolar disorder, but it also has important benefits outside of the manic-depressive symptom lists. It is the only mood stabilizer that significantly reduces the risk of suicide, and it reduces mortality in other ways as well. Although lithium is often avoided out of concerns of toxicity, it actually lowers the risk of cancer, heart disease, stroke, and viral illnesses.

 All of those occur at higher frequency in bipolar disorder. Vascular disease is the leading cause of death in bipolar disorder,

 and viral illnesses are both a consequence (ie, STDs) and cause (ie. inflammatory effects) of bipolar symptoms.

 bipolar disorder tend to respond best to lithium. They are characterized by full remission between episodes, predominance of manic over depressive symptoms, illness onset in late teens, and a family history of bipolar disorder. They also tend to lack significant mixed states, rapid cycling, and psychiatric comorbidities, although a recent study found that comorbid panic disorder predicted lithium response.

Quetiapine covers ground that lithium does not. It is more effective against mixed manias, while lithium is preferred for the purer, euphoric highs. It also works better in acute depressive episodes. Quetiapine cannot claim the medical benefits that lithium does, but it does assist with two symptoms that patients find particularly troubling: anxiety and insomnia.

 Although its long-term adverse effects give me pause, it did provide the best protection against both poles of the illness in Terrence Ketter’s analysis of the numbers needed to treat (NNT) for long-term maintenance.

Lurasidone (Latuda) and Lamotrigine (Lamictal)

Both of these occupy a unique niche in bipolar depression. Lurasidone is the more effective of the two, with a number needed to treat (NNT) of 5 compared to lamotrigine’s 12.

 But lamotrigine is the better tolerated option, with few of the adverse effects that matter most to patients: weight gain, fatigue, sexual dysfunction, and long-term medical risks. Lamotrigine is better at preventing depression than it is at treating it.

There is some evidence that lamotrigine works better in bipolar II disorder, where frequent cycles of depression predominate, than bipolar I.

 Some experts favor it for the rapid mood fluctuations of cyclothymic disorder, and I’ve found it useful there as well.

 The main risk of lamotrigine is during the first three months of treatment, when Stevens-Johnson syndrome and other life threatening allergic reactions can occur at a rate of about 1:3000.

Long-term tolerability is not the strong suit of atypical antipsychotics like lurasidone, but these medicines can work quickly to get patients out of severe episodes. The ones that 

 are cariprazine (Vraylar), lurasidone (Latuda), olanzapine-fluoxetine combo (Symbyax), and quetiapine (Seroquel). Among them, lurasidone offers a good balance of efficacy and tolerability. Lurasidone’s main problems â nausea, akathisia, cost, and lack of evidence in mania â are less likely to occur with quetiapine, so patients who cannot tolerate one will often tolerate the other.

Matching the mood stabilizer to the patient is a matter of balancing competing goals. Each stands out in its own way, whether for tolerability, treatment of comorbidities, or benefits in depression, mania, or the maintenance phase. Together, these four treatments cover lot of ground, but you also need to know how to use them. That is covered in the next installment.

1. Parker GB, Graham RK, Tavella G. Is there consensus across international evidence-based guidelines for the management of bipolar disorder? 

2. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. 

3. Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. 

4. Wang D, Osser DN. The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An update on bipolar depression. 

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Advances in Treatment of Bipolar Disorders,

 1st Edition. American Psychiatric Publishing, Washington, DC.

7. Post RM. The new news about lithium: An underutilized treatment in the united states. 

8. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. 

9. Tucker JD, Bertke AS. Assessment of cognitive impairment in HSV-1 positive schizophrenia and bipolar patients: Systematic review and meta-analysis. 

10. Scott J, Bellivier F, Manchia M, et al. Can network analysis shed light on predictors of lithium response in bipolar I disorder?

11. Pompili M, Rihmer Z, Gonda X, Serafini G, Sher L, Girardi P. Early onset of action and sleep-improving effect are crucial in decreasing suicide risk: the role of quetiapine XR in the treatment of unipolar and bipolar depression. 

12. Wang Z, Kemp DE, Chan PK, et al. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. 

13. Terao T, Ishida A, Kimura T, Yarita M, Hara T. Preventive effects of lamotrigine in bipolar II versus bipolar I disorder. 

14. Manning JS, Haykal RF, Connor PD, Cunningham PD, Jackson WC, Long S. Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament. 

None of them are perfect, but a few rise to the top, according to recent guidelines.

Recovery from depression is a process, and patients need steady, realistic guidance to move through each stage. Insights here.

Author | Chris Aiken, MD

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