Depression Treatment

Author: Daniel Carlat M.D.
Last Updated: 4/1/20

Diagnosis

Depression is the most common presenting symptom in most inpatient units. Inpatient depression tends to be very severe, and you’ll see certain variations more commonly, such as depression with psychosis, anxiety, agitation, rumination, and catatonia. Many of your depressed patients will have been on many medications and most would probably benefit from a trial of ECT. Suicidality is more severe in the inpatient population as well.

In approaching the diagnosis of a depressive disorder, it’s good to be systematic in order to make sure you don’t miss anything.

Here are the most common variations of depression that you’ll want to rule in or out:

• Atypical depression
• Melancholia

Let’s go through each of these in turn.

Major depressive disorder

As in outpatient psychiatry, a good mnemonic for guiding your evaluation of depressive symptoms in inpatients is SIGECAPS plus mood. Try to establish that the patient has had a depressive mood state (sad, empty, irritable, discouraged, never happy, etc) in addition to 5 out of 8 SIGECAPS for at least 2 weeks.

Mood. “How has your mood been over the last 2 weeks?” “Have you felt so depressed that you felt like your entire life has been affected by your mood?”

Sleep. “Have you slept well or poorly over the last 2 weeks?” “Do you sleep too much or too little when you are depressed?”

Depressed patients may have insomnia or hypersomnia, though insomnia is more common. Insomnia may be described as sleepless nights, and it may include early morning awakening. Pay close attention to sleep habits because our meds are very good at improving them quickly. Insomnia is usually the first symptom to improve during an inpatient stay, typically on the first night.

Interest (loss of interest or pleasure). “Have you been able to enjoy doing anything over the last few weeks?”

Guilt, worthlessness, hopelessness. “How has your self esteem been? Do you feel that you are a good person? Do you still have hope? Have you felt guilty about things you’ve done or haven’t done?”

Energy. “How has your energy level been over the last couple of weeks?”

Concentration. “Have you been able to focus on things well? How has your concentration level been?”

Appetite. “Have you felt like eating? Have you lost weight lately?” “Have you been eating too much, just to feel good?”

Consider adding Ensure to the meals of patients who have lost a lot of weight.

Psychomotor retardation or agitation. This is usually diagnosed more by observation than by asking questions, but you can try questions like, “Have you felt like everything has become slowed down? Or have you felt unusually restless or agitated?”

Suicidality. “Have you had thoughts of wishing you were dead? Have you been thinking about ways to kill yourself?”

Bipolar depression

An unknown percentage of people who present with depression will actually have bipolar disorder, and if you can establish a history of mania you’ll be less likely to prescribe antidepressants. Clues to bipolar disorder in a depressed patient include a family history of bipolar disorder and the presence of psychosis.

“Have you ever had an entire week when you felt so good and energetic that you hardly needed any sleep and you felt like you could get anything done?”

We get into detail on diagnosing mania in the bipolar disorder chapter, but just for convenience here are the basic criteria:

Manic episode = One week of expansive mood + DIGFAST (3/7, or 4/7 if primary mood is irritable).

D: Distractibility

I: Indiscretion

G: Grandiosity

F: Flight of ideas

A: Activity increase

S: Sleep decrease

T: Talkativeness

Psychotic depression

Clearly, there are many ways to ask about psychosis, but the key point is that you should make sure to screen for psychosis in all depressed patients, even if they appear superficially to be thinking normally.

You can get at psychosis by coming right out and asking directly:

“Have you ever had psychosis, like hearing voices, having hallucinations, having delusions, or being really paranoid?”

Alternatively, if you sense the patient isn’t sophisticated enough to understand these terms, you can ask in more subtle ways, eg:

“Have you had any experiences like dreaming when you’re awake? Have you heard things that other people can’t hear? Do you feel like other people, even strangers, are bothering you or trying to make like difficult for you?”

Ruminative depression

Ruminative depression is similar to psychosis but with an emphasis on difficulty processing thoughts. Delusions might be present but usually aren’t bizarre.but not as extreme or bizarre. The most common presentation is the patient who is obsessed by their symptoms and believes that they will never get better. The typical ruminative patient will anxiously ask you (often over and over) whether they will ever get better, and they cannot be reassured by you. Other ruminative patients will be thinking over and over about something they did in the past that causes them intense guilt.

You will be tempted to try to reason with these patients, perhaps even using some cognitive therapy. They have distorted automatic thoughts, so why wouldn’t you point that out and see if they can come up with something more rational?

“Ms. Jones, how strongly do you believe that you will never get better? When you’ve had depression before, did you improve? If you’ve improved in the past, is it rational to believe that you won’t improve this time?”

Such therapeutic interventions are usually futile in my experience. Typically after a seemingly productive conversation, the patient will still have the same rumination. And may actually feel worse about themselves because they feel they are disappointing you.

Patients with rumination typically need both antidepressants and antipsychotics, and the response is quite gradual. Be patient.

Major depression with mixed manic features

This is often considered a variation of bipolar disorder. These are patients who meet the criteria for major depression, but in addition, they also have been experiencing at least three symptoms of mania, and all three symptoms are present nearly every day, alongside the depression.

Diagnostic criteria:

1. Patient meets criteria for a major depressive disorder
2. In addition, the patient must have at least 3 of the following

Such patients will have generally presented with suicidal ideation and depression but on the unit they seem to have a lot of energy, are pretty talkative, impulsive, and want to do stuff.

View this as a flavor of bipolar disorder and go easy on the antidepressants. You will be more likely to use mood stabilizers and antipsychotics.

Substance-induced depression

This syndrome may be one of the most common reasons for admission in many hospitals, especially those with a strong dual diagnosis program. The term “substance-induced” is quite non-specific. Generally, you won’t be able to ascertain that a particular substance caused depression. Instead, you’ll be treating a patient who has a long history of severe polysubstance abuse who is admitted for a combination of depression/suicidal ideation/drug withdrawal/poverty/homelessness/poor nutrition etc…. Within a day or two, these patients typically are no longer suicidal and they’re feeling a lot better. A comfortable bed, central heat, three square meals, and sympathetic staff are the curative elements.

Melancholic Depression

Melancholia has a kind of mystique because it was one of the earliest types of depression described, and it’s thought to be more “biological” than other types of depression.

Here are the diagnostic criteria:

One of the following:

And at least three of the following:

• Depression that is subjectively different from grief or loss

These are often older patients, and they frequently have some degree of guilty or hopeless rumination. The treatment is usually similar to psychotic depression, and ECT is often considered. There is some evidence that tricyclics are more effective than other medications.

Atypical depression

Atypical depression comprises about 15% of patients with depression, and it’s important to diagnose it because it is particularly responsive to MAOIs.

A. Mood reactivity (mood brightens in response to positive events)

Ask: “When you get some good news, or when something good happens, does your mood get much better…or do you just stay completely blue?”

B. Two or more of the following:

TREATMENT

In the inpatient unit, we want to help patients relieve depressive symptoms quickly, and that means using creative combinations of medication and therapy.

MEDICATIONS

Symptom profiling

Matching antidepressants to a symptom profile is more art than science, since few studies have attempted to determine whether this method can improve outcomes. Nonetheless, symptom matching gives us a reasonable rationale for making medication choices.

Consider SSRIs when anxiety and irritability are prominent, bupropion for lethargy and poor concentration, and mirtazapine to target insomnia and poor appetite.

Psychiatric comorbidities

Generally the presence of comorbidities will tip the scale in the direction of SSRIs. Although different SSRIs carry different indications, as a class, these multi-purpose drugs are effective for nearly every anxiety disorder (panic disorder, GAD, social anxiety disorder, OCD, and PTSD), as well as other diagnoses, including eating disorders, premenstrual dysphoric disorder, and intermittent explosive disorder (or anger and irritability in its less severe form).

Several other antidepressants are “twofers” or “threefers.” Wellbutrin helps with smoking cessation and can treat ADHD symptoms in addition to depression. Cymbalta has been FDA-approved for various pain conditions, including fibromyalgia, chronic musculoskeletal pain, and diabetic neuropathy. Tricyclic antidepressants can also help with these pain syndromes as well as migraines.

Side effects

• If a patient is concerned about weight gain, avoid paroxetine and mirtazapine.
• If he or she is concerned about sexual side effects, you are limited to bupropion.
• Cardiac issues. Since both tricyclics and citalopram (at dosages higher than 40 mg) may prolong the QT interval, you should probably avoid these as first line (or even second line) agents.
• If your patient has a history of overdosing, avoid tricyclics and MAOIs.
• If your patient has medical issues requiring several other medications, you would be concerned about drug interactions. The only antidepressants that cause significant drug interactions are MAOIs, paroxetine, fluvoxamine, and fluoxetine, so avoid these.
• Discontinuation syndrome. Five antidepressants stand out as the worst offenders in terms of discontinuation syndrome and therefore should rarely be first-line agents: venlafaxine, desvenlafaxine, duloxetine, paroxetine, and fluvoxamine.

History of medication response

Theoretically you would want to get a detailed medication history from patients, which would inform your medication choices. It’s difficult to do this. Patients have poor memories for names of meds they’ve taken. Getting prior medical records is difficult, and often they won’t arrive until a few days into an admission. Talking to the outpatient prescriber is usually your best bet, but since so many inpatients are underinsured and live chaotic lives, it may be hard to locate a prescriber who knows the patient well enough to give you a meaningful medication history. For all these reasons, you’re often in a situation of starting the patient on a “new” trial of a medication, even if they have a long history of antidepressant treatment.

1. If the patient clearly responded to an antidepressant in the past, try it again.
2. If the patient responded in the past but developed intolerable side effects, consider a re-challenge, because side effects may not recur and if they do they can be mitigated. Alternatively try another antidepressant from the same class.
3. If a patient reports that a close family member responded well to a particular antidepressant, it’s reasonable to try that one.

FIRST LINE ANTIDEPRESSANTS

Fluoxetine. It has a long track record of success and safety (first approved in 1988). Since it is the most famous antidepressant, most patients have heard of it and may have a positive association, so you can optimize the placebo response. It is the only medication approved for bulimia nervosa. I may act as a mild stimulant for some patients who present with anergia. It does cause some drug interactions so run an interactions check on your smart phone before prescribing for patients on other meds.

Sertraline. Sertraline often makes it to the top of lists of best antidepressants based on meta-analyses, because it was a good combination of efficacy and tolerability. Its most common bothersome side effect is mild GI distress with diarrhea.

Escitalopram. This is one of the most well tolerated antidepressants. It has become quite popular since its close relative, Celexa, fell out of favor due to an FDA alert about Celexa’s cardiac effects at high doses.

Bupropion. Bupropion is the antidepressant with the best side effect profile (no sexual side effects, no drug interactions). However it can cause insomnia and jitteriness especially if started at too high a dose.

Mirtazapine. Although mirtazapine often causes weight gain, its sedative properties are useful, as well as the lack of sexual side effects and drug interactions. Good antidepressant for those with anxiety, insomnia, who want to avoid sexual side effects, and who may benefit from appetite stimulation.

SECOND LINE ANTIDEPRESSANTS

For patients who are admitted with a history of having recently failed an adequate trial of one or more antidepressants (or who failed a trial while on the unit), what should you do next?

SNRIs (Serotonin Norepinephrine Reuptake Inhibitors)

SNRIs will typically be the first of the second line agents. Here you have three options: duloxetine, venlafaxine, or desvenlafaxine—however, desvenlafaxine is rarely used, probably because it there are no clear advantages over venlafaxine, which has long been available generically.

My first choice is almost always duloxetine, which has various advantages over venlafaxine: less likely to increase blood pressure, milder discontinuation symptoms, and a broader range of FDA indications.

Tricyclics

As mentioned in the diagnostic section, there is evidence that tricyclics are especially effective for severe melancholic depression. Unfortunately, they tend to be underprescribed, because of side effect issues and because few psychiatrists have been properly trained in their use.

You should prescribe a tricyclic for any patient with severe depression who has failed three or more standard agents. The exception is if your patient is chronically suicidal with a history of overdoses.

When choosing among tricyclics, there are four potential medications: amitrypiline, imipramine, nortriptyline and desipramine. Typically we start with one of the secondary amines with the fewest side effects: nortriptyline and desipramine.

In patients older than 40, order an EKG before starting either medication. Then start with 25 mg QHS, and increase daily up to 75 mg-100 mg daily. If there’s no response after about a week, increase to 150 mg. Some recommend ordering nortriptyline levels, though the data correlating blood to efficacy is not very strong.

MAOIs

MAOIs are important to try for patients with atypical depression or any treatment resistant depression. Unfortunately, they are particularly hard to start on the inpatient unit, because the vast majority of candidates are already on an antidepressant, and you have to wash out the prior antidepressant before starting an MAOI. This washout period takes a minimum of 1 week, by which time most patients are on their way to discharge.

Nonetheless, in patients who have atypical symptoms or who have been through every other class of ADs, you should offer a trial of MAOIs. First, make sure they are capable of following an MAOI diet, which includes avoiding aged cheeses and some other more obscure foods.

Then choose one of the MAOIs. My personal favorite is tranylcypromine (Parnate) because it is somewhat better tolerated than phenelzine (Nardil). Start at 10 mg BID, and gradually increase to 30 mg BID. Common side effects are insomnia and orthostatic hypotension. See the appendix for useful patient information sheets on dietary and drug interactions.

Newer Agents

There are a number of newer antidepressants. Their role in our algorithm is still unclear, and because of formulary restrictions on branded medications, they are rarely started in the inpatient setting—though they will usually be continued if an admission is already taking one of them.

I will call out vortioxetine, because it may have some advantages over other antidepressants, namely in improving cognition and sexual functioning. If your hospital’s pharmacy stocks it, and if the patient’s insurance is likely to cover the cost after discharge, switching to vortioxetine is reasonable in patients who have failed a standard agents.

Switching strategies

When switching from one antidepressant to another you have two main choices: an immediate switch or a cross-taper. An immediate switch means discontinuing the old drug and starting the new drug the next day. A cross-taper means gradually decreasing the dosage of the first agent at the same time as you are gradually titrating up the dose of the new agent. These two options cover most of the switches you will make. An exception is switching to an MAOI, when you will have to do a wash out of the original antidepressant to ensure there is very little in the bloodstream before starting the MAOI.

SSRI to SSRI, bupropion, mirtazapine, SNRIs, vortioxetine, vilazodone: Immediate switch (exceptions: start meds at lower doses when switching from fluoxetine or paroxetine).

SSRI to tricyclic: Immediate if switching from Escitalopram or Sertraline; cross-taper if switching from fluoxetine or paroxetine (due to inhibition of tricyclic metabolism).

SNRI to SSRI: Taper venlafaxine to minimize discontinuation symptoms. The SSRI can be started immediately.

SNRI to SNRI: Immediate switch.

Bupropion: Switching to or from bupropion can me immediate, with the exception of switching from fluoxetine or paroxetine, both of which can increase blood levels and potentially incur the risk of seizure.

MAOIs: At least one week washout of SSRI (6 weeks if fluoxetine) and other antidepressants before starting MAOI. Similar precautions when switching from MAOI to other agents.

AUGMENTATION

There are dozens of augmentation strategies, and precious little head to head research to help us decide which ones are best. I’ll go through the most commonly used agents.

Atypical antipsychotics. Atypical antipsychotics have been by far the most studied augmentation agents, largely because pharmaceutical companies have invested in such studies. They are clearly moderately effective, yielding about 10% better response rate than placebos. These meds are great for inpatient settings, because they work quickly, usually within one week. The medications in the table have the most empirical support for efficacy for treatment resistant depression. (Lurasidone is approved for depression in bipolar disorder only). At the time of this writing, my personal first choice among these agents is aripiprazole because of its good side effect profile and the fact that it is available as a generic.

These are helpful for anyone with depression, but they especially appropriate for patients with psychotic states, including those with ruminative or racing thoughts.

Atypical Antipsychotics for Antidepressant Augmentation

	Target dosages	Notes
Aripiprazole	5-15 mg	Stimulating
Brexpiprazole	2-3 mg	Stimulating
Cariprazine	1.5-4.5 mg	Lethargy
Lurasidone	20-120 mg	Approved for bipolar depression
Olanzapine	5-10 mg	Good for insomnia/agitation
Quetiapine	300 mg	Good for insomnia/agitation
Risperidone	1-3 mg	Neither sedating nor stimulating
Ziprasidone	100 mg	Can be sedating or stimulating, depending on dose

Benzodiazepines

Depression and anxiety are the peanut butter and jelly of psychiatry—they co-occur very frequently. As many as two-thirds of patients with depression have a comorbid anxiety disorder, and it’s clear that patients with both depression and anxiety don’t respond as well to antidepressants. That’s why anxiolytics are such an important tool. In addition, since they provide immediate relief, they are particularly important in inpatient settings.

Benzodiazepines are been shown to be effective for antidepressant augmentation, with an effect size nearly as high as using SSRIs alone for depression.

Which benzodiazepine should you choose? All benzodiazepines work by the same mechanism of action so the main thing that distinguishes them is how quickly they work and how long they last. Of the most commonly used benzodiazepines, they can be ranked from shortest to longest acting in the following order: alprazolam, lorazepam, clonazepam, and alprazolam XR. For daytime anxiety, you’ll generally use the mid-range benzodiazepines, lorazepam and clonazepam.

Bupropion

Add bupropion to any antidepressant for patients who have anergia and/or sexual dysfunction.

Buspirone

Efficacy data are mixed, but buspirone is sometimes used as augmentation, especially when there is significant anxiety and when benzodiazepines can’t be used. Usual dose is 15 mg BID.

Hypnotics

Sleep disturbance are ubiquitous among depressed patients, – as many as 80-90% of depressed patients report having sleep problems (Antidepressant treatment of the depressed patient with insomnia. Thase ME. J Clin Psychiatry. 1999;60 Suppl 17:28-31), and research has consistently shown that persistent insomnia a risk factor for depressive recurrences (JAMA. 1989 Sep 15;262(11):1479-84.)

The choice of sleep agents, of course, are numerous. For patients whose main problem is insomnia without significant anxiety, my go-to sedatives are trazodone, benadryl, gabapentin, and clonidine. Each of these are safe, effective, have no dependency potential, and are weight neutral. They each also offer a unique mechanism of action so that if one doesn’t work, another one very well may.

For patients with insomnia and more severe anxiety, I usually recommend a benzodiazepine. Diazepam works quickly and lasts approximately 8 hours for most patients. It is therefore well-suited to treat insomnia, and for most patients does not cause much in the way of morning grogginess (diazepam earned a bad reputation in the 1970s as “mother’s little helper,” but it was no doubt overprescribed back then, and this has little bearing on its true merits). Alternatives to diazepam include clonazepam or alprazolam XR. Short acting BZDs like alprazolam and lorazepam, may help patients fall asleep, but often lead to rebound insomnia in the middle of the night once the medication starts to wear off.

Zolpidem (ambien) is an option but is not commonly prescribed because it causes amnesia and complex sleep behaviors in a significant subset of patients. Although it is not as addictive as the benzodiazapines, it is abused by some.

Lamotrigine

Studies of lamotrigine for antidepressant augmentation have largely been negative. So why use it anyway for that purpose? Two reasons: lamotrigine is clearly effective for bipolar depression, and many of the inpatients who we label “depressed” are often hard to accurately diagnose—eg., many might have bipolar spectrum elements. Thus, lamotrigine is not a bad drug to try when all else fails. See dosing suggestions in the bipolar chapter.

Lithium

Several meta-analyses have concluded that lithium augmentation of antidepressants is effective, with a NNT=5. It is also the only antidepressant medication shown to reduce suicidality. It is underused, with one VA study reporting that of 53,000 depressed patients who were prescribed an augmentation agent, only 2% received lithium—vs. 50% who received a second antidepressant and 33% who received an atypical antipsychotic (Vanlenstein 2006). This is partly due to a range of potential side effects, including hypothyroidism and kidney damage. In the chapter on bipolar disorder we cover using lithium in more depth, including some aspects of side effect prevention and management.

Start patients on regular lithium carbonate 300 mg BID or 600 mg QHS. Increase to 900 mg daily in a day or two, depending on side effects. Once the patient is on the 900 mg dose, wait 5 days for steady state before checking the lithium level, TSH, and BUN/creatinine.

Mirtazapine

Mirtazapine is often combined with antidepressants because it’s a potential two-fer: it is helpful for insomnia and there is some positive data on antidepressant augmentation. And if your patient has lost weight due to lack of appetite, this little drug becomes a three-fer. Use 15-30 mg at bedtime.

Pramipexole (Mirapex)

Use for lethargy and apathy. It has dopaminergic properties and can be thought of as similar to stimulants, but without the potential for abuse and tolerance. In one trial, patients with hard-to-treat MDD who received pramipexole combined with an SSRI/SNRI achieved better response than patients taking an SSRI/SNRI and placebo (Cusin C et al, J Clin Psychiatry2013;74(7):e636–e641).

When using pramipexole, starting low (around 0.125–0.25 mg per day) and increasing the dose slowly (by 0.25 mg every week) helps reduce nausea and orthostasis, two common side effects with this drug. Sedation is also possible, and there have been rare reports of visual hallucinations and compulsive behaviors such as gambling (Aiken CB, J Clin Psychiatry 2007;68(8):1230–1236).

Stimulants

Stimulants can offer immediate relief for depressed patients who struggle with lethargy, motivation, and poor concentration. Because of the increased concern about substance abuse over the last several years, relatively few psychiatrists use stimulants as an augmenter for depression, even though most (though not all) studies of the practice have had positive results (A review of the use of stimulants and stimulant alternatives in treating bipolar depression and major depressive disorder. Corp SA, Gitlin MJ, Altshuler LL. J Clin Psychiatry. 2014 Sep;75(9):1010-8). For patients who complain of low energy, poor concentration, and not getting things done, it’s reasonable to start with 5 mg of methylphenidate, and increase in 5 mg increments for a response.

Thyroid

It’s not clear that thyroid augmentation works, because most of the positive data comes from uncontrolled trials. Nonetheless, it falls in the category to strategies that are worth trying. Among the thyroid formulations, T3 (liothyronine, or Cytomel) is better studied than T4 (levothyroxine, or Synthroid) and was superior to T4 in a double-blind comparison (Joffe RT et al, Neuroendocrin Letters 1987;9:172). T3 is the more active form in the central nervous system, and some patients have difficulty converting T4 to T3. After checking a baseline thyroid panel, start T3 at 12.5–25 mcg/day and increase gradually toward a dose of 50 mcg daily. Check another thyroid panel 4–6 weeks after reaching the target dose (it takes at least that long for the thyroid gland to respond to changes in serum thyroid level). The dose should be lowered or discontinued if TSH < 0.5 mIU/L, which reflects an excessively high level of thyroid hormone.

Thyroid augmentation is best suited for patients with lethargy, poor motivation, and poor concentration.

Published on 4/13/2020. Copyright 2020 Inpatient Psychiatry Today.