Treating depression holistically: the path before ketamine becomes the question

It is Tuesday evening. You are on the sofa, the series is running, and you notice: nothing lands. Not sad enough for tears. Not tired enough for sleep. Just flat.

At the weekend you were away. It changed nothing. Neither did the holiday in spring. And at some point comes the sentence that makes many people search for the first time: maybe this is more than exhaustion.

Many people know this pattern. Usually one of two movements follows. One goes towards psychiatry and psychotherapy, often with waiting times and doubts. The other goes towards blood values, supplements and a search for causes in the body. I consider that split a misunderstanding. Both sides together make the path, each one alone is only half of it.

This article is built as a path. First the classification, then what has the best data, then the physical level, then lifestyle with numbers, then the steps above. Where ketamine belongs comes far down, because it is a late step. I describe this path because I consider the sequence to be the decisive point. Whether a late step such as ketamine is needed in the end is something I cannot predict for anyone. What I can say: the question can be answered more sensibly once the steps before it have been walked properly.

Classification first: depression, exhaustion or something else

The first question is not what you can do about it. The first question is what it is.

That sounds like a formality, but it decides everything that follows. Exhaustion after a hard year needs something different from a moderate depressive episode. And both need something different from bipolar disorder.

That is why the diagnosis comes at the beginning. In practice I often see it the other way round: people try things for half a year, and only when nothing works does someone look more closely. That is lost time, and it weighs heavily.

The criteria, in language you can apply to yourself

The German National Care Guideline works with a simple logic. There are core symptoms and additional symptoms, and there is a time window.

Core symptoms are low mood, loss of interest or pleasure and loss of drive. Additional symptoms include impaired concentration, reduced self worth, feelings of guilt, sleep problems, changed appetite, slowing or restlessness and thoughts of death. The time window is at least two weeks in which the symptoms are present almost continuously.

From this the severity grades follow. A mild episode requires at least two core symptoms, at least one additional symptom and four to five symptoms in total. A moderate episode at least two core symptoms, at least three additional symptoms and six to seven in total. A severe episode all three core symptoms, at least five additional symptoms and at least eight in total.

The difference you can feel yourself

There is a rule of thumb that often helps in conversation. Exhaustion responds to rest. Depression mostly does not.

If something comes back after a free weekend or two weeks of holiday, that points towards exhaustion. If the pleasure stays away even when everything around you is calm, the loss of interest is the key symptom. It is the hardest one to explain away.

On the distinction from burnout: in the ICD it is not a condition of its own but a factor influencing health status and contact with health services, and it describes work related exhaustion. The therapeutic differences are set out in burnout, depression and exhaustion depression.

On the distinction from brain fog: sluggish thinking, missing words and collapsing concentration overlap strongly with a depressive episode. The two often occur together and belong sorted apart, not played against each other. More in brain fog: recognising the symptoms.

How common this is, and why that may be a comfort

The third number is the reason for the box at the very top. The second is the reason for this article. The biggest gap in care is not the wrong treatment. It is no treatment at all.

What is well documented and therefore comes first

Now comes the part where some readers want to get off. Please stay.

I write about functional medicine, micronutrients and environmental factors. That is exactly why I have to be clear: psychotherapy and antidepressants are the building blocks with the best data. Nothing that comes later replaces them. That is not a polite bow, that is the state of the numbers.

Psychotherapy: 41 versus 17 percent

The most important thing about this number is that it disappoints honestly. If you are not better after two months of therapy, you are in the majority. That is a reason to adjust the approach, not to give up.

Behavioural activation: the low threshold entry point

I like this finding because it builds a bridge. Behavioural activation comes closest to a lifestyle recommendation and is still real therapy. That is why it sits up here and not down among the everyday levers.

With long waiting times, digital offerings are more than a consolation prize. In an individual participant data network meta-analysis of 39 studies with 9751 participants, guided internet based cognitive behavioural therapy was superior to unguided therapy directly after treatment, mean difference 0.8 PHQ-9 points. At scores between 5 and 9 the guidance made hardly any difference, above 9 it did.

Antidepressants: the most honest answer available

Placebo response, latency, side effects

First the placebo response. It is large in depression, and that is not an argument against treatment. Part of the improvement arises from attention, expectation, structure and time. Those parts are real, only not specific to the substance.

Second the latency. Noticeable change rarely comes in the first days, while side effects often come immediately. That order is the most common reason for early discontinuation and belongs discussed before day one.

Third the side effects: nausea, restlessness, changes in sleep, sexual dysfunction, changes in weight. They are real and unevenly distributed. A medication whose side effects nobody takes seriously does not get taken.

The stepped logic of the guidelines

The German National Care Guideline states that antidepressants are not first choice in a mild first episode. With recurrent episodes, non response or certain risk factors, the benefit risk balance shifts.

One last sentence on this: a waiting time is no reason to do nothing. And trying other things is no reason to stop the search for a therapy place. Both in parallel is the answer. And now you know why this section stands before the laboratory section.

The physical workup that everyday care often skips

Now comes the part many people searched for this article. First the sentence that stands above everything: the physical workup comes in addition, not instead. It is not a detour around psychotherapy and no substitute for medication, but the level alongside.

And a second sentence: depression is not a nutrient gap. It cannot be traced back to the gut, a vitamin or a flat. So why is the workup worthwhile? Because individual findings are treatable, because some symptoms can be mistaken for depression, and because the guideline asks for it.

1. The medication list, right at the start

To be clear again: it does not follow from this number that you should stop anything. It means the list belongs discussed. Who changes which medication and how is decided by the prescribing physician, not by a blog article.

2. The thyroid, and the number that cools the hype

3. Ferritin and iron, with the honest limitation

In clinical practice I observe, and this is observation and not a study statement: people with very low ferritin often describe a heaviness that, when you ask further, feels different from a depressive episode. More in ferritin: what is normal, ferritin above 100 as a target, iron deficiency and mental health and iron deficiency and fatigue.

4. Vitamin B12 and folate

A meta-analysis on folate status found lower values in people with depression, Hedges g equal to minus 0.24. The effect is consistent but clearly smaller than that of psychotherapy or exercise. For B vitamins, observational data from 18 studies are available: relative risks from 0.69 for B1 to 0.86 for B12. What was measured was dietary intake, not the effect of capsules.

What stays clinically relevant is a documented B12 deficiency. It can cause neurological and cognitive symptoms and occurs more often with a vegan diet, after stomach surgery, under certain long term medications and at older ages. Such a deficiency is corrected. That is good medicine, but not a depression treatment.

5. Vitamin D, and the most uncomfortable number in the whole article

6. Blood count and basic values

A complete blood count is unspectacular and still sensible. Together with ferritin, supplemented depending on the situation by kidney and liver values and blood glucose, it helps to sort out whether exhaustion has a mechanical explanation. Usually it exists already.

7. Sleep apnoea, the overlooked chapter

If your partner says you stop breathing at night, that is not a side topic. How to read the signs is set out in recognising sleep apnoea.

8. Silent inflammation, with the number that keeps it small

What an elevated CRP still achieves: it directs attention to things that belong treated anyway. An unnoticed tooth root, a joint problem, a fatty liver, lack of sleep. More on this in silent inflammation and weight.

9. Alcohol, without moralising

A systematic review found that an alcohol use disorder roughly doubles the risk of major depression and vice versa, with pooled adjusted odds ratios between 2.00 and 2.09. The authors examined shared third factors and considered the direction more plausible in which the alcohol use disorder raises the depression risk.

I say this without a wagging finger. People who drink in the evening are not being reckless. Alcohol can help with falling asleep and can shorten the time it takes. In the second half of the night it can make sleep considerably more restless. If you drink to come down, that belongs in the conversation. Not as a confession, but as information.

10. Housing and environment, with the handbrake on

Mechanistically plausible, human studies thin: moulds form metabolites that can trigger inflammatory pathways in the laboratory and can influence mitochondrial function. In humans no causation of depression can be derived from this. What is documented is the association between a damp home and symptoms, not the causal chain of mycotoxin, neuroinflammation, depression. The classification is in mould and mycotoxins and in brain fog and mycotoxins.

On the gut-brain axis in two sentences: there is real communication between gut, immune system and brain, and changes of the microbiome in depression have been described repeatedly. Cause and consequence are not settled in humans, however, and no depression treatment of its own follows from this axis today.

The lifestyle levers with real evidence

There is a sentence almost every person with depression has heard: why not go for a walk.

I understand why it makes people angry. It often comes from people who do not know what absent drive feels like. Only, the thing behind it has numbers. Anyone who knows them can separate the content from the platitude.

Exercise: effect sizes per movement form

The German National Care Guideline gives two strong recommendations on this. People without contraindications shall be encouraged towards sporting activity, ideally in a group, and towards participation in structured, supervised training. It sees the best evidence for aerobic endurance training, strength training or their combination.

The group is not in both guidelines by accident, the social part is probably part of the effect. Volumes and weekly plans I deliberately do not write down. What moderate endurance work does to metabolism is set out in zone 2 training explained. If small loads knock you over, exercise with chronic exhaustion is the better starting point.

Sleep: the lever with the best everyday return

What matters is the sequence. In depression, sleep is often seen as a symptom that should improve along with everything else. The data suggest treating it as a target of its own. More in CBT-I and sleep restriction, the connection itself is covered by sleep and depression, the wider frame by treating sleep disorders holistically.

Light, outside the winter too

Briefly mentioned: wake therapy, deliberate partial sleep deprivation under guidance, is described in the German National Care Guideline as the only non pharmacological procedure in which improvement can appear as early as the following day. The effect usually lasts only briefly. And it is explicitly not for self experiment: sleep deprivation can trigger a manic phase in people with a bipolar predisposition and can lower the seizure threshold in seizure disorders. The guideline recommends weighing advantages and disadvantages together. That is why wake therapy belongs in a supervised setting and is weighed up together beforehand.

Nutrition: two numbers that belong side by side

Alongside it belongs the second number. A meta-analysis of randomized dietary interventions across 45,826 participants found a small but robust effect on depressive symptoms with Hedges g equal to 0.162, including in the high quality studies. On anxiety symptoms no effect appeared, and women benefited more.

These two numbers do not measure the same thing. SMILES studied people with diagnosed depression, the meta-analysis predominantly samples without clinical depression. Side by side they give an honest picture: a possibly clear effect in a small clinical trial, a small effect across many studies.

On ketogenic nutrition in mental illness there is a discussion of its own with early data. It is set out in ketogenic nutrition in mental illness and is explicitly not a standard path.

Omega-3 and the EPA question

Here two serious sources diverge, and I put them deliberately side by side.

On one side a meta-analysis of randomized placebo controlled trials: the overall effect on depressive symptoms was a standardised mean difference of minus 0.28. In the subgroup analysis, preparations with a high EPA share did better than those with a high DHA share. I deliberately do not reproduce the composition and dose figures from that analysis as a dosing recommendation. Subgroup analyses carry weaker evidence than main analyses, and omega-3 preparations are foods, to which I neither may nor want to attribute an effect against a disease. Anyone who wants to know their status can have it measured. A capsule can replace neither psychotherapy nor a medication.

On the other side the German National Care Guideline with a strong negative recommendation: without a documented deficiency, dietary supplements should not be recommended, explicitly including no omega-3 fatty acids. Reasoning: uncertain benefit, the risk that evidence based therapies are declined or not adhered to, private costs, potential for interactions.

My position is unspectacular. The guideline is right if you think of a supplement as a replacement. Anyone who corrects a documented deficiency is doing something sensible. A capsule, however, replaces neither psychotherapy nor medication. How the status is measured is set out in measuring the omega-3 index, the difference between the fatty acids in ALA, EPA and DHA.

Connectedness: the factor with one of the largest effect sizes

A second piece of work matters to me even more. A team around Choi examined 106 potentially modifiable factors from the UK Biobank and used Mendelian randomization to see which of them withstand a causal test. Few remained, among them being able to confide in someone, with an odds ratio of 0.76. This study supports the sentence that connectedness counts, and at the same time calls for humility.

On stability at the end of an episode: mindfulness based cognitive therapy is a manualised programme for relapse prevention, not a wellness offering. An individual participant data meta-analysis of nine studies with 1258 participants found a hazard ratio of 0.69 against care as usual and 0.79 against active comparison treatments within 60 weeks.

How these building blocks work together in everyday life without turning into a second career is set out in lifestyle as therapy. And now you know why I do not call this section self help but treatment building blocks.

Where the guideline and the functional view diverge

An honest article has to show where it wrestles with the guideline. Otherwise it is advertising with footnotes. There are four points at which my perspective and the German National Care Guideline are not congruent. I find the guideline group's reasoning understandable everywhere, and everywhere a remainder stays.

Point one: supplements without a documented deficiency

The guideline is clear here, and its reasons are good: uncertain benefit, private costs, potential for interactions. What convinces me most is the risk that more effective treatments get postponed because a supplement gives the feeling of already doing something. I see that in practice.

My reading: measure, correct a documented deficiency, do not sell the correction as a depression treatment, and never postpone the actual treatment for it.

Point two: the thyroid

The functional view looks at a TSH in the upper normal range, at antibodies and at the conversion of T4 to T3. The data say: association weak, effect on mood not documented. My reading: workup yes. But no treatment of a laboratory value simply because it can be treated.

Point three: ferritin

Here I limit my own position most strongly. I consider functional iron deficiency underestimated. The controlled data still only give this much: fatigue, anxiety and cognition improved, depression did not. So iron belongs in the diagnostics because it sharpens the distinction. Not because it treats the depression.

Point four: environment and housing

The guideline itself calls for noxious agents to be checked. That covers the housing situation. What it does not give is a causal chain from mould toxins to depression. My reading: the housing situation belongs openly in the history. A damp flat you cannot get under control is a continuous burden.

When none of that is enough: the steps above

There is a point at which this article has to stay honest. Sometimes all of that is not enough.

You have done therapy, tried two substances, sorted out your sleep, your ferritin is at 90, your TSH is unremarkable. And you are still down. That is the moment in which many people search for ketamine. This moment deserves numbers rather than mood.

What treatment resistant concretely means

This is exactly where the second look at the physical level is worthwhile, not as a substitute for the next step but alongside it. If two attempts have not worked, it is worth asking whether the medication list, sleep, thyroid and housing situation were ever looked at.

Brain stimulation: rTMS and ECT, factually

The German National Care Guideline gives a strong recommendation for electroconvulsive therapy in treatment resistant episodes, particularly at older ages and with psychotic symptoms. For repetitive transcranial magnetic stimulation it names two places: an open recommendation as an addition after a single non response, and a weaker recommendation that it should be offered in treatment resistant episodes. The choice of method is to be made by a specialised centre.

What I often say about this: rTMS runs on an outpatient basis and without anaesthesia, but needs many sessions. Headaches and a pressure sensation at the stimulation site are common, and very rarely a seizure can be triggered. Metallic implants in the head region can argue against the procedure.

ECT needs an inpatient setting and anaesthesia and has the strongest effect estimates. It can cause temporary memory disturbance, and that is its most important side effect. In the ELEKT-D trial cited above, delayed recall dropped markedly after three weeks, on average by 9.7 points on the Hopkins Verbal Learning Test against 0.9 points under ketamine, and recovered gradually over the follow up. Both belong on the table before anyone consents. ECT does not suit everyone, but it deserves a fair conversation.

Where esketamine and ketamine belong

And if ketamine does not fit?

This question comes from people who have read who should not receive ketamine: uncontrolled high blood pressure, certain cardiovascular situations, a psychotic illness, an active addiction, a pregnancy. The details are set out in ketamine contraindications, the risks overall in ketamine risks.

The answer is unspectacular and still comforting: a great deal remains.

For further reading: ketamine in treatment resistant depression puts response rates in context, ketamine assisted therapy describes the frame, ketamine assisted psychotherapy explains the weight of integration. With acute suicidality everything from the box at the very top applies in addition, and the data are set out in ketamine in acute suicidality.

For family and friends

Perhaps you are not reading this for yourself at all, but because someone you love has not been the same for months.

Then this section starts with some relief: you are not responsible for ending this depression. You cannot carry it away, talk it away or love it away. What you can do is something else and still valuable.

What often carries

Stay present instead of pushing. The most common mistake made out of love is pressure. Suggestions, plans, encouragement, appointments. For someone with depression that is another list on which one can fail. Regular presence without a programme is usually more helpful.

Relieve concretely instead of offering in general. The sentence "let me know if I can do anything" shifts the work to the exhausted person. Better: I will bring dinner on Thursday. I will drive you to the appointment. I will call three practices.

Help with the search. Finding therapy places is laborious even for healthy people. It is one of the best tasks for family and friends, because it requires drive that the affected person does not have right now.

Do not argue. Sentences like "but you have so much" or "others have it worse" are well meant and land as a reproach. Depression is not a thinking error you can refute.

Talking about suicidal thoughts

That is the part most people are afraid of. The worry is: if I ask, I will put the idea in their head. In clinical practice the opposite is the standard. The direct question is experienced as a relief. That is clinical consensus and experience, not a study result, and I mark it explicitly as such.

Ask concretely and calmly. Are you thinking about taking your own life. If the answer is yes, it is not about arguing it away, but about the person not staying alone and about getting help together.

Your own burden

People who accompany someone with depression often develop exhaustion, sleep problems and feelings of guilt themselves. That is not a character weakness but an expected consequence of long strain. Keep something that belongs to you. And accept that accompanying has limits, without that becoming a betrayal. And now you know why there is so little about advice here.

A realistic roadmap for the coming weeks

Most articles end with a list. I write down a sequence instead, because with this topic that is what matters. This is not a protocol and not a set of instructions, but the structure I orient myself by in conversation.

Where this path connects to other topics

Depression rarely stands on its own. It hangs on exhaustion, on sleep, on inflammation, on the housing situation and on the question of what has already been tried. These articles carry the individual threads further.

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